WEEK 1 - Flashcards

Question

Drug X has greater abuse liability than Drug Y. In terms of the happiness curve, drug X is associated with _________ than drug Y.

Answer 1

a higher maximum value and a steeper slope

Answer 2

This module will examine patterns of drug use. The focus of this week is the history of non-medical and medical drug use and the understanding of drug use in evolutionary terms.

Answer 3

The human is aware of his drug self-administration behavior Humans and animals have the same key structures in their brains that respond in the same ways to most psychoactive drugs. Both humans and animals are equally vulnerable

Answer 4

Self-awareness is a blessing to human drug users because it enables us to catch ourselves when we are at risk of administering a drug (i.e., when we are about to "fall off the wagon" when we're trying to abstain from smoking or drinking). Self-awareness is a curse to human drug users because in some cases, the compulsion to use the drug may be so overwhelming that we do so despite our awareness that we shouldn't. The brains of humans and all vertebrate animals contain structures that are "dedicated" to the experience of pleasure. These structures become activate when we eat food, drink water, engage in sex, or awaken from a good night's sleep. Our brains hardwired to enjoy and to repeat certain behaviors. Collectively, the brain structures responsible for these effects are called The Limbic System. In humans, these structures form a branch or Limb connecting the primitive regions of the brain with the more advanced regions of the brain.

Answer 5

Several thousand years BC Psychoactive drugs appear to have been used in a variety of civilizations since the earliest days of recorded history. "The deliberate seeking of psychoactive experience is likely to be at least as old anatomically (and behaviourally) as modern humans: one of the characteristics of Homo sapiens sapiens" Sherratt, 1995, p. 33).

Answer 6

Plants are the largest source of the psychoactive chemicals in non-medical drugs Marijuana and hashish come from the cannabis plant (temperate regions worldwide) nicotine comes from tobacco (North and South America) cocaine comes from the coca leaf (South America) heroin, morphine and opium come from the opium poppy (Asia) alcohol comes from fermented fruit and vegetables (temperate regions worldwide) LSD and magic mushrooms come from fungi

Answer 7

From an evolutionary standpoint, this would increase the chances of animals eating them as opposed to other plants. Why is this good for a plant? Because animals can move around, whereas plants cannot. As a result, animals can transport plant seeds wherever they go, and deposit them widely (along with natural fertilizer to help ensure their growth). Thus, an inter-dependence appears to exist between plants and animals that increases the likelihood of animals eating plants containing psychoactive chemicals, which in turn increases the chance of survival of those species of plants.

Answer 8

animals and humans have a built-in capacity to enjoy psychoactive drugs These drugs are often naturally occurring and are widely distributed worldwide Humans and animals likely too, have been ingesting psychoactive drugs in plant form since the earliest days of civilization. This pattern of use also serves a valuable purpose for plants These trends suggest that to some degree, use of psychoactive drugs may represent a natural behavior, or a "Fifth Drive."

Answer 9

when it is removed from a context that serves to restrain the level of use (e.g., chewing coca leaves to sustain energy while working) when the chemicals in drugs are synthesized to much more potent forms that vastly increase the highs they produce (and subsequent lows), paving the way for abuse and addiction

Answer 10

The earliest reports of alcohol use come from Egypt and Mesopotamia (present day Iraq) 4000 years BC These civilisations discovered beer, which probably first resulted from fermented grain stored in granaries with little air or light The ancient Greeks and Romans began the practice of wine making by fermentation of dates and grapes in 1000 BC, much as we do today A similar process was used to create a wine called Mead from honey by medieval Europeans in the early centuries AD.

Answer 11

The plant, cannabis sativa, was first cultivated in present day Romania, the Caucasus (a mountain range in present day Russia), and China around 3000 BC These civilisations found that it was useful in making hemp, a sturdy fibre for rope and clothing. Smoking hemp was a common practice among sailors in these regions who had large quantities of rope onboard during their voyages. A mixture of cannabis, ephedra, and papaver, known as Soma was synthesised in India around 1000 B.C. This concoction had some of the mildly hallucinogenic effects of hemp coupled with the stimulant effects of ephedra - and euphoric effects of papaver (a derivative of the opium popium) This combination of effects provided a unique experience to Soma users enabling them to experience dream-like pleasures without falling asleep.

Answer 12

The opium poppy was first cultivated by civilisations in the Middle East and China around 2000 B.C Opium is a potent heroin-like drug that is particularly addictive when smoked Like heroin and morphine, opium possesses strong pain-killing properties and also slows down the activity of the intestinal tract. As a result, opium was widely used not just recreationally, but also as a medicine to soothe pain or treat diarrhoea and dysentery, a disease that kills by diarrhoea-induced dehydration

Answer 13

This crop was cultivated, chewed and smoked by indigenous tribes in North and South American long before the arrival of the Europeans to the Americas. Its combined stimulant and anti-depressant effects made it useful for maintaining energy and long hours of work under difficult physical or climatic conditions It was introduced to Europe by Sir Walter Raleigh in the late 16th - early 17th century.

Answer 14

These hallucinogenic drugs were derived from cacti and were used by ancient inhabitants of Mexico (Aztecs) and central America (Mayans) as early as 2000 BC. Some North American tribes still use these drugs as a means of achieving contact with the Spirit world, and are granted legal access to them for religious purposes.

Answer 15

Has been used by indigenous South Americans for several 1000 years. Chewing of coca leaves provided energy for difficult agricultural work in the low oxygen air of the Andes mountains in Peru Cocaine was introduced to North America in the 19th century. Its initial use here was as a topical painkiller in dentistry, and was later replaced by a synthetic version, called novocaine. When alcohol was outlawed during the 1920's prohibition, cocaine became a popular substitute because it was difficult to detect. This shift in drug use practices led to an increase in smuggling and the deliberate use of cocaine to create addiction and manipulate women into prostitution. Cocaine and derivatives of opium (e.g., laudanum) provide an example of how medicinal use of drugs in Europe and North America in the 19th century made a transition to recreational use and eventual abuse outside the contexts (to facilitate work, treat disease) that otherwise constrained their levels of use.

Answer 16

Over the course of history, organized religion has played a key role in establishing standards of "appropriate" drug use. These guidelines remain with us today in the form of social "norms" - unwritten rules of how drugs should be used. It is not surprising that drugs should have found a role in religious practice, given their ability to transform consciousness. These uses range from the symbolic (i.e., a sip of wine in the Communion ritual) to the biologically relevant (i.e., ingestion of hallucinogens to commune with God) Regardless of the purpose of the drug use, the circumstances (when, where, how much, by whom) of use were clearly defined in these religious rituals. This set of rules almost always aimed to prevent excessive use - i.e., gross impairment or intoxication. As such, they served as a governor on excessive drug use.

Answer 17

Wine - Judaeo-Christian religions have used small amounts of wine to bless significant religious events. - Communion is the clearest example in Christianity. - The drinking of wine to welcome the Sabbath and during the festival of Passover are examples of prescribed alcohol use in Judaism. Marijuana - Central and South American religions use marijuana for similar purposes. - The dose and manner of consumption are carefully controlled, and the smoking occurs under prescribed conditions. Peyote - Some Aboriginal Americans (First Nations peoples) eat peyote buttons, derived from cacti, to achieve hallucinogenic experiences, similar to, but milder than, those induced by LSD - The term "Psychedelic" has been used to describe the "mind-manifesting" properties of such drugs - It is the belief of those who use peyote and similar hallucinogens for sacramental purposes that they can induce mystical states in which the person has direct contact with the divine - Experimental evidence on the effects of psychedelic mushrooms in seminary students supports their ability to create bona fide mystical states of consciousness - The use of peyote in a communal context helped to ensure that the drug was not abused, but instead used "instrumentally" - that is - as a tool to achieve communion with others, with nature and with God. Tobacco - Although the low doses of tobacco typically consumed as cigarettes do not possess hallucinogenic properties, at high doses, tobacco can alter consciousness in a manner similar to LSD - However, most smokers would experience a toxic reaction (e.g., heart attack, seizure) before they felt these hallucinogenic effects - Tribal leaders in South America, known as "shamans" or medicine men, appear to possess the ability to ingest these very high doses, due largely to tolerance (decrease in the response to a standard dose) acquired from years of heavy tobacco use. - For these shamans, one cigarette might produce the same effect as one puff for a regular cigarette smoker. Caffeine - While the South Americans used tobacco, indigenous tribes in central Africa ate Kola nuts, containing caffeine. - The stimulant effect of the drug facilitated rituals involving dancing and song, again, in the context of well-defined rules.

Answer 18

A prescription is an order to do something (e.g., to take a drug). A proscription is an order to NOT do something (e.g., to not take a drug). Just as religions have served to promote moderate drug use in the context of specified rituals, they have also acted to restrict drug use outside these ceremonial contexts.

Answer 19

Western religions view excessive use of alcohol as undermining our "humanity." Since we are made in God's image, alcohol intoxication can be seen as befouling this state. Not surprisingly, there are strong social prohibitions against excessive drinking in Judaism and Christianity. In Islam, any alcohol is seen as compromising the ability to connect spiritually with Allah. As a result, observant Muslims are expected to abstain from alcohol (and all other drugs). Historically, the social carryover effects of religious attitudes towards alcohol have varied widely. When organized religion was influential (14th century AD), attitudes towards excessive drinking were similarly negative. When religion was less influential (18th century AD), attitudes towards excessive drinking became more lax. The Women's Christian Temperance Movement was a socio-cultural force in the early 20th century. It asserted that alcohol debased the mind and soul, enabling the devil to infiltrate an otherwise devout individual. Advocates of this movement argued for complete abstinence from alcohol and played a role in the bringing in of prohibition laws (outlawing alcohol use) in the US in the 1920's.

Answer 20

In the East and particularly, China, opium was the most widely used drug, and therefore, the most likely drug to be abused. Laws restricting the sale and use of opium were an economic tool used by Britain to retain control over its colonies (i.e., Hong Kong) The ability to achieve large profits from opium trade would give considerable economic power to the native Chinese, which Britain opposed. Thus, commerce rather than religion drove the restriction of opium use in the East.

Answer 21

In continental Europe, an alternative to alcohol emerged - coffee. Excessive use of this drug was rare due to its mild psychoactive properties and its unpleasant side effects at high doses. For many, coffee thus became the "sober" social drug. The coffee shops that today line our streets are the offspring of the coffee houses that have existed for decades in Europe.

Answer 22

Prevent excessive drug use These rules are designed to promote responsible use of drugs or temperance - a little pleasure, but not too much.

Answer 23

In North America and Europe, cocaine was first used as a topical analgesic - one applied to the surface of the skin or gums - in dentistry. In moderate doses it effectively numbed the tissue enabling gum surgery or tooth extraction, which would otherwise have been too painful for dental patients to tolerate. Accidental or experimental inhalation of the ground powder would have produced the pleasurable "high" that is the familiar effect of cocaine we recognize today. Because of its powerful addictive potential (high abuse liability), it was just a matter of time before such experimentation led to systematic use of cocaine for reward as opposed to pain management. Cocaine also had a role in early psychiatric practice. Like other stimulant drugs, cocaine activates parts of the brain and nervous system responsible for feelings of power and confidence. Early psychiatric practitioners, particularly Sigmund Freud, became strong advocates for cocaine as a cure for "neurosis" - the pervasive doubt and low self-confidence typical of people who are depressed or anxious. Only after experiencing the downside of cocaine (the crash), and the concomitant craving for more, did Freud realize the inherent dangers in cocaine. Fortunately, at this point, he ceased to advocate its use in psychiatry. However, by that time, the "genie was out of the bottle" and abuse of cocaine for pleasure had begun.

Answer 24

Nitrous oxide - or laughing gas - was also used to alleviate dental pain. Because it was harder to distribute, initial abuse of nitrous oxide than cocaine was likely restricted to dentists or their assistants who had ready access to the gas. The doctor in the film/book, The Cider House Rules, by John Irving provides an illustrative example of how nitrous oxide could be abused to escape into reverie for a time.

Answer 25

The term "morphine" comes from the Greek term "morpheus" - to dream. The powerful analgesic effects of this opium derivative were first extensively utilized in the latter part of the 19th century. The American Civil War left many soldiers maimed and suffering from chronic pain. Morphine was often prescribed to manage this pain. The sheer numbers of soldiers injured and receiving morphine contributed to its unintended transition into recreational use and abuse. Like cocaine, its powerful addictive potential and abuse liability led many of those who experimented with it recreationally to quickly become dependent.

Answer 26

A number of related chemicals, called amphetamines, were synthesized in the early 20th century for the treatment of respiratory ailments, like asthma. The stimulant effects of these drugs resulted in their application to the treatment of sleep disorders such as narcolepsy (a tendency to fall asleep quickly and involuntarily). The appetite suppressing of these drugs led to their use in situations where energy was required for long periods but eating was not practical, specifically fighting in trenches in the First World War. Amphetamines have many of the same psychoactive effects as cocaine, and the proliferation in their abuse was similarly rapid.

Answer 27

LSD was unintentionally synthesized in the late 1940's. Its powerful psychedelic or "mind-manifesting" properties led psychiatrists at the time to consider its use as a means of rapidly accessing unconscious concerns that otherwise took years to reveal in therapy. However, the very rapidity of its effects, made it rather uncontrollable, often causing intense confusion and mental disturbance rather than insight. he US and the Soviet Union were locked in the Cold War at that time, with each side attempting to gain an advantage over the other. LSD's mentally disruptive effects coupled with its extreme potency - a half teaspoon could produce a full-blown "trip" in the entire population of New York City - led the US secret service to consider its use as a means of "chemical warfare" against the Soviets. Distribution of the drug into the drinking water could throw the Soviet citizenry into confusion and thereby facilitate a US attack. Experiments conducted during the 1950's document the perils of LSD use By the 1960's LSD had become a popular tool of youth to achieve altered states of consciousness, and leaders of the counter-culture, such as Timothy Leary and Ken Kesey, advocated its use.

Answer 28

MDMA or Ecstasy has a similar story. This amphetamine derivative was first synthesized with the other amphetamines in the early part of the 20th century. However its apparent lack of therapeutic effects caused it to be shelved for the next half century. By the 1970's psychiatrists had begun to experiment with the use of MDMA as a means to facilitate open communication in marital therapy. The ability of the drug to produce strong feelings of empathy and understanding led to its abuse by a small underground contingent in Europe at that time, which burgeoned in the 1980's. By the 1990's Ecstasy use had become widespread - most often in the context of Raves - or all-night dance parties. At the turn of the 21st century, Ecstasy use had escalated dramatically - even outside the Rave scene Unlike LSD, MDMA appears to have the potential to cause brain damage By the end of the 20th century the toxic effects on brain tissue and mental function were well documented Unfortunately, the popularity of MDMA persists despite the mounting evidence of irreversible brain damage. The continued use of Ecstasy in the face of this evidence provides a powerful illustration of how the reinforcing effects of a drug promote its continued use, despite the consequences - the hallmark feature of "abuse."

Answer 29

Prior to the 1950's, treatment of schizophrenia consisted of ice baths, massive doses of sedatives, electro-shock therapy, and in extreme cases, surgical removal of brain tissue (lobotomy). None of these treatments had any reliable effects in schizophrenia, a devastating disease whose symptoms included delusions (beliefs not based in consensus reality) and hallucinations (sensory experiences with no physical source - e.g., hearing voices) As a result, hundreds of thousands of patients with schizophrenia lived in state or provincial institutions, as there was no way they could function in general society. However, a landmark discovery occurred in Paris in 1950 that would drastically change this scenario. A scientist named Laborit was testing the effects of anti-histamines in rats in an effort to discover ways to reduce allergic reactions. He noted that one of these drugs produced a form of "artificial hibernation" - powerful sedation in his animals. He considered that this drug, chlorpromazine, might be effective in managing schizophrenia without resorting to massive dosing. To his surprise and that of the entire medical community, chlorpromazine not only effectively calmed patients with schizophrenia; it actually reversed their delusions and hallucinations. Almost overnight, individuals who for years were plagued by thoughts of persecution and inner voices were "restored to sanity." The drug, chlorpromazine was the first formal anti-psychotic medication. The term "anti-psychotic" refers to the reversal of psychosis - or thought disorder - that typifies schizophrenia Although anti-psychotic medications are used for purposes other than treating schizophrenia, the alleviation of thought disorder is their defining feature.

Answer 30

Because of the remarkable effectiveness of chlorpromazine, huge numbers of patients who for years had lived in locked hospital wards were quickly granted freedom. Unfortunately, although the drug alleviated their symptoms it could not replace the years of socialization, education and work experience they had lost during their hospital stay. As a result, most of these people were unable to find jobs and thus became indigent. To this day, the vast majority of homeless people suffer from schizophrenia. The stress of life on the street, or the false promise of sustained normalcy that arose when patients took chlorpromazine often led to relapse, and re-institutionalisation In the first case, stress aggravated the brain systems that were disturbed in schizophrenia causing a breakthrough of symptoms and a need for heavier dosing In the second case, the clarity of thought produced by chlorpromazine made patients wrongly believe they were cured, and to stop taking the medication. In either case, it quickly became apparent that chlorpromazine was not the panacea, or cure-all, for schizophrenia that people first believed. In the decades since de-institutionalisation, new steps have been taken (group homes, sheltered work shops, community mental health centres) to provide a support structure for people with schizophrenia. These steps reflect the growing recognition that treatment of psychiatric symptoms by a drug is only a small piece of the problem of mental illness.

Answer 31

Around the same time of Laborit's discovery, another Frenchman identified a drug that had the ability to prevent deviations in mood. While investigating immune reactions in rats, Cade found that a simple salt, lithium carbonate, exerted a strong stabilizing effect on activity and emotional responses in his animals. The normal agitation or freezing that rats typically exhibited under stress were quickly abolished by this drug. Based on this finding, lithium was adopted as a treatment for bipolar affective disorder, which at that time was called manic-depression. Bipolar disorder involves extreme mood swings from exhilaration to exhaustion and thoughts of suicide. These were effectively counteracted by lithium so that the patient's mood did not get too high or too low. Although lithium was very effective, it could also be toxic if levels accumulated in the blood stream. For this reason, close monitoring of patients in lithium treatment was required. As in the case of chlorpromazine, lithium alleviated the symptoms of bipolar disorder but did not cure the disease. Thus, patients receiving lithium typically continued to take it throughout their lives.

Answer 32

In the 1950's, doctors searching for a cure for tuberculosis ran some experiments on patients who were housed in sanitaria. Because these patients were isolated they often experienced bouts of depression. During the course of the experiments, the mood of the patients receiving the experimental treatment began to lift. Their tuberculosis symptoms, ironically, remained unchanged. Based on these observations, the doctors considered using the experimental drugs to treat depression in patients without tuberculosis. In line with their suspicions, the drugs worked and the first bona fide treatment for clinical depression was born. If schizophrenia represented the cancer of the mind, depression represented the common cold. It was extremely prevalent, occurring in about 15% of all people over the course of their lives. At the same time, left untreated, the symptoms typically resolved spontaneously after about 6 months. Nevertheless, the symptoms of depression could be very disabling These included disturbances of sleep and appetite, emotional sensitivity, intense sadness, and most troubling, thoughts of hopelessness and suicide Because of the real threat of suicide in depressed patients, it was not acceptable to "wait out" the 6-month cycle of depression. A treatment was needed to control the symptoms until the body's natural emotional rhythms returned to normal. The mood-elevating drugs used in tuberculosis patients, called mono-amine oxidase inhibitors (MAOI's) made drug treatment of depression possible. Like chlorpromazine and lithium, the MAOI's were not without their downside. Because these drugs acted to disturb the function of critical enzymes in the brain and body, the role of these enzymes as catalysts was disturbed. In particular, the ability to digest dairy products was lost, turning milk, cheese and yoghurt into poisons that the body could not metabolise As a result, patients taking MAOI's had to adopt a strict diet that excluded dairy products and other common foods or drinks (e.g., red wine) The possibility of a toxic reaction made eating in restaurants or other unfamiliar venues hazardous At the same time, residual symptoms of depression - like suicidal feelings - in patients receiving these drugs could lead to deliberate consumption of forbidden foods to induce the toxic reaction. Thus, while the MAOI's provided valuable relief to the clinically depressed, they had inherent risks.

Answer 33

Collectively, anxiety disorders such as generalized anxiety, phobias, panic, and post-traumatic stress disorder are the most prevalent form of mental illness - accounting for nearly half of all psychiatric referrals. Prior to the 1960's these disorders were treated primarily with drugs called barbiturates. These drugs were sub-optimal because they were highly addictive due to their potential for euphoric effects at high doses, and rapid development of tolerance at therapeutic doses. In addition, barbiturates were extremely dangerous because of a high risk of accidental overdose, particularly when combined with alcohol. A clear need existed for a medication to manage anxiety without these risk factors. Hundreds of experimental trials were run in the laboratories of Hoffman-LaRoche, a large pharmaceutical company. During these trials, the chemical compounds synthesized consistently failed to work The chemists who developed these compounds noted a crystalline residue that was a frequent by-product of their experiments. After years of discarding these "pretty crystals," the lack of success with the intended compounds led to the suggestion of using the by-products. The crystalline substance, chlordiazepoxide, trade name Librium, was introduced in the late 1950's as the first benzodiazepine for the treatment of anxiety. This drug was much safer than barbiturates, had lower risk of abuse and addiction, and effectively reduced anxiety without producing undue sedation. It was soon replaced by an even more popular drug, diazepam, trade name, Valium The effectiveness and safety of Valium for the management of anxiety, led doctors to begin to prescribe it as a way to pacify day-to-day stress in people without clinical anxiety disorders By the mid-1960's the little yellow pill had thus become known as "Mother's Little Helper," for its widespread use as a lifestyle aid To this day, benzodiazepines collectively remain the number 1 prescribed psychoactive drugs In the years since their advent, there has been a growing recognition of the subtle risks of these drugs. First, they reliably impair memory, making it difficult for people who take them on an ongoing basis to retain new information. Second, some benzodiazepines have abuse liability and can be used to produce euphoria rather than to manage anxiety. Third, tolerance will develop to these drugs, requiring increased dosing and eventual dependence, particularly when they are used as a sleep aid. Such dependence is revealed when people try to get off the drugs and experience rebound increases in anxiety well above their original levels. Benzodiazepines also appear to disinhibit behaviour leading to a paradoxical increase in aggressive or impulsive behavior in patients using them. Finally, these drugs operate on a chemical system that is also affected by alcohol, so that even social drinking can produce extreme intoxication. Like barbiturates, benzodiazepines can produce a toxic reaction when combined with large amounts of alcohol.

Answer 34

partially/sometimes dangerous but

Answer 35

The 20th century witnessed exceptional developments in the field of medical psychopharmacology. However, in each case, the medications were limited in important ways - either in effectiveness or associated risk. Because drugs require no effort on the part of the patient or the physician, they remain an attractive option to the time-consuming, often painful work of therapy. Most research shows that the best results occur when medication and interpersonal therapy are combined. The medical use of psychoactive drugs is the clearest case of negative reinforcement - continued use of a substance to relieve discomfort rather than to achieve reward. The primary difference between the medications developed in the 20th century and those used in prior centuries was that 20th century medications, in general possessed less abuse liability. This was a major step forward due to the potential for drugs to "cross over" from medical to recreational use. The generally low rewarding effects of newer psychoactive medications provide a natural constraint on abuse. The social norms and religious rules serve a parallel purpose in constraining levels of non-medical drug use. Despite these constraints, the unique ability of psychoactive drugs to directly tap motivational structures in the brain gives them the ability to override conscious intentions (e.g., decisions not to use or to limit the dose taken). As a result, initial use of drugs all too often escalates to abuse and eventual addiction. The biological processes that underlie this escalation are the focus of the next two modules.

Answer 36

Learned that most psychoactive drugs originally come from plants Discussed ways in which drug use is similar to the other 4 drive-based behaviors: eating, drinking, sex, and sleep Proposed an evolutionary role of drug use Considered the pervasiveness of drug use over time and across culture Examined similarities and differences between non-medical and medical psychoactive drugs

Answer 37

psychoactive drugs often lead to addiction

Answer 38

drugs are usually not sufficient to produce ongoing mental health environmental factors often interact with biological factors compliance (taking a drug as directed) is a critical issue in drug treatment

Answer 39

This module will examine the structures and functions of the brain and the central nervous system. Although drug effects are profoundly influenced by the environment (setting) in which the drug is used and the beliefs about its effects (expectancies), ultimately drugs modify thoughts and feelings through their effects on the brain. A basic understanding of the brain is therefore necessary to an understanding of psychoactive drug effects. The focus of this week is an overview of the nervous system and the brain, and a discussion of brain regions "dedicated" to motivation, emotion, and the experience of pleasure As noted in previous modules, these areas are vital to the subjective and behavioral effects of drugs and to addiction.

Answer 40

The body of vertebrate animals, including humans, is comprised of several systems, e.g., digestive, cardiovascular, nervous, etc. The nervous system has the responsibility of co-ordinating the activity of all the other systems. The cells of the nervous system branch out like a vast cable network throughout our bodies. This network is organized in tiers or levels. This organization plan is called a hierarchy: Structures on the top level direct the activity of structures at lower levels. CNS At the top of the hierarchy is the central nervous system (CNS), which consists of the brain and the spinal cord. The CNS can be thought of as the CEO and top management team of the nervous system organization. PNS Below the CNS is the peripheral nervous system or PNS. This is comprised of everything that is not part of the CNS. The PNS can be divided into two branches, the Somatic and the Autonomic. SOMATIC The Somatic branch contains all those nerves that send messages from the brain to the muscles for example, and relay messages from the body (e.g., skin) back to the brain. AUTOMATIC The Autonomic nervous system is responsible for controlling the activity of our internal organs. This system operates automatically - we don't need to think for our heart to beat, our lungs to breathe, or our stomachs to digest. PARA AND SYMPATHETIC The Autonomic Nervous system in turn is divided into 2 sub-branches, the parasympathetic branch and the sympathetic branch. These two branches govern the activity of our internal organs during periods of relaxation and activity, respectively. The operation of the parasympathetic and sympathetic sub-branches is mutually inhibitory. That is, when the parasympathetic branch is operating, the sympathetic branch is not, and vice versa. Some parasympathetic activities include digestion and excretion. The sympathetic nervous system takes over when our body is active, and most specifically in times of stress. This system is specially designed to ensure the survival of the organism in the face of threats to its welfare - i.e., stress. When we encounter a situation that we perceive as stressful (i.e., threatening), a characteristic response of the sympathetic nervous system kicks in.

Answer 41

This response is a complex set of reflexes that work together to enable the organism to run away from or confront an adversary A cascade of events is set in motion that includes detection of the threat by the brain, the secretion of a hormone from a region in the brain that mobilizes the activity of the body by signaling the adrenal glands to release adrenaline into the blood stream. Adrenaline in turn causes the heart to beat faster and lungs to breathe more rapidly enabling the organism to run at top speed or fight with utmost strength. Additional responses include contraction of the skin producing goose bumps and dilation of the pupils of the eye to enable maximum visual information input. At the same time this cascade of events is occurring, the vegetative functions controlled by the parasympathetic nervous system are turned off - digestion stops and other maintenance and repair activities are put on hold. The same brain structures that signal the lower levels of the nervous system to flip into "sympathetic" mode also signal the organism to seek out safety. Repeated use of a drug appears to trick the organism into recalling drug-related behavior patterns, as if drugs somehow serve a survival purpose or means of escape from threat. Activation of this circuitry by stress may account for the strong association between stressful events and relapse to drug use in users who have stopped using drugs.

Answer 42

In sum, the CNS and brain in particular govern the activity of the body through a highly coordinated network of nerves. This enables the body to respond effectively to challenges and adapt to the environment. The evidence linking the body's stress response system with the system that governs drug use is particularly noteworthy It suggests that the idea of drug use as "escape" may in fact reflect the operation of a hardwired instinct, which like all instincts may be extremely difficult to override. Because stress is an inevitable part of life, it is not surprising then, that a defining feature of addiction is relapse.

Answer 43

hierarchy The nervous system is stratified with the higher levels controlling the lower levels, and the brain the topmost position

Answer 44

The human brain can be divided into three main regions 1. hindbrain - The region at the back - It is the most primitive region in terms of evolutionary development and sophistication - This part of the brain exists in very low organisms like fish. - The role of the hindbrain is to govern basic maintenance functions such as respiration and circulation. - It does this through its connections with the autonomic nervous system 2. midbrain - more advanced - This region exists in reptiles and amphibians, and could be called the "frog brain." - This region enables the organism to orient in space, make simple decisions and to scan the environment - This provides some flexibility and independence to the organism such that it is no longer limited purely pre-programmed behaviour. 3. forebrain - leftmost region - the most advanced in evolutionary terms - This region is represented in mammals, the most sophisticated forms of animals - The forebrain is responsible for complex acts like goal-directed behaviour - The greater the proportion of forebrain to the other regions, the more advanced the organism - Rats have a very small forebrain to mid/hind brain ratio - By contrast, humans and monkeys have a very large ratio of forebrain to mid/hind brain, reflecting our high degree of sophistication and relative autonomy over our behaviour (i.e., choosing to act rather than following instincts or drives alone)

Answer 45

A set of structures extends from the mid- to the forebrain in mammals These structures together are called the Limbic System because they form a branch of limb connecting the mid- and forebrains The limbic system controls motivation, emotion, reinforcement (pleasure/pain) and memory Through limbic connections with the forebrain, these "drive-based" activities can influence and in some cases over-ride conscious "higher" functions such as planning, decision-making and reasoning Indeed, this powerful influence contributes to the experience of "loss of control" that often accompanies addictive behaviour Although the individual consciously knows that continued drug use or relapse is wrong (i.e., dangerous), he or she feels compelled to do it despite all rational beliefs to the contrary The term "addiction" captures this feeling of compulsion - the siren song that beckons the user In Latin, "ad" means "toward" and "dictum" means "a calling or command." Addiction thus involves the calling to drug use and the activity of the limbic system is the neural basis for this experience. Indeed, the activity of the brain can be characterized as a complex pattern of signals, whose net effect determines the emotions we feel and actions we perform.

Answer 46

Signals in the brain are conducted by highly refined nerve cells called "neurons." These cells are like electrical wires of varying lengths and densities They communicate with each other by chemical messengers, and this communication is the physical basis of experience It is important to note that no experience can occur without a physical event (and more likely thousands or millions of events) taking place in the brain. Thus, even effects that we presume are "strictly psychological" have a physical basis in brain activity - that is, they are real The range of experiences we can have is virtually infinite. This diversity owes to the 100 billion neurons in the brain, almost all of which have the capacity to interact with the others.

Answer 47

Unlike cells in the body, when a nerve cell in the brain dies, it is not replaced. Nevertheless, the brain is not depleted over time due to a vital process of linkage that occurs among the individual nerve cells. That is, neurons that start out as individual, isolated cells forge connections with adjacent cells to create a network.

Answer 48

The network of interconnected neurons has a greater capacity to process information than each individual cell alone Thus, the forging of connections with other neurons is how the brain "grows," and offsets the depletion of individual neurons as they die off

Answer 49

The process responsible for forging the connections is learning The interconnection of formerly isolated neurons is the physical manifestation of the experience we have when we acquire knowledge or have a new experience. Some of the most powerful connections - the strongest forms of learning - involve emotional events. A single traumatic event, such as being bitten by a dog as a child, can create a learned association between dogs and fear that leads to a lifelong avoidance of dogs, even if at some level the person knows it's irrational. Similarly, a powerful positive experience, like the "high" felt from a dose of cocaine, can forge a learned association between cocaine and pleasure, that leads to a lifelong pursuit of cocaine even if the person knows at some level that it's irrational or dangerous. In short, learned associations in the brain, forged by powerful chemical transmissions between neurons, can bias our behavior away from or towards a stimulus sometimes forever. In this way, drug use etches itself on the neural hardware of our brain With each new dose of a drug, the linkage becomes stronger, increasing the likelihood of further use - a "vicious cycle" of reward and re-administration mediated by learning

Answer 50

mental event, physical event, and lasting representation of experience

Answer 51

Neurons are cells in the brain and nervous system designed to transmit information by means of chemical messengers. The structures of the neuron may vary depending on what the neuron is designed to do, but the essential components are the same. The overall design of a neuron is like an electric cable, and that in fact is what it is. It conducts an electric pulse, called an action potential, from one end to the other The action potential only occurs when the neuron is stimulated; at other times, the neuron is dormant or inactive.

Answer 52

The event that stimulates the neuron is the binding of a chemical - the neurotransmitter - with specialized gates on the neuron The gates are called receptors Each receptor is designed to bind with a particular neurotransmitter - like a specific key fits into a specific lock and opens it When enough receptors are stimulated by neurotransmitter molecules, they signal the neuron to become active The signal is sent along the dendrites (neuronal branches) into the body of the neuron (the soma) At that point, the charge builds up until there is enough energy to surpass the cell's threshold for activation At that moment, the neuron fires the action potential, which can be thought of as an electrical pulse or blast - an all-or-nothing event In other words, if the threshold for activation is exceeded, the cell will generate a complete action potential; if it does not exceed the threshold, no action potential will occur There is no in-between state; either the action potential fires or it doesn't

Answer 53

Once the action potential fires, it is propagated down the length of the neuron on a filament or cable called an axon This is like the electrical cord carrying electricity from the outlet to an appliance And like an electrical cord, many axons are insulated with a fatty substance called myelin, which prevents the electricity from leaking out into the extra-cellular fluid

Answer 54

When the action potential reaches the end of the neuron it causes another important event - exocytosis - the release of neurotransmitter contained within the neuron (i.e., the cell's own neurotransmitter) from the terminal buttons The transmitter is contained in tiny film-like sacs called vesicles that disintegrate soon after the transmitter is ejected from the terminal buttons

Answer 55

The region into which the transmitter is released is called the synapse - a gap between neurons If sufficient transmitter makes its way across the synapse to bind with the receiving neuron, it may instigate an action potential in that cell, starting the process all over again This sequence of events occurs in milliseconds Millions of these events cause an electro-chemical cascade throughout the brain. This cascade is the physical basis of the thoughts and feelings we experience and the behaviors we perform.

Answer 56

Although we have talked in terms of neuronal stimulation, it is also possible for a neurotransmitter to de-activate or inhibit the activity of a receiving neuron This would make it less able to fire an action potential even if it were stimulated by another kind of transmitter. Receptors for both of these types of transmitters often co-exist on the same neuron Whether or not an action potential fires in a receiving neuron depends on the net balance or summation of excitatory (stimulating) and inhibitory (de-activating) transmitters that bind with the receptors It's not unlike an election: if enough votes are cast for a particular candidate relative to the votes cast for her opponent, the candidate wins (and she immediately fires an action potential to signal her victory)!

Answer 57

The transmission of chemical messengers across the synapse is the critical mode of communication between neurons Intense of repeated patterns of transmission are important in forging the links between neurons that we associated with learning. Neurotransmitters are specialized chemicals that have a range of properties or effects Although particular transmitters play particular roles in the brain and other parts of the nervous system, there are some features common to all of them. 1. Neurotransmitters are synthesized from chemicals in our bodies - Most often these chemicals come from our diet - Amino acids are a very common dietary source or precursor for neurotransmitters - Amino acids are relatively small molecules that link together to form polypeptides, which when they get long enough are called proteins - So when you eat a steak, you are eating the raw materials for neurotransmitters 2. Neurotransmitters are localized in neurons - They do not float freely about the brain or body. 3. A mechanism exists to turn off the activity of neurotransmitters - The neurons are constantly recycling or destroying unused neurotransmitters from the synapse - This occurs by two means: (a) Re-uptake, a vacuum-like process by which excess transmitter is sucked into the sending cell by a re-uptake pump or transporter. The second form of re-cycling is called (b) enzymatic degradation. - Enzymes are chemical catalysts in our bodies that both synthesize and digest other chemicals. - In the case of neurotransmitters, enzymes in the synapse will prowl about in search of excess transmitter, which they will literally digest or break down into smaller molecules that are then washed away into the fluid that bathes the brain and spinal cord 4. Neurotransmitters act over short distances - Unlike other chemical messengers in our bodies (e.g., hormones), neurotransmitters exert their effects over very short distances (cell to cell) rather than at a distance - As a result, neurotransmission is a very rapid event (millisecond duration) - However, because it is going on constantly, these discrete transmissions are experienced as an ongoing process 5. Neurotransmitters are specialized - A given neurotransmitter will only bind with its own receptor - Moreover, it will only perform a particular function at that receptor (either inhibition or excitation) - Without this specificity - the dedication of a particular transmitter to a particular receptor, communication within the brain and nervous system would be a hodge-podge of garbled messages rather than the exquisitely synchronized pattern of transmissions that defines our experience - Even the experience of being confused is likely caused by a very specific set of events at the neuronal level in the brain

Answer 58

Neurotransmitters exist in the brain as well as in the body However, the same chemical serves a different function inside and outside of the CNS Indeed, the pathway between the body and the CNS is heavily guarded by a densely-packed layer of cells called the blood-brain barrier These cells are fatty in nature and therefore only permit fat-soluble - or very small water-soluble - molecules to pass through Think of oil and water - you cannot dissolve oil in water or vice versa Similarly, you cannot dissolve a chemical that will dissolve in water in fat In short, the only chemicals that can get into the brain from the body are either fat-soluble or very small and water-soluble

Answer 59

to protect the brain from harmful chemicals (e.g., germs, poisons)

Answer 60

The blood-brain barrier can influence the effect a drug has on the brain The reasoning is as follows: Drugs exert their effects at specific target sites: most often the neuronal receptors in the brain In order to reach these sites, the drug must be delivered by the blood stream to the brain Indeed, there is only 1 way for a drug to produce a psychoactive effect - to enter the brain by way of the blood stream The more rapidly a drug diffuses through the blood-brain barrier, the more of it that will be available to "hit" its target sites at a given time Drugs that are small or highly lipophilic (fat-soluble), pass rapidly through the blood-brain barrier. The greater fat solubility of heroin vs. morphine contributes to heroin's more intense subjective effects (and greater abuse liability).

Answer 61

We know that dose makes a big difference in the strength of drug effects The rate of diffusion into the brain determines the "functional dose" that acts on a particular set of neurons Other things being equal, the faster the diffusion rate, the greater the effect for a given dose

Answer 62

Alcohol is a very small, hydrophilic (water-soluble) molecule Its small size enables it to pass through the tight mesh of the blood-brain barrier even though it does not dissolve too readily in fat Once inside the brain, alcohol is widely distributed throughout the various brain regions, because water is everywhere in the brain This accounts in part for alcohol's widespread effects on different structures in the brain; it literally affects every cell and neurotransmitter In general, the more water-soluble a drug is, the more diffuse or widespread its effects will be in the brain

Answer 63

The more fat-soluble a drug is, the more focal or restricted its effects will be This is because water is distributed rather evenly throughout the brain, whereas fat is more densely concentrated in certain regions than others THC, the major psychoactive ingredient of marijuana, is highly fat-soluble THC is the classic example of drug with a focal effect If you were to perform a brain scan of a person under the influence of alcohol or marijuana you could see these differences The brain of the person under alcohol would light up evenly all over, while the brain of the person under marijuana would light up very brightly in a few regions but be completely inactive in many others Note, however, that a focal drug effect may be just as intoxicating as a diffuse drug effect The intoxicating and impairing effects of a single dose of marijuana are comparable in many ways to those of a single dose of alcohol

Answer 64

Drugs produce psychoactive effects by altering the naturally occurring process of neurotransmission Some drugs increase the rate of activity of neurotransmitters; others decrease their rate of activity Some drugs mimic the effects of the neurotransmitters themselves (e.g., heroin, nicotine) Other drugs fit nicely into the receptors for a particular neurotransmitter but rather than activate them like the transmitter, they sit inert, thereby preventing the transmitter from activating the neuron (e.g., PCP) Whether a drug increases or decreases the spontaneous rate of neurotransmission does not predict its subjective effects Instead, a drug's subjective effects are determined both by its mode of action (increase/decrease neurotransmission), and by the neurotransmitter(s) it acts upon

Answer 65

1. Receptor Activation. - The primary process responsible for experience and behavior is the binding of a neurotransmitter with its receptor - (a) One way a drug can influence experience or behavior therefore, is to increase the amount of neurotransmitter available to bind with its receptors - Some drugs cause the sending neuron to release more of the transmitter thereby increasing the amount available to bind with its receptors. Amphetamine is a good example of a drug with this effect - (b) A second way that a drug can increase receptor activation is by mimicking the effects of the neurotransmitter itself at the receptor site - The molecular structure of some drugs is so similar to the neurotransmitter that the receptor cannot distinguish between the drug and the transmitter - As a result, the receptor (i.e., "the lock") may activate (open) in response to a chemical that it "believes" is the neurotransmitter (i.e., "the key") when in fact the chemical is actually a drug (i.e., a lock-picking device, like a "bobby pin") - As noted above, heroin and nicotine are good examples of drugs that exert their effects primarily by binding directly to the receptors for their respective neurotransmitters. 2. Enzyme Inhibition - Enzymes in the gap between sending and receiving neurons - the synapse - break down excess neurotransmitter, thereby preventing this residue from binding with receptors on the receiving neuron - Drugs may inhibit the normal operation of the enzyme - By preventing the enzyme from doing its job, the neurotransmitter that would normally be broken down by the enzyme remains available to bind with the receptors on the receiving neuron, causing a net increase in neurotransmission - It's as if the garbage man stopped taking away your garbage. Pretty soon you have a huge pileup outside your house - Thus, if an enzyme decreases neurotransmission, a drug that inhibits the enzyme will increase neurotransmission - The saying I use to remember this process is: "The enemy of my enemy is my friend." - The enemy of the neurotransmitter is the enzyme - The enemy of the enzyme is the drug that inhibits it. - The first drugs used to treat depression, called monoamine oxidase inhibitors (MAOI's), worked in this way - "Monoamine" was the name of the class of neurotransmitter. - Monoamine oxidase was the enzyme that normally broke down these neurotransmitters - And monoamine oxidase inhibitors were the drugs that prevented the enzyme from exerting this breakdown effect 3. Re-uptake Blockade - Another process involved in turning off the action of neurotransmitters is re-uptake - This process is essentially recycling of excess transmitter from the synapse by ferrying it back into the sending neuron - The structure responsible for this is the re-uptake transporter or re-uptake pump - Drugs that block the re-uptake pump, prevent it from recycling the excess transmitter, leaving more available in the synapse to bind with receptors on the receiving neuron - In other words, re-uptake blockade leads to a net increase in neurotransmission - Thus, the effect of re-uptake blockade is the same as enzyme inhibition (increased neurotransmission), although the mechanism of these two effects is different - Cocaine is a good example of a drug that blocks re-uptake of a neurotransmitter

Answer 66

There are over 100 neurotransmitters in the CNS, and more chemicals are being discovered every day that meet the criteria of neurotransmitters. Nevertheless, there are a half dozen neurotransmitters that are believed to play critical roles in many aspects of our experience and behavior. These are the chemicals that have received the greatest attention and that are still the primary focus of attention in the study of drug effects.

Answer 67

The first transmitter to be discovered was acetylcholine This chemical is critically involved in memory and specifically the consolidation and storage of new memories Acetylcholine is derived from the dietary amino acid, choline.

Answer 68

Alzheimer's

Answer 69

Monoamines are a class of neurotransmitters implicated in depression However, each of the members of this class plays an important role in psychopathology (mental illness) as well as addictive behavior

Answer 70

This is perhaps the best candidate for the "Star" neurotransmitter in psychopathology and addictions Ultimately, many of the effects of the other major neurotransmitters appear to derive in some way from the manner in which they interact with and influence dopamine The principal role of dopamine is in the initiation and maintenance of motivation Dopamine helps orient the organism to potentially important stimuli; it impels movement towards (approach) these stimuli when they are beneficial and impels movement away (avoidance) from these stimuli when they are dangerous Once a stimulus is encountered, dopamine labels its effects as positive (i.e., rewarding) or negative (i.e., punishing) In this way, dopamine regulates the process of reinforcement Although dopamine was originally believed to underlie the experience of pleasure, more recent research indicates that, although dopamine can create one kind of pleasure, its primary role in this regard is to designate or label stimuli as pleasurable rather than causing the pleasurable experience itself It's as if dopamine puts a chemical "ü" mark on chocolate (pleasurable) and an "x" on broccoli (not pleasurable) Whether the actual pleasure of eating chocolate results from dopamine transmission however, remains a matter of debate The association of meaning to a stimulus can result in some profound effects on behaviour For example, dopamine is believed to underlie the effects of "cues" or "triggers" on drug and alcohol use One reason why Alcoholics Anonymous demands complete abstinence from its members is because of the triggering effects of the first drink. In other words, even though the first drink may not cause intoxication just the smell or taste of alcohol can set of an intense craving for more, which ultimately can result in a full-blown relapse Dopamine transmission is believed to underlie the triggering effects of cues associated with drugs as well as the subjective experience of craving or compulsion to use that often follows exposure to these cues Excessive dopamine transmission can also alter thoughts When stimuli that are normally unimportant are infused with meaning (i.e., labelled as rewarding or punishing), distortions in thought can arise about those stimuli ex. People walking behind you are perceived as "following you." People who try to give you something to eat or drink or who invite you to stay with them are perceived as "plotting to kill you." These distortions in thoughts (delusions) are believed to derive from excessive dopamine transmission They are a hallmark symptom of schizophrenia

Answer 71

Norepinephrine is involved in the modulation of attention, arousal and mood Activation of norepinephrine results in an involuntary focusing of attention on a stimulus - like the stop-and-listen reflex we exhibit when we hear a loud bang Maintenance of attention, or concentration, that is critical to mental tasks is also influenced by norepinephrine The feeling of alertness we experience just prior to an important event (e.g., a test or competition) is governed by norepinephrine Finally, the feeling of calm, and in particular, calmness in the presence of others (e.g., potential competitors), is governed by norepinephrine Deficits in norepinephrine have been implicated in the cognitive (difficulty concentrating) and social aspects (feeling worthless) of depression Excesses in norepinephrine have been implicated in the hyper-vigilance and arousal associated with panic disorder Both norepinephrine and dopamine are synthesized from a dietary amino acid called tyrosine

Answer 72

If dopamine is the "Star" of the neurochemical show, serotonin is the star's "manager." Serotonin serves a modulatory role on dopamine as well as many other neurotransmitters This means that serotonin regulates how much / how little dopamine activity is allowed to occur as well as the turning off of dopamine after it has served its purpose In this way serotonin modulates appetite (for food and drugs), aggression, mood (highs and lows), sleep, and pain In general, increased serotonin reduces appetite, aggression, pain and sleep, while stabilizing mood Drugs that powerfully increase serotonin, like LSD, can produce a complete cessation of appetite, and a super-awake like state (the opposite of sleep) that is involved in the heightened sensory experience of the LSD "trip." Drugs that enhance serotonin in a more measured way, like Prozac, provide energy while also stabilizing mood. Antidepressants that act on serotonin appear primarily to reduce "the lows" of depression, resulting in a better balance of positive/negative experience, rather than directly increasing the highs By providing energy, these antidepressants also reduce the effort that a person must expend to do things that will bring reward or pleasure (e.g., going to work, doing exercise, interacting socially) This is another indirect way they reduce depression Serotonin is synthesized from a dietary amino acid called tryptophan.

Answer 73

activation of neuronal receptors by acetylcholine reflects the direct mode of action of this drug

Answer 74

decrease the break down of neurotransmitters and increase neurotransmission

Answer 75

an all-or-nothing event; a graded event

Answer 76

This module will examine how drugs alter biological processes to produce their effects, and factors that influence the strength and nature of those effects. The focus of this week is defining "drug effects" in biological terms. For decades, cocaine was considered not to be addictive. The advent of crack - a smokable form of cocaine - in the 1980's showed that cocaine is in fact one of the most addictive substances. Ecstasy and LSD both influence a common neurotransmitter system in the brain and both produce hallucinogenic effects. However, Ecstasy often causes permanent brain damage to the user, while LSD does not. What accounts for these differences in the effects of similar types of drugs? The answer lies in the biological mechanisms of drug action - what the drug does to the brain and conversely what the brain (and body) do to the drug. That is the focus of today's module.

Answer 77

Drugs produce their psychoactive effects by altering the spontaneous (i.e., drug-free) activity of neurons in the brain. Neurotransmitters are the agents that turn on or turn off neuronal activity Thus, the effects of drugs are "mediated" by their actions on neurotransmission or chemical signaling between neurons The two basic types of drug effects are: (1) to increase the spontaneous effects of a neurotransmitter (2) decrease the spontaneous effects of a neurotransmitter. When a drug increases, or facilitates the spontaneous effects of a neurotransmitter it is called an AGONIST (which derives from the word "to go" in Latin) When a drug decreases, or opposes, the spontaneous effects of a neurotransmitter it is called an ANTAGONIST (which derives from the word "to go against" in Latin)

Answer 78

A drug can increase the spontaneous effects of a neurotransmitter in one of two basic ways: 1. It can mimic the effects of the drug at the receptor site, tricking the neuron into believing it received its neurotransmitter (instead of the drug) 2. Alternatively, the drug can increase the amount of neurotransmitter molecules that are available to bind with the receptors on the receiving neuron The same basic reasoning applies to drugs that decrease the effects of a neurotransmitter. 1. A drug may decrease the ability of neurotransmitter molecules to bind with their receptor by blocking the receptor sites but not turning on the neuron (i.e., this is a bit like the plastic child-safety plugs that are used to prevent accidental shock by blocking the flow of electricity from wall outlets) 2. A drug can also decrease the activity of a neurotransmitter by: a) impairing the ability of the neuron to fire its action potential OR b) by increasing the activity of processes that normally act to stop neurotransmission like enzymatic degradation and re-uptake In both (a) and (b) the decrease in activity results from some process other than blockade of the receptor sites.

Answer 79

When a drug exerts its effects (increase or decrease neurotransmission) by binding directly with neuronal receptors the drug effect is said to be DIRECT

Answer 80

When a drug exerts its effects (increase or decrease neurotransmission) by some mechanism other than receptor blockade, the drug effect is said to be INDIRECT. Notice that the type of drug effect (increase/decrease) and the mechanism of a drug effect are completely independent: Either type of effect can be combined with either mechanism and vice versa.

Answer 81

Mechanism of Effect: Direct increase: (A) Binds with receptors and mimics Neurotransmitter effect Direct decrease: (B) Binds with receptors and blocks the ability of neurotransmitter to activate receptors Indirect increase: (C) Increases levels of transmitter in synapse that are available to activate receptors WITHOUT binding with receptors (e.g., block re-uptake) Indirect decrease: (D) Decreases ability of transmitter to produce action potential in receiving neuron WITHOUT binding with receptors (e.g., makes receiving neuron leaky or unable to conduct an action potential). The table above shows four classes of drug action: A, B, C, and D.

Answer 82

(A) direct agonist: Nicotine (transmitter=acetylcholine) Valium (transmitter= GABA) (B) direct antagonist: PCP (transmitter=glutamate) Chlorpromazine (transmitter=dopamine) indirect mechanism of action (C) indirect agonist: Cocaine (transmitter=dopamine) Prozac (transmitter=serotonin) (D) indirect antagonist: Alcohol (transmitter=norepinephrine) Reserpine (transmitter=dopamine) The type and mechanism of a drug effect tells us nothing about whether or not it is primarily a medication or primarily a drug of abuse.

Answer 83

a) increased binding of the neurotransmitter with its receptors b) decreased binding of the neurotransmitter with its receptors c) increased neurotransmission by binding with its receptors (a) and (b) are self-evident. (c) is true because neurotransmission is increased when the drug binds with receptors and mimics the neurotransmitter effect. For example, 10 transmitter molecules could bind with 10 receptors to turn on the neuron, or 5 transmitter molecules and 5 molecules of drug could together bind with 10 receptors (total) to turn on the neuron. In the latter case, neurotransmission is increased over what it would be without the drug (i.e., only 5 receptors would be activated).

Answer 84

In a previous Discussions discussion the issue of individual differences in vulnerability to drug abuse was discussed. Today we will examine some of the biological factors that influence vulnerability to drug abuse. As we all know, genes play a critical role in a variety of personal traits, ranging from eye colour to athletic ability and in some cases even intelligence. Genes also play an important role in risk for addiction. For example, the son of a male alcoholic has a 4 times greater risk of becoming an alcoholic himself than the son of a non-alcoholic father. This is true even if the son was adopted by a non-alcoholic family at birth. This consistent risk of alcoholism based on the biological father's alcoholic status is strong evidence of a genetic component to alcoholism.

Answer 85

There are many possible answers to this question. One very important way that genes influence risk for addiction is by dictating the number or sensitivity of receptors on a particular class of neurons. Specifically, genes tell the organism how to link various chemicals when building cells within the body. The genes literally provide the blueprint for the body's structure. In the brain, genes provide the code for the structure and number of neuronal receptors, which in many cases are basically made up of proteins. If a person's genes code for highly sensitive or highly populous receptors of a particular class of neurons (e.g., dopamine), that person will have a different response to drugs that affect neurotransmission at those receptors, compared to someone whose genes code for low sensitivity or low density of receptors.

Answer 86

The term "D2" is used to describe a sub-class of receptors for dopamine neurons. These receptors have proven to be extremely important to the understanding of abnormal thought and motivation. Recall that dopamine is the "star" of the neurotransmitter show, apparently acting as a neurochemical signal for events with adaptive significance (i.e., things that are important for survival). Research shows that dopamine receptors play a critical role in individual differences in dopamine transmission. Moreover, genes appear to dictate the expression of high or low numbers of dopamine receptors. In recent years, technology (Positron Emission Tomography - PET scans; genotyping - characterising an individual's genetic profile based on samples of his/her blood or tissue) has enabled us to examine the relationship between genes, dopamine receptors, and individual differences in novelty or sensation seeking. The results of these investigations are remarkable.

Answer 87

Recall that cocaine is a potent dopamine agonist, increasing levels of dopamine transmission by blocking its re-uptake from the synapse. Schizophrenia involves excessive dopamine transmission, due in part to their heightened levels of D2 receptors. The figure indicates that individuals with high levels of D2 receptors show high rates of schizophrenia. In contrast, individuals with low levels of D2 receptors show high rates of cocaine abuse. A high level of D2 receptors would lead to abnormally high dopamine transmission, whereas a low level of D2 receptors would lead to an abnormally low level of dopamine transmission. Individuals with low levels of D2 receptors - (those at risk for cocaine abuse) - tend to be sensation seekers. They love risky activities and things that provide a rush. Such individuals would really enjoy a roller coaster or skydiving. Individuals with high levels of D2 receptors are just the opposite; for them everyday activities may be overly stimulating and "exciting" activities would probably be experienced as stressful or frightening. When individuals with low levels of D2 encounter a substance like cocaine, they tend to like it. As a result, such individuals progress to abuse and addiction much more rapidly than individuals with high levels of D2 receptors. It is as if cocaine provides a chemical equivalent of a roller coaster for the low-D2 individual. For these people, cocaine exerts a powerful "cybernetic" function: It brings them closer to their internal optimum state. Thus, the abuse liability of cocaine is greater for individuals with low levels of D2 receptors, whose internal state is chronically discrepant with their ideal (i.e., under-stimulated).

Answer 88

Notice that low-D2 individuals prefer the cocaine as compared with the high-D2 individuals. This is called an inverse relationship: The lower the baseline transmission, the greater the preference for a drug that enhances that transmission. Thus, even normal individuals (non-cocaine users, non-schizophrenics) show predictable differences in their preference for a stimulant drug, as a function of their levels of D2 receptors.

Answer 89

Yes, and it appears to involve an inverse relationship between baseline transmission of a particular neurotransmitter and liking of a drug that acts on that transmitter. The addictive personality is likely specific to certain drugs or types of experience. The lower the baseline activity of a neurotransmitter, the higher the liking of a drug that increases activity of that transmitter (an inverse relationship). Different drugs/activities influence different transmitters - when a drug or activity specifically acts on a transmitter whose baseline levels of activity are low, the individual is more likely to use that drug to achieve his/her internal optimum. However, a drug that does not act on a transmitter system that is deficient will not assist the achievement of one's internal optimum standard and therefore may not be especially appealing to that individual.

Answer 90

As mentioned in previous lectures, the body reacts to the administration of a drug. That is, it compensates for changes in neurotransmission induced by the drug. This is especially true when the drug is given repeatedly (i.e., chronic administration). If a drug increases neurotransmission by increasing levels of transmitter in the synapse, the body may compensate by reducing the number of sensitivity of those receptors. It's as if the body is trying to preserve conditions as they are - the "status quo." If you administer cocaine repeatedly, you increase the levels of dopamine in the synapse each time. To compensate, the body will then reduce the number or sensitivity of dopamine receptors available to be activated by the transmitter = "Down-Regulation." Thus, regardless of where a person starts out in terms of D2 receptors, after chronic cocaine use, his/her D2 receptors will decline in sensitivity or number Normal individuals with lower levels of D2 receptors like cocaine more. Therefore, regardless of baseline D2 receptor sensitivity, chronic cocaine use will increase the preference for cocaine relative to before cocaine use. This is the addictive spiral. Chronic cocaine users often report that cocaine initially made them feel high, whereas now it only serves to make them feel normal - it just allows them to function. An important difference between drugs and non-drug reinforcers is that drugs possess the ability to produce intense prolonged activation of neuronal receptors. It is this intense activation that promotes compensatory responses (down-regulation) by the body, which in turn promotes further drug use, just to restore one's subjective state to "normal." Non-drug reinforcers can occasionally produce such intense activation. However, the probability and severity of this effect is usually much less. As a result, drugs are much more likely to produce "addiction" than non-drug reinforcers.

Answer 91

Down-regulation is not only involved in the pathological effects of psychoactive drugs (i.e., addiction). It appears to be involved in the therapeutic effects of some psychoactive medications. A universal feature of antidepressant medications is their "delayed onset" of action. Drugs like Prozac, or earlier antidepressants, like the Mono-amine-oxidase inhibitors, typically do not produce a therapeutic effect for 2-6 weeks after the individual begins to take them daily. Evidence from animals shows that during this 2-6 week interval, the receptors for the transmitters affected by the drug (i.e., mono-amines) decline in sensitivity - that is, they undergo down-regulation. It is at this point that the relief from depression begins to occur. Importantly, the effects of these drugs on the levels of mono-amines in the synapse occurs with the very first dose. However, it appears to be the body's compensatory response to the enhanced levels of mono-amines in the synapse (i.e., down-regulation) that makes the person feel less depressed. Because of the inherent risk of suicide in depression, it is not always possible to wait 2-6 weeks for a treatment to have an effect. In such cases, doctors will sometimes employ a procedure called electro-convulsive therapy (ECT), which involves administering a focused charge of electric current to specific regions of the brain ECT has been shown to have rapid therapeutic effects in individuals who are extremely depressed. This effect appears to involve a rapid compensation (down-regulation) of receptors by the body in response to the massive surge of receptor stimulation produced by the electric current.

Answer 92

People with schizophrenia, start out with excessive D2 receptor levels = super sensitivity Drugs that treat schizophrenia (like chlorpromazine) block D2 receptors. As a result, the net level of dopamine transmission is reduced, to a level more similar to that of people without schizophrenia. The more effectively a drug binds with D2 receptors and blocks their activation by dopamine, the greater is its ability to reduce the so-called "positive" symptoms of schizophrenia. Positive symptoms do not imply "good." Rather, this term refers to the fact that the symptoms involve behaviours or responses that are "greater than" normal. So if normal = 0, positive simply means > 0 (e.g., +3, +5, etc). The two main positive symptoms of schizophrenia are hallucinations (sensory experiences that have no real source) and delusions (beliefs not grounded in consensus reality) A typical hallucination in schizophrenia is hearing voices that nobody else hears. A typical delusion is a belief that someone is trying to kill you or a belief that you are someone who you are not, e.g., Napoleon or Jesus Christ. Drugs that block D2 receptors are particularly effective in reducing these positive symptoms of schizophrenia. In conceptual terms, it's as if the excessive activation of D2 transmitters were making things more meaningful than they should be (the thought becomes a voice, and the fear and happiness become delusions of paranoia and grandeur). By reducing the excessive transmission (D2 blockade), drugs that treat schizophrenia restore normal levels of meaningfulness to everyday events. Because of their ability to reduce disordered thoughts, drugs that treat schizophrenia have been termed "anti-psychotics."

Answer 93

One of the great tragedies of schizophrenia is that the anti-psychotic drugs that reduce its symptoms also often produce unintended effects that are in some cases equally devastating. The word "tardive" means occurring late. The word "dyskinesia" means disturbance in movement. Chronic treatment with anti-psychotic drugs involves chronic blockade of D2 receptors. Research shows that chronic blockade of D2 receptors can evoke compensatory expression or up-regulation of more D2 receptors. Because dopamine D2 receptors participate in psychomotor function, up-regulation of these receptors in response to medication-induced chronic D2 blockade can lead to involuntary movements which are the core features of "tardive dyskinesia," a syndrome that often occurs in patients with schizophrenia after they have received an anti-psychotic medication for some time. The symptoms of tardive dyskinesia include disturbances in motor function such as tics, lip-smacking, facial contortions, hand tremors and shuffling gait (walking oddly). These are a sub-set of the symptoms seen in another brain disorder, Parkinson's disease. In other words, the medication that alleviates schizophrenia symptoms often induces Parkinson-like symptoms. This reflects the fact that D2 receptors are important for executing co-ordinated movements as well as for infusing events with meaning. Tardive dyskinesia symptoms do not emerge immediately; they only occur after a period of chronic anti-psychotic treatment. Unfortunately, the symptoms once they do emerge, do not appear to be reversible. That is prolonged blockade of D2 receptors appears to have a toxic effect - a permanent disturbance in receptor function. An important goal of recent research is to develop medications to treat schizophrenia that do not produce or produce less severe tardive dyskinesia.

Answer 94

independent of

Answer 95

because factors other than D2 account for the abuse of cocaine and cocaine-induced increases in dopamine can temporarily offset the toxic side effects of anti-psychotic medication (i.e., tardive dyskinesia)

Answer 96

be beneficial in the treatment of schizophrenia

Answer 97

This module will examine how the body "processes" psychoactive drugs and how this processing influences the addictive potential of non-medicinal drugs as well as the therapeutic effect of medicinal drugs.

Answer 98

In this module you will: 1. Learn how the manner in which a drug is taken (e.g., by mouth, injection) can influence its effects. 2. Examine how the body's compensatory response to a drug (alcohol) can influence the degree of intoxication during the course of a single dose. 3. Consider how such dynamic responses to a drug raise questions about the validity of the concept of "legal intoxication" (i.e., a blood alcohol level of .08% in Ontario). 4. Learn how dynamic processing of a medication can influence (1) its therapeutic effects, (2) the marketing of the medication, and (3) the balance of risk/benefits in taking it 5. Become familiar with key concepts related to the risks and benefits of psychoactive medication.

Answer 99

Roughly 65% of adolescents experiment with cigarettes, but only one-third of those progress to regular smoking. Although social factors (e.g., peer pressure) undoubtedly influence the progression to nicotine dependence, recent research shows that some individuals are inherently protected against getting addicted to cigarettes. This research found that a sub-group of individuals, described as "slow metabolizers," fail to process nicotine in the usual way. As a result, a given dose of nicotine is more likely to produce 'toxic' effects (e.g., nausea and dizziness) as opposed to the positive effects of smoking (e.g., alertness, calm). Slow metabolizers will therefore smoke less to avoid these unpleasant effects. Smoking less reduces their exposure to nicotine, which in turn reduces the likelihood of tolerance (needing to smoke more) and withdrawal (irritability, cravings), and ultimately the risk of addiction. A similar phenomenon is seen with alcohol among some individuals of Asian extraction: they get sick to their stomach when they have even a little bit of alcohol. In both cases - cigarettes and alcohol - the decreased ability to metabolize the drug confers protection against addiction. This module will discuss the manner in which the body processes non-medical and medical psychoactive drugs and how this impacts on addiction and treatment.

Answer 100

Our bodies process food and nutrients primarily by way of the gut. For example, before you eat a hamburger, your mouth salivates to begin the process of chemically preparing the food for digestion. Once in the stomach, special agents break down the hamburger into its constituents (e.g., proteins, fats). From there, these constituents are transferred into the blood stream by way of the small intestine, and delivered to the places in the body where they are needed. Along the way further filtering and breakdown may occur in the liver. Who or what is this "Special Agent?" The answer is Enzymes. These are structures whose sole purpose is to facilitate the break down (catabolism) or build up (anabolism) of chemicals in the body. As we have noted in previous modules, the body and brain appear to be physiologically "prepared" to respond to many psychoactive drugs. It is not surprising therefore, that we also have processes designed to process or metabolize many psychoactive drugs. As in the case of food digestion, metabolism of drug is accomplished by enzymes. These enzymes exist in the stomach, liver, muscle tissue, and even in the brain itself. Enzymes begin to work the moment a drug is taken into the body. Thus, the effect of a drug depends on how quickly the drug is delivered to the target cells - i.e., the neurons - in the brain. The faster the delivery, the less opportunity for enzymes to break down the drug, the more of the dose that reaches the target.

Answer 101

This figure depicts the relationship between the route of administration of a standard dose of cocaine and the size and time course of its effects (i.e., the "high"). The solid line indicates the effect that would occur when the dose was taken intra-nasally, that is, by snorting the powder into the nose. The graph shows that the effect is roughly 70% of the maximum possible (assuming an experienced cocaine user was making this rating). To the left of the curve, you see two steeper curves. At the extreme left you see the effect that would occur when the dose was smoked, as in the case of crack cocaine. The graph shows that the same dose now produced a 90% rating on the high scale. By looking at the horizontal axis you can also see that the time from dose administration to the onset of the drug effect was also much briefer, and also that the effect wore off more rapidly. It takes approximately 7 seconds for a drug to get from the lungs to the brain - very little time for the body to exert much of a metabolic effect. In other words, the maximal dose reaches its target sites in the brain when a drug is smoked. The curve to the immediate right of the "smoking" curve shows the effects of the cocaine dose when it is administered by means of intravenous injection. The effect is still greater than snorting, but less than smoking. This reflects the relative efficiency of the delivery system carrying the drug to the brain in these different conditions. Snorting involves slow absorption into the bloodstream by way of the mucous membrane. Smoking involves rapid absorption by way of the capillaries in the lung and direct delivery to the brain by way of the carotid arteries. IV injection involves rapid delivery to the bloodstream but a relatively indirect route to the brain (vein to heart to brain).

Answer 102

On the right-hand side of the graph you see the relatively slow routes of delivery: anal and trans-dermal. Anal refers to the slow absorption of the drug through the mucous membrane of the colon and slow transport by way of the vein to the heart and brain. Notice that the subjective "high" is much weaker than with the other 3 routes of administration, reflecting the relative inefficiency of this delivery route. The only circumstance where an individual would be prone to ingest cocaine by this route would be accidentally: Cocaine smugglers often put the powder into condoms and swallow them to avoid detection. If the condom were to break before it was passed out of the body, a huge amount of cocaine could be administered all at once. Under these circumstances, the relative inefficiency of the anal route of administration may save the smuggler from an overdose. The familiar term for this mode of administration is "The Patch." This technique is now a common way to assist in quitting smoking by maintaining a constant low level of nicotine in the blood stream for several hours thereby allaying cigarette cravings. There has been some talk of using this approach to help people quit cocaine. However, because the intense "high" is central to reinforcing effects of cocaine (which is not the case for smoking), there is much doubt about the feasibility of a cocaine patch.

Answer 103

The answer is that the neurons themselves are dynamic; they respond almost immediately to the presence of a drug by altering the availability or sensitivity of neuronal receptors. In short, the neurons compensate for the change in neurotransmission induced by the drug. When the dose is delivered quickly to the brain, the neurons are temporarily swamped and have little opportunity to compensate for the rapid change in neurotransmission. With little compensatory effect of the neurons, the net effect of the drug is near maximum.

Answer 104

Johnny likes to snort powder cocaine and enjoys the pleasant high this produces. Jimmy likes to smoke cocaine, and loves the intense rush of pleasure it produces. Other things being equal, what is the relative risk of addiction to cocaine for Johnny and Jimmy? greater for Jimmy: The faster the route of administration, the greater the net dose and concomitant effects on the body (tolerance, withdrawal). Also, the steeper the decline in high and drug-opposite Just as there is very little opportunity for the body to compensate for the drug effect and for the enzymes to metabolize it, there is also a much greater risk of overdose when a drug is smoked or injected in a vein. Thus, sharp increases in rates of addiction and accidental overdose are two of the most damaging consequences associated with the advent of crack cocaine.

Answer 105

Like crack cocaine, nicotine is most commonly administered by means of smoking. As a result, the nicotine patch, which is the slowest route of delivery, may not satisfy the cravings for the "pulse-like" increase in brain nicotine levels required by some smokers. Accordingly, drug companies have developed a nicotine puffer not unlike the one used by asthma sufferers to quickly alleviate their symptoms. The nicotine puffer delivers the rapid pulsatile dose without the cancer-causing agents found in tobacco. Although it would be desirable for the smoker to wean him or herself off the puffer and onto the patch or gum, they are still better off with the puffer than with a cigarette. The nicotine puffer thus represents the upside of a rapid route of administration for the management of addiction.

Answer 106

Most experienced drinkers know that rapidly downing a shot of liquor will produce a more intense feeling of intoxication than slowly sipping a 12 ounce beer, even though both drinks contain the same amount of alcohol. This effect mirrors the effect of smoked vs. snorted cocaine discussed above. Common to both of these scenarios is the issue of compensatory processes, and how much time the body has to put them into effect (relatively little when the dose is delivered quickly). Perhaps the nicest illustration of the body's compensatory processes at work is the phenomenon known as "acute tolerance." This refers to the decline in the effect of a dose of alcohol during the time when the dose is being metabolized. Because alcohol is water-soluble, it is distributed relatively evenly throughout the brain and body, which are mostly water. When a police officer takes a breath sample, he or she is estimating the concentration of alcohol in your blood based on its concentration in the air in your lungs. As it happens, the correspondence between alcohol in the blood and alcohol in expired air is very good. Like other drugs, your body metabolizes alcohol starting in your stomach and liver and then later in your brain. During the course of dose, the concentration of alcohol in your bloodstream will rise as the dose diffuses out of the stomach/small intestine and into the blood. At some point, some maximal blood alcohol concentration (BAC) will be achieved. For a 70-kg male who consumed 3 beers in 40 minutes, the maximal or 'peak' BAC would be 0.08%, the legal definition of "intoxication" in Ontario. If these beers were drunk steadily over the 40-minute period, peak BAC would occur about 70-80 minutes after he began drinking.

Answer 107

This figure shows the relationship between BAC and impairment under a 3-beer dose of alcohol consumed in one 40-minute sitting. The left vertical axis shows BAC, and the right vertical axis shows impairment (e.g., number of errors made on a driving simulator). The horizontal axis shows the time in minutes since drinking commenced. The solid curve tracks the change in BAC from the time drinking commenced to the time the entire dose has been metabolized or excreted. The dashed line shows the impairment displayed by the same individual on the driving simulator (assuming simultaneous measurements are taken of BAC and impairment over the entire time interval). The left side of the graph shows that impairment and BAC increase at the same rate while BAC is rising soon after drinking commenced. Thus as alcohol in the blood goes up, the degree of impairment displayed due to alcohol goes up proportionately. The right side of the graph shows a marked divergence in the two curves while BAC is declining after the peak was achieved. In this case, impairment declines much more sharply while BAC tapers off more slowly. Look closely at the point on the graph that corresponds to a BAC of .06%. On the left side of the graph, while blood levels were rising, we see that this BAC was associated with 80% impairment (relative to sober levels of performance). In contrast, on the right side we see that a BAC of .06% is associated with only 40% impairment an hour later when blood levels are declining. Thus, the same blood alcohol level (.06%) - the functional dose that is operating on the brain - produced twice as much impairment while blood levels are rising as when blood levels are declining. The difference in impairment reflects "acute tolerance" - the decline in the effect of the drug during the course of a single dose.

Answer 108

What accounts for the differential impairment during rising vs. declining BAC's? the neurons in the brain have adapted to the presence of alcohol

Answer 109

No, At 1 hour, you may still be on the rising limb of the blood alcohol curve. If you continue driving now, your BAC may rise to .08% or beyond. At 2.5 hours, your BAC is more likely to decline if you continue driving. Of equal importance, you will have achieved some acute tolerance over the extra 1.5 hours and will likely show considerably less impairment than you would have at 1 hour. In other words, a BAC is not a BAC is not a BAC. To fully evaluate risk, behavioral impairment and time since last consumption must be factored in along with BAC.

Answer 110

The figure of BAC and impairment is an example of a dose response curve: It illustrates how the response to the drug varies as the dose (in this case the level in the blood) rises and falls. In general, dose response curves are shaped like an "S." As dose rises initially, there is only a modest increase in response. Past a certain dose, the response begins to rise more sharply, and then again at very high doses, the increase in response with further increases in dose tapers off, reflecting the maximum effect of the drug.

Answer 111

While the S-shaped dose-response curve is the norm for most drugs, there are a few drugs that exhibit what is known as a "threshold" effect. A threshold is a boundary that demarcates a major shift in the drug effect. To the left of the boundary or threshold, increases in the dose have virtually no impact on the response. To the immediate right of the threshold, an increase in the dose produces a massive increase or full manifestation of the response. Notably, further increases in dose have negligible or small effects on response. A non-medicinal drug with threshold-like effect is LSD. Up to a certain point, hallucinogen effects are absent. Once the critical dose is achieved (~200 micrograms), the hallucinogenic "trip" effect manifests itself completely. Further increases in dose beyond the critical level can impact rate of onset and disorienting effects but the transition to the trip is like crossing a threshold. A medicinal drug that appears to have a threshold-like effect, at least when used for its primary indication, is Prozac. Up to 20 mg/day, Prozac has little benefit in the treatment of uncomplicated clinical depression. At 20 mg/day, the antidepressant effect appears in full bloom. Beyond 20 mg/day, the increase in benefit with increase in dose is marginal in the case of depression, although it may help in some other types of disorder (e.g., obsessive-compulsive disorder). The figure below illustrates the typical dose-response curve (for an old-style antidepressant) as against the threshold dose-response curve for the new antidepressant Prozac. Interestingly, both LSD and Prozac exert their effects primarily by altering serotonin transmission. The threshold effect of Prozac, in addition to its high level of safety, contributed greatly to the incredible marketing success of the drug. Prior to the advent of Prozac in 1988, antidepressants had to be administered by a trained psychiatrist who could titrate or carefully micro-manage the dose administered. To make this possible, the depressed patient often had to be hospitalized for 2-6 weeks even if he or she were still functioning at a reasonably high level. Prozac changed all that. With Prozac, the family doctor could administer the medication and monitor the patient over the 2-6 week period: "Take 20 mg Prozac and call me in 2 weeks." Because there are so many family doctors, and because depression is so common (and readily diagnosed), Prozac was a marketing marvel. It revolutionized the management of depression, and remains to this day one of the single most profitable drugs in history.

Answer 112

Because family doctors are not specialists, they may misdiagnose depression and wrongly prescribe Prozac. As a powerful psychoactive drug, Prozac may have adverse effect for a non-depressed individual. In addition, the outpatient management of depression means that critical issues may be overlooked or not adequately addressed (side effects and compliance - taking the drug as prescribed). Finally, and perhaps most importantly, like other antidepressants, Prozac takes 2-6 weeks to produce clear therapeutic effects. During this time depressive symptoms, including suicidal thoughts, may persist and in some cases intensify, before they improve. Failure to carefully monitor these symptoms could obviously be catastrophic.

Answer 113

Headache sufferers know that 1 ibuprofen tablet will often relieve a headache as well as 2 standard aspirin tablets. People who use hallucinogens know that a few "micro-dots" of LSD can alter consciousness as much or more as a much larger quantity of hallucinogenic mushrooms. Indeed, it has been estimated that 1 teaspoon of pure LSD, dissolved in the water system, would be sufficient to induce a full blown "trip" in the entire population of New York City (15 million people). These kinds of effects reflect the potency of ibuprofen and LSD respectively. Potency is formally defined as the ability of a given dose of a drug to induce a particular effect relative to other drugs that can also induce this effect. Notice that potency involves the relative strength of a drug, rather than it absolute or maximum strength.

Answer 114

Liquor. 1.5 ounces of liquor will produce the same effect (if consumed over the same interval) as 12 ounces of beer. Thus, liquor is 12/1.5 = 8 times as potent as beer. Note: The blood alcohol concentration (BAC) resulting from these two beverages will be about the same ~.03%. Similarly, the intoxication resulting from the two beverages should be similar. The only difference then is the dose required to achieve this effect. Large differences in the potency of drugs that exert similar effects are important because it means that less of the more potent drug can be administered. This can reduce the metabolic work the body has to do and also reduce some of the side effects and neuronal changes produced by a given dose. For example, highly concentrated marijuana may be a better alternative to weakly concentrated marijuana for the management of chronic pain. This is because fewer carcinogens (cancer-causing agents) are taken for each therapeutic dose with the concentrated form (e.g., 1 "joint") as opposed to the less concentrated form (3 joints).

Answer 115

A patient has suffered third degree burns in a house fire. The doctors at the hospital administer morphine to him to alleviate the intense pain. A smaller dose of morphine would be required to produce this analgesic (pain-reducing) effect than if the doctors had to rely on Tylenol, for example. Thus, morphine is more potent than Tylenol. More important in this case, however, is the fact that morphine will be able to get rid of more of the pain (e.g., 80% relief) than will Tylenol (e.g., 40% relief). You likely couldn't produce more than 40% pain relief with Tylenol even if you poured gallons of it into the patient. The maximum ability of a drug to achieve its intended effect, regardless of dose, is referred to as its "efficacy." (you can think of efficacy as effectiveness).

Answer 116

A patient has suffered third degree burns in a house fire. The doctors at the hospital administer morphine to him to alleviate the intense pain. A smaller dose of morphine would be required to produce this analgesic (pain-reducing) effect than if the doctors had to rely on Tylenol, for example. Thus, morphine is more potent than Tylenol. More important in this case, however, is the fact that morphine will be able to get rid of more of the pain (e.g., 80% relief) than will Tylenol (e.g., 40% relief). You likely couldn't produce more than 40% pain relief with Tylenol even if you poured gallons of it into the patient. The maximum ability of a drug to achieve its intended effect, regardless of dose, is referred to as its "efficacy." (you can think of efficacy as effectiveness).

Answer 117

In the example above, what is the relative efficacy of Tylenol vs. morphine for burn analgesia? Tylenol is half as efficacious as morphine

Answer 118

Up until now we have been talking as if a given dose of drug will exert identical effects in everyone who receives. In fact, this is rarely the case. Instead, there typically are large individual differences in response to psychoactive drugs - both medicinal and non-medicinal. As noted in previous modules, genes can play an important role in this, as can prior exposure to the drug (i.e., tolerance). When considering the administration of a medicinal drug, it is important to bear in mind not only its efficacy but also the potential adverse effects associated with it. For example, we may find that 50% of all anxious patients will achieve complete relief of their symptoms with a dose of 20 mg Valium. However, 30% of these patients may also be so sedated by this dose that they cannot go to work, drive a car or do other basic activities. Clearly, there is a trade-off between the therapeutic effect of a drug (its efficacy) and its adverse effects (e.g., side effects, toxicity). The most extreme adverse effect of a drug is death. Because it is often difficult to fully reverse a drug effect once it has begun to occur, it is vital to know the possible adverse consequences and specifically the likelihood of accidental toxicity or death BEFORE the drug is administered. The risk: benefit ratio of a drug is formalized by the term "Therapeutic Index." The therapeutic index = LD50 / ED50, Here LD50 refers to the "lethal dose" for "50%" of all individuals who receive it (i.e., the dose at which half of all people who ingested it would die). ED50 refers to the "effective - or efficacious - dose" for 50% of all individuals who receive it (i.e., the dose at which half of all people who ingested it would receive its intended effect, e.g., pain relief). The LARGER the therapeutic index of a drug the SAFER it is in terms of accidental overdose. For example, a drug with a therapeutic index of 10 means that a person would have to ingest 10 times the dose that would produce the intended effects in order to die. e.g., 10 mg / 1 mg = Therapeutic Index of 10. In this case, 1 mg is the ED50 (so 50% of recipients will receive its intended effects, while the LD50 is 10 mg. As a general rule, the greater the difference between LD50 and ED50, the safer the drug will be.

Answer 119

Drug A has an LD50 of 8 mg and an ED50 of 4 mg. Drug B has an LD50 of 12 mg, and an ED50 of 8 mg. Which of these 2 drugs is safer in terms of accidental overdose? A is safer than B

Answer 120

The first imperative of medical practice is "To do no harm." Thus, the responsible doctor will aim to minimize the risk of accidental death, even if the symptom relief is not complete. An alternative index of the safety of a drug, that takes this issue into account, is called the "Margin of Safety" Margin of Safety = LD1 / ED99 In this case, LD1 is the dose at which 1% of recipients would die, while ED99 is the dose at which 99% of recipients would achieve the desired effect. Because LD1 is lower than LD50, and ED99 is higher than ED50, a drug's margin of safety is typically much closer to 1.0 than is its therapeutic index. However, this reflects the fact that the margin of safety is a more conservative (i.e., safer) standard than is the therapeutic index. In the case of street drugs, one reason heroin is more dangerous than many other drugs is its relatively small margin of safety: The LD1 dose is only slightly greater than the ED99.

Answer 121

Yes. It is possible. Drugs of this type are better described as "poisons." For example, para-methoxy-amphetamine (PMA; street name "death") has psychoactive effects similar to MDMA (Ecstasy). Sadly, the dose that will produce these effects will almost certainly kill the person who takes it.

Answer 122

1. The more rapidly a drug is delivered to its target sites in the brain, the ___________ the potential for ______________. greater; addiction less; metabolism and greater; overdose 2. A patient requires 40 mg of drug X to fully alleviate his chronic back pain. However, 4 mg of drug Y will accomplish the same effect. Based on this information you can conclude that drug X is ________ drug Y. less potent than 3. A person is given an antidepressant medication and instructed to take 1 tablet every day and contact the doctor in 2 weeks. In the first week the person experiences little change in his mood but continues to take it as prescribed. By the middle of the 2nd week, he is beginning to feel his energy increase and his mood brighten ever so slightly. The delayed onset of these antidepressant effects can be attributed to. alterations in receptor sensitivity due to chronic drug administration achievement of steady state drug blood levels the influence of active metabolites working in concert with the parent compound

Answer 123

The influence of route of administration on response to drugs. The phenomenon of "Acute Tolerance" - the compensatory response of the body to a drug within the course of a single dose The behavioral effects of acute tolerance The role of body-drug interactions in the intended (e.g., treatment) and unintended (e.g., overdose, addiction) effects of a drug Key terms that define properties of drugs in terms of intended and unintended effects.

Answer 124

This module will examine further the dynamic drug-body interactions. The focus of this week is effects of chronic (i.e., repeated, long-term) drug administration.

Answer 125

The term "kinetic" comes from the Greek for movement. Pharmacokinetics refers to the processes involved in the movement of a drug through our bodies from ingestion to excretion. As noted in previous modules, the body is not a passive recipient of drugs. Instead it is an active processor of these drugs, modifying the sensitivity of neuronal receptors to compensate for heightened levels of neurotransmission and implementing actions designed to break down the drug molecule to facilitate elimination from the body. Like food, drugs are metabolized by our bodies. Indeed metabolism begins the moment the drug is ingested. In most cases, metabolism is accomplished by means of enzymes. These natural 'catalysts' or chemical helpers, actually digest the drug, turning it into new chemicals that typically is smaller and therefore more readily excreted in the urine, feces, sweat, nails and hair. In many cases, metabolism not only reduces the size of a drug; it also negates its psychoactive properties. For example, nicotine is metabolized by enzymes into the chemical, cotinine. Whereas nicotine has clear psychoactive properties, cotinine does not. The more efficient the enzymes, the more rapidly a drug will be converted into a new chemical that is not psychoactive. In other words, enzymes can "turn off" the drug effect. As noted earlier, genes may partly determine the rate of activity or amount of enzymes available to turn off a drug. This in turn can influence the risk of addiction (as well as therapeutic response to a medicinal drug).

Answer 126

Thus efficient or "fast metabolizers" need more drug to get high or get a therapeutic response than "slow metabolizers." Fast metabolizers will therefore administer more of the drug and will in turn increase the addiction-related processes (tolerance and withdrawal) associated with increased drug exposure. Drug metabolism occurs at the Peripheral Level (in the body), at the Central Level (in the brain and CNS), and at the Cellular Level (within the neuron).

Answer 127

The Liver is the organ that plays the most important role in peripheral metabolism. Although the liver is extremely resilient, bouncing back after years of drug abuse, there are limits to its ability to recover. Cirrhosis of the liver is a disease often found in long-term alcoholics. In this case, the cells of the liver have died and ceased to be replaced. If cirrhosis proceeds too far, the liver may fail entirely. Because the liver is required to metabolize and filter many chemicals other than drugs, liver failure is fatal.

Answer 128

Enzymes in the stomach also assist in peripheral metabolism, when a drug is taken by mouth. This is certainly true in the case of alcohol. Recall that certain Asian individuals are slow metabolizers of alcohol and can get sick to their stomachs if they drink a very small quantity. Research shows that the place where such Asian individuals display their lower levels of enzymes is in the stomach. In addition, women will often experience a greater intoxicating effect of alcohol than men, even if the dose they consume has been adjusted for differences in body weight and body water content. As it happens, most women have lower levels of alcohol enzymes in their stomach than men, leading to less breakdown of alcohol in the stomach, and consequently, higher levels of alcohol being diffused into the blood and transported to the brain.

Answer 129

In the brain, enzymes exist in the synapse between neurons. Their purpose is to grind up excess transmitter as well as foreign chemicals, like drugs. These enzymes may initially become more active to counteract increased neurotransmission in the presence of drugs. Thus, enzymes can exert a regulatory function in the brain. Finally, enzymes and other related factors exist within the neurons themselves. These factors break down and recycle a variety of chemicals in addition to neurotransmitters and amino acids (pre-cursors of neurotransmitters), representing a final point of drug metabolism.

Answer 130

A particularly important class of enzymes for metabolism of psychoactive drugs is termed, cytochrome P450 (CYP 45). Variants of these enzymes exist in body (e.g., liver), brain and cell (neurons). CYP 450 is responsible, in part for the metabolism of nicotine, alcohol, amphetamine, and heroin, to name but a few of the substances it handles. Individuals with highly efficient CYP 450 are more prone to the initial development of nicotine dependence and dependence on other stimulants, like amphetamine. This is because such individuals do not experience the unpleasant side effects that deter high levels of use in people who have not yet used these drugs. In other words, efficient CYP 450 promotes fast metabolism and risk for addiction - particularly at the initiation stage of drug use. Conversely, inefficient CYP 450 results in slow metabolism, increased likelihood of unpleasant or low level toxic responses to a drug during the early stages of use, and accordingly, decreased risk of addiction. Interestingly, antidepressant drugs like Prozac or Paxil, in addition to their primary therapeutic effects also inhibit CYP 450 activity, especially in the liver. As a result, individuals taking these medications on a chronic basis may receive some of the protection against addiction that characterizes "slow metabolizers." For example, it may take only 2 alcoholic drinks to get intoxicated while an individual is taking Prozac, whereas the same individual would have required 3 or 4 drinks when s/he was not taking Prozac. At the same time, a failure to take this into account could result in unexpected effects if a person typically drinks 3 or 4 drinks without problem suddenly finds themselves stuporous or completely "smashed" when they drink this much while they're taking Prozac.

Answer 131

The Elimination Half-life or simply "half-life" of a drug refers to the time required for the body to metabolize 50% or half of a given dose of a drug. So, if the half-life of Drug X were 8 hours, and you take a dose of 2 mg at 12 o'clock, by 8 o' clock the amount of drug remaining in your system (that has not been metabolized) will be 1 mg. Like the LD50 and ED50, half-life refers to the property of a drug itself. That is, these indices are specific features of a chemical that do not change from situation to situation or person to person. A drug has only one LD50, one ED50, one half-life and so on. There are factors that can interact with these features of a drug (e.g., age, genes, enzymes), but the features themselves do not change. The half-life of a drug is particularly important in the case of psychoactive medications, which are often taken on a chronic basis. If a drug has a short half-life this will entail a frequent schedule of dosing, e.g., twice or three times a day. This can be inconvenient, and the patient may forget to take the dose at the appropriate time, and may lose some of the therapeutic effect as a result. A good example of this is Ritalin, a medication used for the treatment of attention deficit hyperactivity disorder (ADHD). Ritalin has a half-life of 4-6 hours so that ADHD patients must take their dose 2-3 times per day to have a sustained effect. Children are far more likely than adults to suffer from ADHD. Such young patients are more likely to forget to take their dose on time, and this tendency may be aggravated by ADHD itself which can make people impulsive and disorganized. Thus, the short-half life and concomitant need for frequent dosing of Ritalin are an important clinical issue in the pharmacological treatment of ADHD.

Answer 132

An equally important issue arises with drugs that have long half-lives. For example, some of the early antidepressants developed in the 1960's had half-lives of 50 or 60 hours. However, patients were instructed to take them on a daily basis. As a result, much of an original dose taken on Day 1 would still in tact when the individual came to take their next dose on Day 2, 24 hours later. Over the course of days or weeks, daily dosing of a medication with a half-life longer than 24 hours would result in a gradual build-up of the drug in the system. This is because the drug was coming into the body faster than the body could get rid of it by means of metabolism. Such an effect could lead to increased side effects, alteration in clinical response and even unintentional overdose. Accordingly, drug companies have tried hard to develop drugs with half-lives as close to 24 hours as possible to facilitate daily dosing without this kind of dangerous build-up.

Answer 133

The drug illustrated here is "Zoloft," a relatively new antidepressant similar to Prozac with a half-life of ~24 hours. Zoloft is given in 50-mg doses. The figure shows that an initial dose, taken at 9 am in the morning, raises the level of the drug to 50 mg, and that by 9 am the next day, the level in the body has declined to 25 mg, one half the value it was 24 hours earlier. When the second dose is taken at 9 am on day 2 it raises levels to 50 mg plus the residual amount that was not metabolized from the previous dose (25 mg). Thus, on day 2, the total level of Zoloft in the body is 50 + 25 = 75 mg. By 9 am on day 3, this level has declined by half, 75/2 = 37.5 mg. This residue is in turn added to the new dose of 50 mg to yield a new level of 37.5 + 50 = 87.5 mg on day 3. Notice that the pre-post capsule difference in the blood level of the drug at 9 am on a given day is getting smaller over the course of days. On day 1 the difference was 50 mg (the full dose); on day 2 the difference was 37.5 mg and so on. By day 5, the difference is approaching zero, (although it never will actually reach zero).

Answer 134

The very small difference in pre-post capsule blood levels on day 5 reflect the occurrence of "steady state." A point where blood levels of the drug are as stable as they can be. This occurs when the rate at which the body metabolizes the drug almost exactly matches the rate at which the drug is being replenished by additional doses.

Answer 135

At steady state, deviations from the optimal level of drug effect are as small as they can be. In terms of the "cybernetic" model of drug use, the patient's internal state and behavior - which are regulated by the drug - would be most consistently "normal" (i.e., in line with his/her optimum) at this point. In the case of Zoloft, at steady state, the patient's blood levels will never dip below 50 mg and never exceed 100 mg in the course of a given day, provided he/she continues to take 50 mg each day at the same time of day. This will help to ensure that the therapeutic response to the drug is also very stable.

Answer 136

As mentioned earlier, the half-life of a drug is the property of the chemical itself, like a person's height or facial features, and therefore cannot be directly modified without changing the chemical. In the case of drugs with short half-lives, this would entail frequent dosing in order to minimize deviations in blood levels and associated deviations in therapeutic response. To get around this problem, drug companies have developed ways to slow down the rate at which the drug is introduced into the body. Sustained release medications are drugs with short half-lives that are mixed with materials (tablet or capsule) that are designed to protect the active chemical from the being rapidly broken down by enzymes and other metabolic factors. Typically, the drug is embedded in a matrix of inert material, like cellulose, and is gradually allowed to "seep" out into the stomach or small intestine. This ensures that at any given time, only part of the current dose is undergoing metabolism while the remainder is kept on hold for future dosing. Recall the example of Ritalin, a drug with a short half-life that made correct dosing difficult. A sustained release version of this drug now exists that enables the patient to take a single dose each day rather than 3 per day as originally required. Note: the sustained release medication does not change the half-life of the drug. Rather, it changes the rate at which this drug is exposed to metabolic factors. To extend the analogy, a person cannot change his/her height directly. However, that person can change his/her height indirectly, say, by wearing high-heeled shoes. Sustained release medications are essentially short-acting drugs made to function in a long-acting manner by indirect means.

Answer 137

Until now, we have assumed that metabolism essentially de-activated a drug, by breaking it down into its component parts. In most cases, this is true. However, in a few cases, the product of metabolism or "metabolite" is itself psychoactive. A good example of this is the drug, bupropion (trade name, Zyban) which is used to help people quit smoking. Bupropion enhances brain levels of the neurotransmitter norepinephrine, and this effect seems to help curb the cravings to smoke. Like other drugs, bupropion is metabolized by enzymes into a variety of other chemicals. One of these chemicals, call it Metabolite-x, is a more powerful enhancer of norepinephrine than bupropion itself. Metabolite-x is called an "Active Metabolite" because it possesses therapeutic effects over and above those of the "parent compound" (bupropion), the drug from which it was derived. Active metabolites are another way to extend the therapeutic effects of short-acting drugs. There are also some fascinating applications of active metabolites. For instance, one of the drugs (clomipramine, trade name Anafranil) used to treat the repetitive checking and washing rituals of Obsessive-Compulsive Disorder has an active metabolite. Research shows that clomipramine is a powerful serotonin enhancer. However, the active metabolite of clomipramine is a powerful norepinephrine enhancer. Because clomipramine is taken on a repeated basis, both the parent compound and the active metabolite are present in the body at the same time once steady state has been achieved. As a result, the drug in concert with its metabolite exerts a "dual action" on neurotransmission. It may be this dual action that accounts for the unique efficacy of clomipramine in the treatment of obsessive-compulsive disorder. Active metabolites illustrate the dynamic relationship between the body and a drug and show how this relationship can strongly influence the net effect of the drug.

Answer 138

Many social drinkers will, at some time in their drinking careers, consume more than 2 or 3 drinks in a sitting. This type of drinking will lead to a familiar set of after-effects collectively described as a "hangover." The symptoms of a hangover are quite consistent: headache, nausea or vomiting, hypersensitivity to light and sound, body aches, chills, difficulty concentrating. Some of these effects are directly attributable to the alcohol itself. Others are related to the toxic metabolite of alcohol. Still others derive from the body's compensatory response to alcohol. In contrast to most drugs of abuse, whose psychoactive effects result from altering the transmission of one or two neurotransmitters, alcohol appears to act on all major neurotransmitters. Both its immediate effects (during the dose), and its after-effects (once the dose is completely metabolized) are mediated by these multiple transmitter systems. For instance, during low, rising blood alcohol concentrations (BAC's) alcohol acts to increase dopamine transmission. This contributes to the increased talkativeness and sociability that come from having a "cocktail." As blood alcohol continues to rise (e.g., drink # 2) anxiety begins to decline and strong feelings of relaxation may be felt. These effects result from increased GABA transmission (recall that GABA was characterized as the "dimmer switch" in the brain). By the third drink, the individual may begin to experience heightened confidence and a "devil-may-care" attitude that is uncharacteristic of their sober demeanor. These effects likely involve a temporary increase in serotonin transmission, which seems to "steel" them against negative evaluation or other unpleasant consequences. At peak BAC's, which may be .08 % to 1.0% after drink 4, the person may experience a warm, enveloping sense of euphoria coupled with impairment in speech, psychomotor co-ordination, and mental efficiency. The euphoria likely involves the activation of endogenous opioids (endorphins), while the impairment likely involves the inhibition of glutamate, which keeps the brain alert and the neurons clicking efficiently.

Answer 139

As noted in previous modules, compensatory responses to alcohol begin to occur almost as soon as drinking begins. These responses act in the opposite direction to alcohol. Thus, the body will compensate to alcohol by decreasing transmission of dopamine (sluggishness), GABA (anxiety), serotonin (doubt and uncertainty), and endogenous opioids (aches, discomfort). Conversely, the inhibition of glutamate by alcohol will lead to a rebound increase in glutamate as an after-effect (headache, sensitivity to light and sound, possible "aura"). Although these compensatory effects will begin exerting themselves while the alcohol is still in the system, they will only be fully felt when the alcohol has been completely metabolized. At this point, there is no drug effect to offset the body's responses. Instead, there are a number of reactions that are now "unmasked" in the absence of the drug (alcohol), which manifest as the symptoms of a hangover. In simple terms, a hangover represents a low-level withdrawal effect from an acute dose of alcohol. Like the other forms of rapid compensatory response to alcohol, this withdrawal can occur even in the absence of a long history of drinking; i.e., you don't have to be an alcoholic to experience some aspects of alcohol withdrawal. At the same time, the hangover only represents a sub-set of the symptoms that are seen in the alcohol withdrawal syndrome of chronic alcoholics. Nevertheless, the hangover provides a nice illustration of how withdrawal represents the unmasking of the body's compensatory response to a drug.

Answer 140

It should be emphasized that the different effects of alcohol are not discrete events that occur in the course of a dose. Rather, these effects overlap to varying degrees with other effects (e.g., decreased anxiety and euphoria, etc). Similarly, some of the after-effects of alcohol have multiple causes. For example, the body aches of a hangover likely reflect both (a) the compensatory decrease in endorphin activity coupled with (b) the loss of water throughout the body and associated cramping effects produced by the dehydrating effects of alcohol.

Answer 141

Metabolic factors also play an important role in the after effects of alcohol. For example, the primary metabolite of alcohol is a substance called "acetaldehyde." This chemical is a toxin to most body structures - that is, it can destroy the tissue and interfere with normal maintenance and restorative processes at the cellular level. Because it is a toxin, the body tries to get rid of acetaldehyde, by creating feelings of nausea and vomiting. These feelings may carryover to the next day. Thus, residual acetaldehyde (which itself is metabolized) contributes to the nausea and vomiting of a hangover.

Answer 142

Another way metabolic factors come into play is by competing for enzymes that are designed to metabolize other substances. For example, some enzymes in the liver synthesize the dietary amino acid, tryptophan, into the neurotransmitter, serotonin. When alcohol is consumed, it enters the liver and competes with tryptophan, using up the enzymes that would otherwise help make more serotonin. As a result, serotonin transmission declines during the hangover phase. Notice, that this decline in serotonin synthesis intensifies the compensatory response of the body (decreased serotonin transmission) which occurs as a reaction to alcohol-induced increases in serotonin. The compound after-effects of alcohol on serotonin can result in depression, if alcohol use persists. At the same time, the initial increase in serotonin by alcohol soon after drinking begins may lead the serotonin-deficient chronic drinker to go back to alcohol, just to get the short-term relief from depression it provides. This vicious circle represents another path to addiction that often occurs in the case of alcohol.

Answer 143

Another serious after-effect of alcohol consumption is the rebound activation of glutamate. When glutamate is inhibited the receptors for glutamate initially become more sensitive to the small amount of glutamate that remains (a compensatory response). When alcohol is no longer present however, the now super-sensitive receptors are hit with their normal levels of glutamate causing excessive activation (headache, hypersensitivity to environmental stimuli). When people drink heavily on a chronic basis, they subject their brains to recurrent bouts of receptor up-regulation while the alcohol is present coupled with rebound hyper-activation during the hangover stage. This pattern can lead to a phenomenon described as "excitotoxicity," in which the excitatory effects of glutamate cause glutamate neurons and receptors to burn out like an old light bulb. Like other brain cells, these glutamate neurons will not replenish themselves. Excitotoxicity has been implicated in the memory impairment and other irreversible disturbances in cognitive function associated with chronic alcohol use. The hangover illustrates how the body's response to a drug accounts as much if not more to the debilitating effects of drug use. It is ironic that the body's efforts to restore optimal functioning should ultimately undermine functioning when the drug is absent. In fact, some investigators have proposed that what appears to be sub-optimal functioning (e.g., hangover) may in fact reflect functioning optimized for a different state - namely, the state of drug intoxication.

Answer 144

1. Helen has a genetic deficit in the enzymes that metabolize nicotine. As a result, the first time she smokes a cigarette she will experience ________, and will be ________ to progress to nicotine dependence. more unpleasant effects; less likely 2. Jenn has difficulty falling asleep some nights, but otherwise is functioning pretty well at her job. After several weeks of this problem, she asks her doctor for some sleep medication. He prescribes a mild sedative similar to Valium, but with different pharmacokinetic properties. Based on this information the best drug for Jenn's insomnia will have. a half-life of 2 to 4 hours 3. Kevin is taking Paxil for depression. After drinking three beers, he heads out to his car and is pulled over by a police officer just as he exits the parking lot. Earl, who is not taking Paxil, is the same age and weight as Kevin and drank three beers at the same pace. Relative to Earl, Kevin is: more likely to exceed the legal limit of .08% because Paxil inhibited cytochrome P450

Answer 145

What is it about drugs as opposed to non-drug reinforcers that raises concern? We began this course by discussing ways in which drug and non-drug reinforcers are similar. We cited evidence showing that: Animals and humans both have brain structures designed to respond to psychoactive drugs. Animals and humans use drugs in similar ways when given access to them. Drugs are often readily available in nature, primarily in plants. Use of drugs by animals may contribute to an ecological balance between plants and animals. Drug use is similar in many respects to other drive-based behaviours like eating, drinking (water), sleeping and sexuality. Despite these strong similarities, the opening question about your hypothetical friend highlights the fact that drugs also differ importantly from non-drug reinforcers. This module will define two key ways that drugs differ from non-drug reinforcers and discuss the implications of these differences.

Answer 146

Let's return to the example of your friend who got heavily into drugs and reflect on the reasons why you might have felt concern. I will suggest that the primary distinction between a friend who gets into drugs and a friend who gets into food is HARM. Although excessive consumption of food may eventually cause harm (e.g., increased risk of weight-related disease), this harm is reversible through weight loss. In addition, a lot of food has to be eaten before appreciable harm occurs. Compare this with drugs: a single dose of some drugs can kill you, and chronic use of drugs can induce changes that are irreversible. It is possible, but exceedingly rare to overdose on food. It is possible, but exceedingly rare to die from the immediate toxic effects of food (i.e., food poisoning). In contrast, these events are unfortunately very common with psychoactive drugs. It is possible, but also rare to become addicted to food: Food addiction would manifest as an increase in the quantity required to achieve the same effects (tolerance) and the emergence of intense biological disturbances when food was absent (withdrawal). People who subsist on one or two types of food (e.g., chocolate) have described such effects, but in general they are rare. Contrast this with drugs: Continued ingestion of drugs on a daily basis in most (but not all) cases will lead to tolerance and withdrawal, as well as a preoccupation with obtaining more drugs. In other words, chronic drug use reliably gives rise to addiction. The foregoing discussion highlights two ways that drug-induced HARM differs from the harm associated with non-drug reinforcers: Toxicity and Addiction.

Answer 147

"Toxic" means the same thing as "poisonous." Both of these terms refer to a disturbance in the structure or function of biological systems that is lasting or irreversible. When we refer to drugs as toxic, we mean that they have the potential to damage the structure (e.g., killneurons) or function (e.g., impair the ability of neurons to communicate properly) of various systems in our body. Toxicity can be characterized in terms of time frame (short-term vs. long-term) as well as location (CNS vs. body). Toxic effects that arise in the course of a single dose of a drug (i.e., short-term) are referred to as Acute Toxicity. Toxic Effects that arise after repeated doses (i.e., long-term) are referred to as Chronic Toxicity.

Answer 148

The most common form of acute toxicity is Overdose. Overdose means that the person administers enough of a drug to kill him/herself, barring outside intervention. Overdose is more likely with rapid routes of administration (smoking, IV injection) and with drugs whose potency cannot be verified prior to administration (i.e., street drugs vs. alcohol/prescription drugs). Whereas the intended effects of a drug typically exert their effects on the forebrain and midbrain (limbic system), the unintended effects of a drug - overdose - typically exert their effects on the hindbrain. This is the primitive region of the brain that controls the autonomic nervous system. Recall that the autonomic nervous system acts to regulate heartbeat, respiration, digestion, and other basic functions essential to life. The impact of overdose on the hindbrain is similar for drugs within the same general class (e.g., CNS Stimulants) but distinct from that of drugs from other classes.

Answer 149

Based on your readings, which of the following drugs does not belong to the class of drugs known as CNS stimulants? Cocaine Overdose due to CNS stimulants is reflected by over-arousal in the CNS and by hyperactive sympathetic nervous system function. The symptoms of overdose thus include: - seizures (rapid, uncoordinated neuronal discharge in the brain) - stroke (ruptured blood vessels in the brain due to excess blood pressure) - cardiac arrhythmia (uncoordinated heart rate) - cardiac arrest (heart stops beating) - hyperthermia (overheating) Each of these symptoms, either directly or indirectly, can be fatal.

Answer 150

Along with heroin (and other opiates), the major CNS depressants are alcohol, barbiturates, and benzodiazepines. Although benzodiazepines are less dangerous than the other three types of depressants when taken alone, in combination with the others even moderate overdoses can be fatal. Recall from your readings that barbiturates (e.g., Seconal) are an old class of sedative that has global inhibitory effects on brain function. Benzodiazepines (e.g., Valium) are a class of sedative-tranquilizers developed to replace barbiturates. These Valium-type drugs have a more specific mode of action (enhancing GABA transmission) and are used to manage anxiety as well as sleep disturbance. Depression of the CNS and inhibition of sympathetic nervous system activity results, most obviously, in decreased arousal, heart rate and breathing. The symptoms of overdose from CNS depressants include: - coma - respiratory failure - bradychardia (excessive slowing of heart rate) Each of these symptoms can be fatal. Because of the small margin of safety, uncertain potency, and rapid route of administration (IV injection) of street heroin, overdose is a constant risk. In contrast, alcohol has a high margin of safety, clearly defined potency, and slow route of administration (oral - gut), making alcohol overdose extremely unlikely. The LD50 of alcohol for an adult male is 0.5 %, which is more than 8 times the legal limit for driving (0.08%) in Ontario. On rare occasions a person may bypass the normal regulatory mechanisms (e.g., instead of swallowing alcohol they ingest it through a tube stuck down their throat - a practice on some college campuses called "funnelation"). The large volume of alcohol that can be consumed in this manner can lead to overdose. More commonly, a person will die from complications associated with heavy drinking, such as inhaling vomit into their lungs after they have passed out. Overdose is extremely rare in the case of hallucinogens (LSD, mescaline), and virtually nil in the case of marijuana. Overdose does occur in the case of hybrid stimulant-hallucinogen drugs (MDMA, Ecstasy). Hyperthermia is a particular risk in overdose from MDMA. While overdose is the primary form of acute toxicity, it is not the only one. A number of drugs appear to cause irreparable structural or functional damage following a single dose. For example, at least one study has found significant impairment in mental function in subjects who had taken MDMA/Ecstasy only once. The drugs that are most likely to cause this type of acute toxicity without killing the user are solvents.

Answer 151

These include gasoline, airplane glue, nail polish remover, and certain chemicals used to dissolve factory grease. These drugs are designed to break down the chemical structure of hydrocarbons - molecules comprised mainly of carbon and hydrogen. Because organic structures, and particularly fatty tissue, are made up of hydrocarbons, ingestion of these drugs leads to the breakdown of these structures. Specifically, the tissue that holds neurons in place (glia) in the brain is damaged by solvents. The fatty tissue (myelin) that insulates the neural axons is also damaged by solvents. As a result, the ability to effectively transmit signals (action potentials) is compromised by solvent use. A final kind of acute toxicity occurs when drugs are chemically modified or mixed with substances that are themselves poisonous. As noted previously, the amphetamine derivative, para-methoxy-amphetamine (PMA; street name, "death") can kill the user immediately regardless of the size of the dose taken. Adulteration of Ecstasy tablets with strychnine or other poisons is another common cause of acute toxicity not due to overdose. As noted previously toxicity can be distinguished in terms of time frame and location (brain/body). In the case of acute toxicity that leads to death this damage can occur in the brain (e.g., neural structures) and body (e.g., heart). In the case of non-fatal acute toxicity, like that induced by solvents, the damage is primarily restricted to the brain.

Answer 152

When a drug is taken repeatedly, it will often damage both the body and the brain. The best example of chronic toxicity is alcohol. CNS stimulants (cocaine, certain amphetamines) can cause chronic toxicity. However, the range of effects is generally less pervasive than for alcohol. Interestingly, chronic use of heroin appears to cause little if any damage to the body or the brain of the user in terms of impaired function or tissue death. Instead it is the risks associated with IV injection and needle sharing (e.g., hepatitis, HIV, AIDS) that are dangerous to heroin users.

Answer 153

Toxicity in the body due to chronic drug exposure usually involves disturbances in the processes that are otherwise designed to metabolize and process food and waste. The liver is a critical site for both structural (loss of tissue) and functional (impaired operation) toxicity. Alcohol and its metabolite acetaldehyde will initially (i.e., after heavy drinking) alter the composition of the liver, increasing the levels of fat there. If heavy drinking persists for months or years this can lead to hepatitis (impaired liver function) and ultimately cirrhosis (liver cell death). Very large quantities of alcohol must be consumed to reach this stage because the liver is extremely efficient at repairing itself. Because alcohol is water soluble, and water is located everywhere throughout the body (and brain), heavy drinking will ultimately alter the structure and function of most internal organs. Because it is a dehydrating agent it alters water volume, and over time can lead to hypertension. Because it can substitute for natural sugars (e.g., glucose) it can disturb normal energy transfer processes (e.g., insulin secretion and cellular respiration) leading to diabetes. By altering the pH balance of mucous membranes in the throat and mouth, it can promote throat cancer particularly in those already at high risk (e.g., smokers). This effect can also lead to ulcers in areas that are normally acidic (e.g., stomach), and to atrophy in water-laden tissues like skeletal muscle. Most dramatically, as a very small molecule, alcohol has the ability to enter the cells directly and to disturb the process of transcription. Transcription is the means by which cells synthesize new tissue (e.g., protein) for maintenance and repair by reading the DNA code. Alcohol-induced disturbances in the ability of cells to read the DNA can thus result in mutations in the newly synthesized tissue. The damage to the body caused by chronic heavy drinking is both structural (loss of tissue) and functional (impaired operation without loss of tissue). The same is true for alcohol-induced brain damage.

Answer 154

As noted in previous modules, alcohol readily diffuses through the blood-brain barrier (due to its small size). Once inside, alcohol distributes itself evenly throughout the brain because of its high water-solubility. Although the brain is remarkably resilient to the effects of chronic heavy drinking, other factors increase the likelihood of structural or functional damage.

Answer 155

Alcohol will displace glucose in the brain and may be used to generate energy by brain cells. This process can persist for long periods of time. However, because alcohol contains calories like food, it is common for long-term alcoholics to progressively shift away from food as a source of calories and rely primarily on the alcohol. Food contains vitamins essential to protein synthesis and cellular repair. One vitamin in particular - thiamin (also known as B1) - has been critically implicated in the brain damage associated with chronic heavy drinking. Lack of thiamin can lead to atrophy in the structures of two tiny but critical structures deep in the brain. These structures are called mammillary bodies, and they are involved in the consolidation of memory (through protein synthesis). Alcoholics who fail to take in sufficient thiamin because they get their calories from alcohol instead of food, often exhibit damage to the mammillary bodies.

Answer 156

The structural damage to the mammillary bodies often translates into a functional disturbance known as Korsakoff's Syndrome. Individuals with this disorder have profound amnesia. Specifically, they lack the ability to form new memories. As a result, while they may be able to recount childhood events accurately and in great detail, they have no recollection of things that happened since the onset of the syndrome (i.e., since the structural damage). A person with Korsakoff's syndrome may see his nurse three times a day every day for 10 years, and each time react as if it were the first time they'd met. In addition to memory, problem solving, abstract reasoning, decision-making, and complex psychomotor skills are often disturbed by chronic heavy drinking. These functional deficits also appear to derive from structural damage, although in this case the damage may involve cortical as well as deep brain structures. This figure shows the brains of a normal person on the left and a chronic alcoholic on the right. These are simulated images that might be seen in a CAT scan - which is simply an X-ray of the brain. The pictures are taken as if the camera were aimed directly down the axis of the person's body from the top of his head. Thus, the left side of each picture would correspond to the spot next to the person's left ear, and the right side would correspond to the spot next to his right ear. The pictures themselves are cross-sections of the brain as if the top of the skull had been removed and the brain tissue shaved off by 2-3 inches. The most obvious contrast between the two pictures is the enlarged gaps in the brain of the alcoholic. These gaps are called ventricles and are filled with fluid. The increased size of the ventricles reflects the fact that large amounts of cells are missing. That is, the enlargement of the ventricles represents the space left by brain cells that have died and been excreted from the body (by way of the cerebrospinal fluid). While it is common to see these kinds of enlargements in patients with Korsakoff's syndrome, they are not necessary. Likewise, a patient may display these enlargements and not manifest the behavioral impairment of Korsakoff's. In general, structural toxicity is a stronger predictor of functional toxicity than vice versa. If the tissue is gone (structural), the purpose it served is likely to be impaired (function).

Answer 157

Alcohol; Heroin It is hard to overdose (acute toxicity) on alcohol because of its relatively high LD50/ED50 ratio and slow route of administration (oral). However, alcohol is very likely to produce liver and brain damage (chronic toxicity) when consumed heavily over time. This contrasts with heroin which has a low LD50/ED50 ratio and rapid route of administration (IV injection) and therefore high risk of acute toxicity, but does not seem to damage the brain or the body when taken chronically without overdose.

Answer 158

The second key feature of drugs, which distinguishes them from non-drug reinforcers with respect to HARM, is addiction. As noted in earlier modules, addiction need not be exclusive to drugs, nor are all drugs addictive. However, the likelihood of addiction developing with the use of psychoactive drugs is much greater than it is for non-drug reinforcers. There are three basic levels of involvement with psychoactive substances: Use, Abuse, and Dependence. Addiction most closely corresponds to Dependence. However, only a minority of individuals progress to this level. Moreover, the transition is rarely if ever instantaneous. Instead, there appears to be a trajectory to dependence that varies in accordance with increasing substance use. This trajectory varies for different substances: It is extremely rapid for cigarettes (weeks or months), and much slower for alcohol (years). For a given substance, there are also large individual differences in the trajectory curve, with some "high-risk" individuals accelerating quickly from use, to abuse, and then to dependence, and others progressing much more slowly. We have already discussed some of the factors that constitute high risk (e.g., low D2 dopamine receptor density; family history of alcoholism).

Answer 159

Occasional administration of drugs with no appreciable consequences in terms of health, professional or social functioning constitutes substance use. Social drinking, occasional smoking of marijuana, and experimentation with cigarettes are normative behaviours judging from statistics. When these behaviours begin to cause unwanted consequences, most individuals will stop doing them or cut back. In the case of cigarettes, alcohol and marijuana, peer group influence plays a powerful role in continued use. In contrast, family role models (e.g., a parent who smokes) do not have as great an instigating effect. Family rules and values can act as a constraint or moderator of peer group influence. In particular, they can foster independence in decision-making, and self-esteem.

Answer 160

This module will begin our discussion of the five major theories of addiction and how they correspond to the major paradigms in psychology. The focus of this week will be the first three paradigms to emerge historically, and how each of these attempted to explain addiction. Fred is the son of an alcoholic. By the time he is 18, Fred himself exhibits many of the signs of alcoholism. To what can you attribute Fred's apparent slide into alcoholism? The answer is, "It depends." It depends on which factors you believe best account for the familial transmission of alcoholism. If you believe in the "nature" (i.e., biology) side of the debate, you would focus on the fact that Fred and his father, (and probably his grandfather), share a set of genes that give rise to the following characteristics. (a) A resistance to the impairing effects of alcohol (i.e., tolerance). (b) A tendency to experience the excitatory effects of alcohol rather than its sedative effects. (c) A tendency to experience a stronger disturbance in serotonin function as an after-effect of drinking and a strong restoration of serotonin function when actually drinking. In contrast, if you believe in the "nurture" (i.e., upbringing) side of the debate, you would point to factors related to growing up in an alcoholic family. These include the following: (A) Lack of emotional stability and bonding during early childhood. (B) The development of pathological coping responses to this emotional instability. (C) The modeling of maladaptive coping responses to stress and emotion, particularly, the use of alcohol as a means of self-medication and as an excuse for irresponsible behaviour. Regardless of whether you took the nature or nurture side of the debate, the evidence you cite would be valid. In other words, alcoholism and addiction in general are multi-faceted problems that involve both nature and nurture. The perspective you adopt does not reflect the validity of the evidence; one side is not "more right" than the other. Your perspective reflects which evidence is most persuasive TO YOU. This is a matter of opinion, not science. The next two modules will introduce you to the major theories of addiction - the ways that people have tried to explain its many aspects. The evidence put forward by each of these theories is equally valid. Indeed, the "true" explanation of addiction probably involves evidence from all these theories. For the purpose of understanding, it helps to break down the evidence and assertions made by the different theories. From a practical standpoint, it also helps to consider the different perspectives because, in any given case, one theory may be more applicable than another. That is, nature may play a bigger role in the addictive behaviour of one person, while nurture plays a bigger role in the addictive behaviour of another.

Answer 161

The term paradigm, means "conceptual framework." It includes certain assumptions about the causes of a certain event, which determine the kinds of questions that are asked about that event, and the kinds of evidence that is sought to explain it. There are 5 major paradigms that have emerged to explain addictive behaviour. These paradigms correspond roughly to the major paradigms in psychology. These paradigms have emerged in the past 125 years, since the advent of the "modern" discipline of psychology in the late 19th century. The paradigms reflect not only the assumptions of their advocates but also the attitudes and assumptions that were prevalent at the time they first emerged. Some ideas may seem "crude" or uninformed. However, this assessment must be placed in historical context, given that the technology we now have at our disposal was not available 100 years ago.

Answer 162

The table shows a direct correspondence between the psychodynamic and humanistic-existential theories of addiction and these paradigms of psychology. The correspondence between the remaining theories and their respective paradigms is not quite so neat, but the basic assumptions of these theories is essentially consistent with their paradigms.

Answer 163

The psychodynamic theory of addiction developed in the 1890's and flourished into the middle part of the 20th century. The principal author of this theory was Sigmund Freud, the Viennese neurologist whose ideas about the link between sexuality and human behaviour stirred great controversy in Europe during the reign of the prim and proper Queen Victoria. The most important innovation Freud introduced to the study of addiction and psychology in general was the idea of the Unconscious. According to Freud, the unconscious was a region of the mind that was unavailable to awareness or "introspection" (looking inward). At the same time, Freud argued, the unconscious played a major role in mental illness and addiction. In particular, the unconscious was believed to undermine our conscious intentions and beliefs and to impair adaptive functioning by creating mental conflict. Until this conflict was resolved, the person could not get well mentally and would thus continue to act in maladaptive ways (e.g., to abuse alcohol or drugs). The term psychodynamic literally means "mind in conflict." The paradigm contends that there are 3 components of the mind that are constantly at odds with one another.: 1. Ego - Mostly Conscious - Conscious Thoughts and Behaviour - Operates on Reality Principle - Rational Decision-Making - Attempts to Regulate Id and Superego 2. Superego - All levels, but mostly Preconscious - Mostly Unconscious, partly conscious - Contains Society's Rules and Expectations - A caricature of the "Right Thing to Do" - Contributes to Neurotic Feelings like Guilt and Shame 3. Id - Unconscious - Unconscious Urges and Impulses - Operatates on Pleasure Principle - Child-like, Irrational Decision-Making - Attempts to Gratify Needs (appatite, sex, anger) Adaptive functioning occurs when the degree of conflict between these components has been reduced to a modest level (conflict never disappears completely).

Answer 164

The largest part of the mind is the Id, which literally means the "it." The Id contains urges and impulses such as the desire for food, sex, and aggression. The Id roughly corresponds to "drive-based" behaviours or motivations. Not surprisingly the Id is believed to predominate during childhood. The Id is completely irrational and "child-like." Freud said that the Id operates on the Pleasure Principle - do what feels good.

Answer 165

The Ego is the logical part of the mind. It makes decisions and carries them out. It is the part of the mind that enables us to function effectively in the real world, doing things like studying or going to work, eating healthily, exercising and so on. The Ego is the rational counterpart to the Id. It operates on the Reality Principle - do what is practical and appropriate to do. The Ego is something that develops over time as a child matures. The older the person gets, the more Ego there is to make rational decisions and carry them out, and, presumably the less irrational, impulse-based behaviour the person will display. Note: The term Ego does not have the same connotation as it does today. For example, a person with a "big Ego" means someone who is full of him or herself and extremely self-centred (unable to see another's point of view). In Freudian terms, such an individual would be better described as having a "big Id." To Freud, a big Ego was a good thing, because it indicated an emotionally mature individual who made rational decisions, and kept his/her impulses under reasonable control.

Answer 166

The third part of the mind, according to Freud, was the Superego. This term simply means "the above-Ego." The superego was the container of the values and lessons of society. It was kind of a caricature of The Right Thing To Do. For example, the Superego contained social rules like "always be fair" "never lie, cheat, or steal," "cleanliness is next to godliness," "do unto others as you would have them do unto you," "respect your elders," "wait your turn," etc. As children grow up, they learn these lessons from their parents and teachers and incorporate them into their mind in a rather unreflective way. As a result, these rules can exert a powerful, even oppressive force on the spontaneous desires and interests of the child. Spontaneous exploration of a mud puddle is not consistent with "cleanliness is next to godliness." The healthy joys and wonders of childhood often came into direct conflict with the superego. When faced with this conflict, the superego might assert itself through the familiar feelings of "guilt" or "shame." It was the job of the Ego to keep the lid on both the Id and the Superego. Failure to achieve this goal, would result in various forms of mental or behavioural disturbance. If the Id was not kept in check, the person might act out in aggressive or impulsive ways (e.g., criminal behaviour). If the Superego was not kept in check, the person might become "neurotic" - that is, plagued by doubt and lack of confidence in themselves and the acceptability of their desires and needs. Either of these imbalances was indicative of "mental illness" to Freud.

Answer 167

The Id. The impulsive, child-like, irrational part of the mind that promoted drive-based behaviours was overactive in alcoholism or addiction.

Answer 168

If an over-active Id (or Superego) were causing problems, one could conceivably learn how to modify these forces directly. However, the Id in particular, and the Superego to a lesser degree, was believed to operate at an unconscious level. That is, the person was unaware they were being influenced by Id-based drives or Super-ego based rules. It was therefore very difficult to modify these forces. Freudian therapy used various techniques to increase insight and to literally "make the unconscious, conscious." However, this often took years of intensive treatment, by which time a good deal of damage (e.g., addiction) could have been done. The emergence of conscious awareness is a natural byproduct of childhood development. By the time a child is 5 she or he will be able to reflect on their behaviours and be aware of themselves as an actor or "an agent" whose actions bring about certain effects. Prior to this the child lacks this capacity and assumes that the whole world thinks and feels like they do. According to Freud, to achieve a healthy Ego, the child must pass through several developmental stages, each of which involves a particular challenge. Failure to meet this challenge at the time it occurs will result in "fixation" at that stage. The person gets stuck psychologically at that level of emotional development, even as their body continues to grow. Until that challenge is met, the subsequent challenges in the path to emotional maturity could not be addressed and the person would remain emotionally child-like. Clearly, this could cause serious problems for an adult trying to cope in society.

Answer 169

The earliest stage in the developmental sequence, which lasts from 0 to 2 years is called the Oral Stage. The primary challenge of this stage is overcoming dependency. Successfully weaning from the breast was an indicator that the child was differentiating from its mother, it was becoming a person rather than simply an appendage to its mother. However, emotional detachment or separation from the mother was often a much more complex challenge than weaning. Freud believed that people who suffered from alcohol or drug addiction, had become fixated at the oral stage of development. Notice that this is a very primitive stage, and addicts were presumed to be emotionally extremely immature. According to Freud, the source of gratification (mother's milk) was merely transferred from the original object (the breast) to another object (the alcohol bottle, the cigarette, the opium pipe). The source of gratification was taken in by mouth, that is, orally. Fixation at the Oral stage was not the child's fault. Indeed, the child is only operating on instinct at this early stage. It is the primary caregiver, most often the mother, whose behaviour accounts for the fixation at the oral stage, according to Freud. Children at the oral stage have no way to communicate their needs except by crying. At the same time, they cannot yet walk or manipulate objects and are thus completely dependent. This can lead to very intense expressions of need. Crying can interrupt the mother's sleep, it can interfere with her other activities and can aggravate her when she herself is feeling needy.

Answer 170

(1) She may defer to the child and put their needs first. (2) She may appear to put the child's needs first but let the child know she resents doing so. (3) She may not put the child's needs first. According to Freud, if the majority of the time, the mother responds with option 2, the child learns that their needs are somehow bad - they are not allowed to feel hungry or lonely or uncomfortable. That is the implicit lesson of a resentful mother. If the mother responds with option 3, the child may simply be ignored. In this case, the child does not get the feedback from an outside source that is necessary to confirm their existence. Like the proverbial "tree that falls in the forest" - if no one is there to hear it, perhaps it didn't really fall at all. In a subtle, but powerful way, the child whose needs are ignored thus develops a profound doubt about their own existence and may feel that they are "invisible" to others. Either option 2 or option 3 can result in fixation at the Oral stage. The child remains dependent, but develops coping strategies to limp onward despite their emotional limitations. According to Freud, when the child reaches adolescence, she/he will have an opportunity to experience drugs and alcohol for the first time. Alcohol for example, will bring comfort unconditionally. Thus, the child who experienced option 2 during the oral stage will find the nurturance they lacked at age 1 or 2. For the child who experienced option 3, being ignored, alcohol can bring the illusion of importance and power. This child may feel emboldened by alcohol and able to make demands on others for the first time. At the same time, the fact that alcohol is always there - the bottle is always at hand - means that the person's emotional needs will never be ignored again.

Answer 171

In short, the person who is fixated at the oral stage of development is extremely liable to abuse alcohol or another substance as a transfer of dependency needs. This is consistent with the modern term for drug addiction, which is "substance dependence." From a motivational standpoint we can say that alcohol and drugs will be especially likely to be abused by someone with this developmental history because alcohol and drugs are more negatively reinforcing to him or her. Recall that negative reinforcement drug use is motivated by the need to "feel better" or to achieve "relief," as opposed to reward. The child who remains fixated at the oral stage nevertheless must make their way through the years of childhood to reach adolescence and discover drugs and alcohol. How do they survive during these years without an emotional foundation?

Answer 172

According to Freud, the fragile Ego is protected from the overwhelming emotions of the Id (e.g., rage) and Superego (e.g., shame) by mental processes called Ego Defenses. Ego Defenses are universal and are necessary to prevent us from being engulfed by powerful emotions. For example, if we act in a way that is inconsistent with our values and beliefs (e.g., we ignore a street person who is begging for change), we may feel a pang of guilt. To ease the discomfort caused by this guilt we may tell ourselves (I'm in too much of a hurry, or If I gave to every beggar, I'd soon be on the street myself). These kinds of mental defenses are commonly referred to as Rationalization. As it happens, Rationalization is one of several ego defenses Freud recognized. Ego defenses could be adaptive or maladaptive. For example, most people cannot afford to give to every street person they encounter, so some degree of rationalization helps a person deal with irrational guilt. On the other hand, excessive ego defenses become maladaptive when they prevent us from feeling or seeing appropriate emotions rather than shielding us from inappropriate ones. Because of the extreme circumstances experienced by a child who is shamed for expressing their dependency needs or whose needs are ignored, the ego defenses that develop to cope with these circumstances are often equally extreme. While they help the child to survive during this developmental period, they impair healthy functioning, once the child reaches maturity.

Answer 173

According to Freud and others, the most common ego defense used by children who experienced shame, abuse or neglect, and who are thus prone to addiction, is Denial. Denial is one step beyond Rationalization. In Rationalization we acknowledge the conflict, but give ourselves an excuse. In Denial, we do not acknowledge that the conflict even exists. In the case of the street person, the person engaging in Denial (who does not give a handout) might come to believe that the beggar wasn't even there, or that the person wasn't really a beggar. This is clearly a pathological distortion of reality. It is extremely common for clinicians to see Denial in substance abusers, particularly alcoholics. The person engaging in denial is protecting his ego from the crushing burden of guilt that would accompany the recognition that he nearly killed someone due to drunk driving and that his drinking behaviour has caused his wife to leave him. The denial that is preventing him from assuming responsibility now (a maladaptive response) protected him from assuming responsibility for being mistreated or neglected by his caregiver when he was a child (an adaptive response). Thus, the ego defense that enabled the child to survive has outlived its purpose and now makes it difficult for the person to get the help they need to change. Denial has become a pathological ego defense.

Answer 174

Denial is a pervasive feature of alcoholism. Scientists interested in this phenomenon have noted that the same structures that enable insight and self-awareness (i.e., the frontal lobe of the brain) are also the structures that are most vulnerable to the initial impairing effects of alcohol, and eventually to chronic toxicity after years of heavy drinking. These findings suggest that the pharmacological effects of alcohol may contribute to the process of denial during a drinking episode and to the intensification of denial as chronic heavy drinking persists.

Answer 175

unmet dependency needs, fixation at the oral stage, and a pathological ego defense

Answer 176

Alcoholics Anonymous (AA) is a self-help group for alcoholics developed in the 1930's by two individuals who were themselves alcoholic. One of the founders was a physician who had been introduced to the principles of Freud and the Psychodynamic Paradigm. These principles clearly inform some of the basic assumptions and practices of AA today. The fact that AA is one of the most successful treatments for alcoholism provides support for the validity of psychodynamic principles. A standard practice of AA is for the speaker to introduce himself by saying, "Hi I'm John Doe, and I'm an alcoholic." This is designed to counter the ego defense of denial. The members of the group then respond by saying "Hi John." This simple response acknowledges the speaker and confirms that he is welcome there without judgment. This counters the feeling that one is invisible or ignore-able and the possible feelings of guilt or shame for "being bad" (i.e., being an alcoholic). A core feature of AA is the belief in a Higher Power who will guide the alcoholic to a sober life. This is designed to transfer the dependency needs from the bottle to a more acceptable form of caregiver. The fact that real peace and tranquility can come from spiritual pursuits and prayer supports the appropriateness of this approach. Whereas substance dependence is maladaptive, spiritual belief is tempered by a balance between responsibility (doing the right thing) and realism (acknowledgement that many things in life are outside of one's personal control). Thus, the dependence upon a Higher Power asserted by AA facilitates rather than deters living productively in the real world.

Answer 177

The Humanistic-Existential paradigm developed in response to the decline of traditional religion in the 19th century and the tragedies of the first and second world wars which seemed to confirm that "god was dead." According to the Humanistic branch of this paradigm, the core principle is that all human beings are inherently good. Mental illness in general and addiction in particular arise when the inherent goodness of the individual is denied. To Humanists, the inherent goodness of the individual is defined by the unique values, beliefs and behaviours of the Self. Society often tries to force an individual to conform to arbitrary values. This can lead the individual to deny his or her own values and to depreciate the unique Self. Health comes from the restoration of belief and acceptance of the unique Self.

Answer 178

The acceptance or denial of the unique Self begin in infancy. Infants lack the capacity of object constancy. That is, if an object disappears from sight, the infant believes it no longer exists. If you show a young infant a doll, then hide it behind your back, the infant will not attempt to look for the doll behind your back. The notion that the doll (i.e., the object) continues to exist (i.e., is constant) is foreign to the infant. This is why very small children are universally thrilled by the game of Peek-A-Boo. When the adult opens their hands and re-appears, the child experiences it as sheer magic, because they believed that the adult, who was no longer visible, was in fact "gone."

Answer 179

Object Relations refers to how the child comes to relate to objects in its world based on the growing sense of object constancy. The most important "object" in this scenario is the primary caregiver (usually the mother). If the mother consistently appears when beckoned (e.g., when child cries), the child learns that the mother is in fact constant, that she does exist even when the child cannot see her. This gives the child a sense of trust in his/her own beliefs, and faith that the mother will return when needed. If, on the other hand, the mother does not respond consistently, the child doubts her constancy. To achieve control over the unpredictable environment (especially the mother), the child learns to modify his/her behaviour to ensure that the mother will return. In other words, the child develops a False Self that meets the needs of the mother, rather than his/her own needs. They also learn that if they do assert their own needs, they run the risk of abandonment. The focus on disturbed object relations in the early childhood years is similar to the psychodynamic model.

Answer 180

The main difference is that Humanists believe that the pathology lies in the child's attempt to conform to the needs of others rather than their own (i.e., to create a False Self), whereas the Psychodynamic theorist believes that misplaced dependency and denial are the sources of pathology. Alcohol and drugs are especially reinforcing to someone with a False Self because they do not have to act a certain way in order to get their needs met. Unfortunately, as long as they are using alcohol and drugs instead of getting their reinforcement from other people, they remain isolated. Health comes from validating the inherent worth of the True Self of each individual. To Humanists this is called "unconditional positive regard." Whatever a person feels or believes is inherently good and worthwhile because it is theirs; there is no need to justify it. Advocates of the Existentialist branch of this paradigm also believe in the inherent worth of each individual. However, Existentialists believe that human beings have the capacity for both good and evil. The Existentialist argues that the core to mental health is the acceptance of responsibility for choosing good or evil. If you choose "good" you reap its rewards. If you choose "evil" you must be prepared to face its consequences. Existentialists focus on lack of responsibility as the source of pathology in substance abusers. Their position is supported by research on the concept known as locus of control.

Answer 181

Locus of control is the personality dimension that describes the extent to which one believes he or she has control over what happens to them. A person with an internal locus of control believes they control their own fate. Control resides (i.e., has its "locus" or location) inside the individual. Such people believe that hard work pays off eventually. A person with an external locus of control believes that fate or forces beyond their control determine what happens to them. Control resides outside the individual. Such people believe that hard work does not pay off; the government or corporations will take it all any way. Luck and fate play a big role in the lives of people with external loci of control, whereas effort and personal responsibility play a minor role. Alcoholics and drug addicts do display much higher levels of External locus of control than members of the general population, supporting the Existentialist perspective. Alcoholics and addicts who benefit from treatment also display a shift toward a more internal locus of control indicating that they see themselves as more effective in determining their own fate and that this is part of their recovery. Another interesting phenomenon that supports the Existentialist perspective is called "Self-Handicapping." This is the tendency for addicts to blame the substance for their misfortunes. For example, alcoholics will display much more impairment on a skilled task after they receive a drink that they believe contains alcohol but in fact does not (i.e., a placebo) than will non-alcoholics. In other words, the mere belief that one has consumed alcohol is enough to make alcoholics behave in a "helpless" manner. In a similar way, bad behaviour performed while intoxicated, is blamed on the alcohol. e.g., "Why did you beat your wife? I was very drunk at the time. Why did you forget the rent money? I was very drunk at the time, etc." To the Existentialist, the alcoholic or drug abuser will not recover until they assume responsibility for their behaviour, first and foremost the responsibility they have for learning how not to continue to use/abuse a substance.

Answer 182

AA has also incorporated elements of the Humanistic-Existentialist paradigm. For example the notion of Fellowship is central to AA. Through the program, the alcoholic learns that he/she is not alone and that the concerns and values are honoured by others. Slowly, through feedback and endorsement (unconditional positive regard) from other members of the group, the alcoholic regains access to his/her True Self and the confidence to function without alcohol. At the same time, AA requires a high degree of personal responsibility from the member. Complete abstinence from alcohol is the number one responsibility. Although relapse to drinking will not be punished (the member can always return regardless of the number of times they fall off the wagon), the AA member is strongly urged to use all resources to maintain sobriety (e.g., call the sponsor, go to a meeting). This sense of collective care and personal responsibility is embodied in the AA saying: "You can't do it alone, but only you can do it."

Answer 183

disturbed object relations Objects (including people) are permanent; their existence does not depend on a person's behaviour. The belief during childhood that the existence of a caregiver depends on one's behaviour is called DISTURBED OBJECT RELATIONS. The FALSE SELF is a byproduct of disturbed object relations in which the child modifies their TRUE SELF to conform to the needs of others (i.e. the caregiver). OBJECT CONSISTENCY is the belief that something continues to exist even if it is no longer visible. OBJECTIFICATION is a concept unrelated to this topic.

Answer 184

The Id is the source of drives and urges. It operates on the Pleasure Principle. Its contents are unconscious - that is, unavailable to deliberate inspection. However, the Unconscious can intrude on conscious thoughts and behaviour and undermine them (e.g., a conscious decision not to drink). In a healthy individual, the Ego progressively gains control over Id impulses during the childhood years. In an unhealthy individual, the Ego is compromised when the individual fails to master a challenge in the course of development. In addiction, a failure to successfully master dependency on the caregiver at the Oral Stage result in the individual become....

Answer 185

denial; it prevents the individual from seeking the help they need Ego defenses are necessary and adaptive when they protected the conscious mind from inaccurate unconscious processes (e.g., excessive guilt or anger). Ego defenses become pathological when they insulate the individual from accurate unconscious (or conscious) information (e.g., awareness that they have a problem with alcohol or drugs).

Answer 186

self; responsibility The Humanistic branch says that addiction reflects a reliance on drugs by someone who does not acknowledge their own self-worth and who has always conformed their values and behaviour to the wishes of others (i.e., developed a False Self). Accepting the inherent worth of one's own values and beliefs (i.e., the True Self) is the path to recovery according to this model. The Existential paradigm argues that individuals are not inherently good or evil. Instead, it is each individual's responsibility to choose good or evil, and to face the consequences of this choice. Drinking and drug use reflect a failure to assume this responsibility. Recovery from these conditions will come from doing so.

Answer 187

The major theories of addiction and how they map onto the major paradigms in psychology. Sigmund Freud's psychodynamic theory of addiction, including the mechanisms and antidotes to this problem (e.g., AA). How disturbed relations between the ?self? and others have been implicated in addiction by the humanistic-existential paradigm. The role of personal responsibility in recovery from addiction according to the humanistic-existential paradigm.

Answer 188

Do you remember the smell of a particular dessert your mother (or father) baked when you were a child? When you smell that smell, what are the thoughts and feelings it conjures up? Are they happy feelings? Do they remind you of particular people or events? Do you feel a sense of longing? Do they make you hungry? - Think about It. Smell is a very "evocative" sense. It evokes or "calls forth" many rich associations. It is also one of the most primitive senses and one of the most strongly wired with the neurons in the limbic system, the system that governs motivation, emotion and memory. It is not inaccurate to say that what you are experiencing when you are responding to a familiar aroma from childhood is an "emotional memory." You will recall that this is precisely the term that was used to describe the experience of heroin addicts when they returned to the corner where they used purchase drugs, or when they smell the familiar scent of the heroin being cooked in preparation for injection. These memories themselves are sometimes so powerful that they can spur the person on to drug use, even if he or she were not motivated to use beforehand. This module will examine the role of learning and memory and the biological elements of learning and memory in drug use and addiction.

Answer 189

The Behaviourist/Learning Paradigm sprung up in the 1930's as a reaction to the psychodynamic model. Behaviourists emphasized the role of observable and measurable evidence over abstract or "unconscious" processes that could not be demonstrated or tested. Pavlov was one of the most important figures in the Behaviourist movement. In his landmark studies with dogs, he demonstrated that living organisms can acquire an association between a neutral or meaningless stimulus (e.g., a bell) and a motivating or meaningful stimulus (e.g., meat) through frequent pairing of these stimuli. The process he discovered was classical conditioning, one of the most fundamental forms of learning. Through classical conditioning, the once meaningless bell could acquire the ability to make the dog salivate, as if it were anticipating or expecting meat. Indeed, Pavlov claimed that the bell (the "conditioned stimulus") could be thought of as the First Signal System - a cue that something important was about to occur. Classical conditioning plays an important role in numerous kinds of adaptive (e.g., mating) and maladaptive behaviour (e.g., phobias).

Answer 190

Wikler noticed that morphine addicts who had been successfully treated for their addiction (they no longer experienced withdrawal symptoms or felt cravings for the drug) would often relapse when they returned to the neighbourhood where they had previously bought or used morphine. Sometimes relapse would occur even after many months had elapsed. Based on interviews with individuals who had relapsed, Wikler proposed that the old neighbourhood was acting as a conditioned stimulus or a trigger for morphine, much like the bell had become a signal for meat to the dog. And just as the bell acquired the ability to evoke salivation, so to did the neighbourhood acquire the ability to evoke an appetite for morphine. Wikler's idea has since received tremendous scientific support. Indeed, classical conditioning in particular and learning in general, are now considered to play an integral role in addiction. Several decades after Wikler put forward his idea of "conditioned relapse," scientists interested in this process explored the role of cues in craving for alcohol. Monti and his colleagues at Brown University administered an in-patient treatment program to alcoholics. At the end of the treatment when the patients were no longer experiencing withdrawal symptoms and were fit to return home, Monti gave them a little test. He poured each patient a glass of his favourite alcoholic beverage. He then had the patient look at, then hold the glass, and deeply inhale the smell of the drink. He did not allow them to drink it. Before undergoing this "cue exposure" procedure, Monti placed dental gauze into the patients' mouths. Each of the rolls of gauze had been carefully weighed beforehand. After a standard period of exposure to the drink, he removed the gauze and re-weighed it. The difference in weight reflected the amount of saliva the patient had produced during the cue exposure interval. Monti followed up these patients for an additional 6 months after discharge. To his astonishment, he found that the amount of saliva produced by each patient directly predicted his likelihood of relapse to alcohol at 6 months. The more saliva a patient produced during cue exposure, the greater the likelihood that he had relapsed 6 months later. Monti's evidence demonstrated that a classically conditioned response - salivation - could predict a complex behaviour like relapse (over and above all the emotional and social factors). This was powerful testimony to the role of basic learning processes in addictive behaviour. Another investigator, named Ludwig, who was a colleague of Wikler's, did some research showing that the number 1 drinking trigger for alcoholics was "tension." In other words, an internal state appeared to be a more powerful conditioned stimulus for alcohol than even the sight or smell of alcohol itself. Ludwig's data were consistent with many reports from relapsed alcoholics who said that depression or negative affect (emotion) were the immediate precursors to relapse. Subsequent research by Cooney and colleagues found that treated alcoholics who reported the strongest cravings when they underwent a procedure designed to make them feel briefly depressed ("negative mood induction"), were also the most likely to relapse 6 months later. In other words, the drinkers for whom a depressed mood was the strongest conditioned stimulus for alcohol were the drinkers most likely to revert to drinking when they experienced a depressed mood outside the treatment facility.

Answer 191

smell of alcohol; salivation negative mood; craving The conditioned stimulus is the signal for the reinforcer (alcohol). The conditioned response is the reflex that occurs when the conditioned stimulus is presented.

Answer 192

Some of the most compelling evidence for the role of classical conditioning in addiction comes from research on drug tolerance. In the early 1970's, an effort was undertaken to clean up the streets of New York. As a result, heroin addicts there were displaced from their usual neighbourhoods. At about the same time, there was a huge increase in the number of heroin overdose cases arriving at emergency wards of New York hospitals. Those individuals who recovered reported that they had taken their usual dose, just like always, but this time they were overwhelmed by the effect. It was as if they suddenly "lost their tolerance." This phenomenon led an investigator by the name of Seigel to propose that the neighbourhood might not only be a conditioned stimulus for the drug (heroin), it might also be a conditioned stimulus for the body's compensatory response to the drug. To test his hypothesis, he administered a standard dose of morphine to laboratory rats for several consecutive days. On each day, he measured the animals' pain sensitivity (measure of morphine's analgesic effects) prior to receiving morphine (baseline assessment) as well as after they had received the morphine. As expected the decline in pain sensitivity produced by the dose became progressively smaller with each day, reflecting the development of tolerance to the morphine. On a final test day, he divided the rats into two groups. The first group was assigned to receive their usual dose of morphine in a new room, one to which they were completely unfamiliar. These animals displayed a complete restoration of analgesia back to the levels displayed on the first day of drug administration. This was clear evidence of loss of tolerance induced by a change in the environment in which the drug was typically administered. To confirm that the body's compensatory response had indeed accounted for the tolerance observed in the animals prior to test day, Seigel gave the second group of rats an injection of salt water - a placebo designed to provide all the cues for the drug, in the absence of the drug itself. These animals received their injection in the same room they had always gotten it. Seigel found that the animals that received a placebo displayed a significant INCREASE in pain sensitivity relative to the level of pain they had displayed prior to the injection on the very same day. This evidence showed that the cues for the drug (the familiar room) had in fact induced a compensatory response (i.e., MORE pain sensitivity) by the body that was "unmasked" when the drug was absent (i.e., when the animals only received a placebo injection). This effect was similar to the withdrawal response we have discussed in previous modules. Indeed, Seigel described his effect as a conditioned withdrawal response, and suggested that this might be the process underlying cue-induced relapse in familiar situations. Although there have been refinements in the understanding of the processes that account for cue-induced relapse, Seigel's evidence did confirm unequivocally the critical role of classical conditioning in tolerance and the body's adaptation to chronic drug administration.

Answer 193

Classical conditioning focuses on cues and triggers for drug use. However, the consequences of drug use also play a critical role in maintaining it. Instrumental conditioning is the process that defines the strengthening of a response due to reinforcement and the weakening of a response by punishment. In the case of drugs, the powerful positive reinforcement (reward) or negative reinforcement (relief) they provide can often override the punishing consequences (hangover, withdrawal, criminal sanctions). The fact that the good part (the reinforcement) almost always precedes the bad part (the punishment) also serves to shift the balance toward continued drug use. Vuchinich and Tucker (1988) applied the concept of instrumental conditioning to predict patterns of drug use. In particular, they noted that drugs and alcohol are just one type of reinforcer among many possible reinforcers (social contact, work, sports, art and drama). They reasoned that the preference for drugs and alcohol over these other reinforcers could be predicted based on the cost/benefit ratio of drugs and alcohol relative to these other reinforcers. The fewer other reinforcers that were available, the more appealing drugs and alcohol became. Vuchinich and Tucker made 3 predictions about the relationship between availability of other reinforcers and the preference for drugs and alcohol.

Answer 194

The preference for drugs and alcohol varies inversely with the direct constraints on their consumption. This figure depicts the relationship between the cost of cigarettes and the number of cigarettes smoked per week by adolescents. The figure shows that the greater the cost of cigarettes (i.e., the stronger the constraints on cigarette consumption), the fewer the number of cigarettes smoked. This is the precisely the "inverse" relationship Vuchinich and Tucker predicted. Notice that the direct constraints prediction runs counter to the prevailing assumption that the reason adolescents smoke and drink alcohol is because these are restricted activities (the "forbidden fruit" theory). Vuchinich and Tucker's evidence directly contradicts the forbidden fruit theory.

Answer 195

The second prediction of Vuchinich and Tucker's Choice Theory was that the preference for drugs and alcohol would vary inversely with the availability of alternative reinforcers. Evidence from prisoners, who have access to contraband drugs but have little else in the way of reinforcement, (e.g., social life, work, sports, arts) supports this assertion. The figure below shows the per capita rate of drug use in prison inmates. The figure shows that a much greater proportion of prisoners use drugs than do members of the general population. Once again, the predicted inverse relationship can be seen: The lower the availability of alternative reinforcers, the higher the rate of drug use.

Answer 196

The final prediction of Choice Theory was that preference for drugs and alcohol would vary directly with direct constraints on alternative reinforcers. This prediction is illustrated by rates of drug use in the inner cities vs. the suburbs of major metropolitan centres in North America and Europe. People who live in the suburbs tend to have more financial resources to access alternative forms of reinforcement (e.g., country club, symphony, cottages). People who live in the inner cities tend to have fewer financial resources for such alternative reinforcers. The figure below depicts the direct relation between rates of drug use and constraints on alternative reinforcers. The figure shows that drug use is relatively low where constraints on alternative reinforcers are low (suburbs). Conversely, drug is relatively high where constraints on alternative reinforcers are high (inner cities). This evidence supports Vuchinich and Tucker's final prediction about drug use and choice. The evidence that stems from Choice Theory comes from animals given different degrees of access to drugs and alternative reinforcers. The findings provide powerful support for the role of social and environmental factors in mediating the decision to use drugs. When few options exist, drug use appears to represent the best strategy to maximize gain and minimize pain. This is the "hedonic" imperative of all living organisms (not just humans). Vuchinich and Tucker's data provide a powerful illustration of how environmental constraints lead to drug use and addiction in marginalized individuals, like aboriginal peoples, those who live in the inner cities, the elderly, and the under-educated. The fact that the same patterns emerge in animals given the same environmental constraints indicates that the "Choice" is not based on human constructs, like "self-respect" (or lack thereof), but rather on a basic cost/benefit tradeoff of survival.

Answer 197

increase marijuana use Direct constraints on marijuana consumption go down, therefore marijuana use should go up. This should be true, on average, across individuals. However, the more access you have to alternative reinforcers, the less your marijuana consumption will be affected (up or down) by a change in constraints on marijuana use. In other words, increased availability of alternative reinforcers to some extent insulates you to changes in the availability of drugs.

Answer 198

Whereas classical conditioning and instrumental conditioning apply equally to animals and humans, cognitive processes (thoughts, memories) and social learning (modeling, imitation) occur primarily, though not exclusively, in humans. Cognitive/Social Learning theorists believe that drug and alcohol use in humans are learned. However, they assert that the way in which this learning manifests itself is not primarily in basic responses like salivation or repetition of a reinforced response. Instead, these theorists argue that learning exerts itself through thoughts and images that are stored in memory. In addition, these theorists claim that we do not need to directly experience an event to learn from it. A huge amount of human learning occurs by observing the behaviour of others (and the good and bad consequences of that behaviour). Learning that occurs either by direct experience or by observation is stored in memory. These stored memories take a particular form called "Expectancies." An expectancy can be likened to a mental "If,…then…" statement. e.g., If the sky is cloudy, then it soon will rain. This expectancy is learned association stored in memory that enables us to anticipate events based on predictive information (the sky is cloudy). It also enables to take action in response to the expected event (e.g., take an umbrella to work). Expectancies can arise from classical conditioning, instrumental conditioning, as well as from social learning. Social learning involves observing the behaviour of others, and imitating those acts that were reinforced, while avoiding those acts that were punished. For example, if you watch a college student drink beer and have fun on a TV commercial, you yourself may be motivated to drink beer, even if you have never tasted beer before. This imitative behaviour would be based on an expectancy: If I drink beer, then I will have fun. Cognitive-Social Learning theorist have shown that elementary school students (i.e., too young to have drunken beer) who endorse statements on a paper-and pencil questionnaire like, "If you drink beer you will have fun" are more likely to drink heavily in high school and to become problem drinkers in college. In other words, expectancies can have a direct causal effect on the initial acquisition of drug and alcohol use as well as on subsequent problem use of these substances.

Answer 199

Cognitive Social Learning Theorists have specified 3 main types of expectancies Stimulus-Outcome Expectancies. 1. Stimulus-Outcome Expectancies: - e.g., If I am with my drinking buddy, Homer, then I soon will be consuming alcohol. The predictive event (the stimulus) is the "drinking buddy, Homer." The outcome is consuming alcohol. - Stimulus-Outcome Expectancies are acquired primarily through classical conditioning. - This type of expectancy would also contribute to the Emotional Memory of the heroin addict who returns to his old neighbourhood. - In this case, the expectancy might be "If I am at the corner of 31st and Main, then I soon will be shooting up on heroin." - It is important to note that these expectancies may not be consciously experienced as "If, then" statements. - In fact, it is much more likely that they are private assumptions or beliefs that we hold, even if we cannot articulate them. 2. Response Outcome Expectancies - correspond to the memories initially formed by social learning and reinforced by instrumental conditioning. - The example given at the outset of this portion of the module illustrates this type of expectancy: "If I drink beer, then I will have fun. " - Note: An elementary school child can hold this expectancy without ever tasting beer. However, if he has an opportunity to drink beer, his preconceptions may colour his experience. That is, he may believe he is having more fun than he actually is. This is sometimes referred to as a "self-fulfilling prophecy." I think I will have fun if I drink beer, so I do. - If the person really does have fun (i.e., if the alcohol makes him happy), his expectancy will be reinforced, and he will be even more likely to drink again. - To Cognitive Social Learning theorists, what has been reinforced is the expectancy or belief about the effects of beer, not the behaviour of drinking beer per see. 3. Self-Efficacy Expectancies - We know from earlier modules that the term efficacy when applied to a drug refers to its ability to achieve its intended effect (e.g., pain relief in the case of morphine). - Cognitive Social Learning theorists contend that efficacy can also be applied to the Self. - Specifically, Self-Efficacy refers to a person's ability to perform a particular behaviour in a particular situation. - Self-Efficacy Expectancies refer to the person's belief that he or she can perform a particular behaviour in a particular situation. - Put simply, a Self-Efficacy can be described as Confidence in a Situation. - Self-Efficacy expectancies can develop from classical conditioning, instrumental conditioning and social learning. - These types of expectancies are most relevant in the case of the drug or alcohol user who is trying to abstain from using drugs or alcohol (i.e., to stay "Clean," or "On The Wagon"). - Self-Efficacy Expectancies are most relevant in situations that present a high risk for relapse in abstainers. - e.g., If a friend offers me a drink, then I will be unable to abstain. - People who hold this type of expectancy are more likely to relapse than people who do not. - Moreover, the situation that evokes the expected outcome (i.e., failure to abstain) varies tremendously for different individuals. - e.g., If I am feeling sad or guilty, then I will be unable to abstain. - This type of self-efficacy expectancy may be relevant for a person who typically drinks to cope with negative mood states. - However, such a person may have "high self-efficacy" in the previous situation (i.e., being offered a drink by a friend) - that is they might have a lot of confidence to remain abstinent. - High self-efficacy = expectancy of success. Low self-efficacy = expectancy of failure.

Answer 200

all three types of expectancies may be evoked a stimulus-outcome expectancy a response-outcome expectancy a self-efficacy expectancy The stimulus-outcome expectancy might be: If I encounter an old drinking buddy, then alcohol will soon be present. The response-outcome expectancy might be: If I drink the alcohol, then I will blow my good record of sobriety. The self-efficacy expectancy might be: If my buddy offers to buy me a drink, then I will/will not be able to abstain (i.e., avoid drinking). An expectancy of High Self-Efficacy would involve a belief that one will be able to abstain; an expectancy of Low Self-Efficacy would involve a belief that one will not be able to abstain. In either case, the belief that is evoked is a self-efficacy expectancy.

Answer 201

The physiological paradigm is perhaps the most prominent conceptual framework for addictive behaviours. You will likely have come to this conclusion from the sheer volume of material you have encountered in this course that deals directly or indirectly with biology. Interestingly, while the paradigm is rich in specific predictions and evidence about the causes and effects of drug use and addiction, relatively few theories have emerged that attempt to unify drug and alcohol use into a single coherent model. A notable exception is the Psychomotor Stimulant Theory. The term "psychomotor" means mental and behavioral. The term "stimulant" means to increase the rate of activity. Thus, a psychomotor stimulant is something that increases the rate of mental and behavioral activity. This term applies to a sub-class of drugs that fall under the general class referred to in previous modules as Central Nervous System (CNS) Stimulants. Two drugs that are considered to be psychomotor stimulants are Cocaine and Amphetamine. However, nicotine, which is classed as a CNS stimulant, is generally NOT considered to be a psychomotor stimulant because it does not reliably increase mental and behavioral activity. The common feature of psychomotor stimulants is that their primary mechanism of action is to increase dopamine transmission in the limbic system. Wise and Bozarth, the authors of the psychomotor stimulant theory of addiction, reviewed a large body of research on the biological effects of drugs of abuse. Their review determined that ALL drugs of abuse share the ability to cause an increase in dopamine transmission in the limbic system, even if that is not their primary mechanism of action. So for example, heroin primarily acts by binding with endogenous opioid receptors.

Answer 202

However, it also causes dopamine release in a key limbic structure called "The Nucleus Accumbens." Nicotine primarily acts by binding with acetylcholine receptors, but it too causes dopamine release in the nucleus accumbens. Marijuana primarily acts by binding with receptors for a substance called anandamide. However, like heroin and nicotine, marijuana causes dopamine release in the nucleus accumbens. The same can be said for alcohol, Ecstasy, barbiturates, etc. Based on these observations, Bozarth and Wise proposed that the ability to increase dopamine transmission (the primary effect of psychomotor stimulants) is a defining feature of drugs with abuse liability.

Answer 203

It was originally assumed that dopamine was the pleasure signal. In other words, more dopamine = more pleasure. Today, that interpretation is considered to be only a partially correct. Instead, the true "psychomotor stimulant" properties of dopamine are today considered more central to its role in abuse liability. Specifically, dopamine causes an increase in "approach" behaviour - the tendency to move forward (motor activation). This is a prerequisite for consumption of a substance, like a drug. However, the approach behaviour caused by dopamine may not always be "pleasurable." For example, the compulsion to eat another piece of cake is also largely caused by dopamine. If you are on a diet, this may not be pleasurable. Indeed, the bulimic patient who finds herself shoving handfuls of cookies into her mouth may not even experience the taste as pleasurable. Rather it is simply an approach response that has gone wild. In short, dopamine appears to act like biochemical "glue" between a stimulus (e.g., piece of cake, cookie), and a response (e.g., move towards it; grasp it; put it in your mouth). The activation of thoughts about a stimulus (i.e., the obsession) may also be linked to excess dopamine transmission. The compulsion to approach and ingest the stimulus acts to turn off the obsession. Thus the psycho- (obsession) motor (compulsion) stimulant effects of dopamine appear to be important in excessive seeking of reinforcers as well as consumption of these reinforcers. Recent evidence shows that environmental cues (e.g., a particular room) that have been consistently paired with drug administration in a laboratory study will eventually acquire the ability to evoke dopamine release. In other words, whereas the drug originally caused dopamine release, this response has now been transferred to the cues for the drug. In classical conditioning terms, the conditioned stimulus has acquired the ability to evoke the appetitive response through consistent pairing with the unconditioned stimulus.

Answer 204

It acts as a signal for a drug (the biochemical "bell" in classical conditioning) It orients attention to the drug itself. It promotes approach towards the drug and facilitates consumption of the drug It consolidates the bond between the drug stimulus itself and the response of consuming it. In some but not all cases (e.g., cocaine), it produces a pleasurable feeling of "high." In a more generic sense, dopamine serves as a biochemical marker for events with adaptive significance: things that facilitate survival. This goes beyond drugs of abuse, to all reinforcers. However, because drugs of abuse have such a powerful impact on normal neurochemical responses, dopamine appears to mark drug stimuli in an especially prominent way.

Answer 205

the conditioned craving for a drug the conditioned response to a familiar neighbourhood the compulsion to return to drug use after a period of abstinence Dopamine is the 'Siren Song' that calls the addict back to the drug. This occurs by several mechanisms: (i) by signaling the availability of a reinforcer; (ii) by recruiting involuntary thoughts about the reinforcer (i.e., obsession about the drug and its effects); (iii) by focusing attention on that reinforcer (iv) by promoting approach toward that reinforcer (i.e., compulsion to use). All of these effects occur because dopamine acts as the critical biochemical counterpart to a conditioned response (salivation/ craving/ compulsion, etc).

Answer 206

make her feel even more high make her overdose The conditioned compensatory response to the cocaine should not be evoked in a new city (there are no familiar cues that predict cocaine is about to be administered). Terri's body will therefore not produce a drug-opposite compensatory response to the cocaine. Whatever dose Terri used to administer to get high, was calculated by factoring the drug-opposite response. As a result, when this dose is administered in the absence of the drug-opposite response, Terri will feel the same effect as if she had taken this dose for the first time. If Terri had only a moderate amount of conditioned tolerance (i.e., a moderate drug-opposite response), she may feel even more high when she takes her usual dose. If Terri had a high level of conditioned tolerance (i.e., a strong drug-opposite response), she may actually overdose in the absence of this conditioned compensatory response.

Answer 207

the critical role of associative processes in drug and alcohol use the critical role of reinforcing outcomes as motivators of drug use All three models assume that learning plays a critical role in addiction. Learning takes the form of associations between cues and drugs and between drugs and reinforcing outcomes (i.e., reward, relief). The models differ in terms of the mechanisms underlying learned drug and alcohol use. Behaviourists assume that bonds between events (e.g., stimulus-stimulus bonds such as neighbourhood-drug; or response-stimulus bonds, such as drink alcohol - have fun) account for learning. Cognitive theorists believe that expectancies in memory

Answer 208

How the basic learning processes of classical and instrumental conditioning influence addiction. Expectancies in memory mediate the effects of these basic learning processes. How learning and memory influence the initiation of, and relapse to, drug and alcohol use. The psychomotor stimulant theory of addiction, which contends that dopamine activation is the critical common feature of addictive substances.

Answer 209

This module will examine the systematic development of new and better psychoactive medications in the period after 1960. The topics covered this week include the forces that promoted the refinement of existing psychoactive medications after 1960, the tools that enabled this refinement, and the features of the drugs developed at each stage in this "drug evolution." If you were born 50 years ago and suffered from depression, you may have been prescribed amphetamine. You would likely have become addicted to it, with the attendant symptoms of tolerance and withdrawal. Moreover, your depression, if anything would likely have deteriorated If you were born 50 years ago and suffered from schizophrenia, you may have been prescribed reserpine. This would have had only a minor effect on your symptoms, but would likely have induced a clinical depression in addition to your schizophrenia. When your schizophrenic symptoms worsened, you would have been put in restraints, ice baths and if these treatments did not work, more extreme interventions like shock treatment or lobotomy (severing the neurons connecting the frontal lobe to the rest of the brain). In sum, not too long ago, the life of the mentally ill was nasty, brutish and, often, short. As discussed in earlier modules, the 1950's were a watershed decade for the discovery of psychoactive medications for the treatment of the three disorders mentioned above. Indeed, the advent of chlorpromazine for the treatment of schizophrenia led to the phenomenon of Deinstitutionalization. This involved the release of tens of thousand inpatients from the locked wards of state and provincial mental hospitals into the general community. While this policy reduced the number of psychiatric inpatients by a factor of 5, it was ultimately shortsighted. The majority of these individuals became homeless wanderers with few skills to obtain work or social support, and too little emotional resilience to function without the structure of the institution. Eventually, group homes, sheltered workshops and community mental health centres developed to meet these demands. These facilities provided structure and security for medicated outpatients with schizophrenia while also affording a modicum of freedom. However, life for people with schizophrenia was far from ideal. The same could be said for clinically depressed and anxious individuals. The medications that were discovered by chance (the Monoamine Oxidase Inhibitors [MAOI's] in the case of depression, and the benzodiazepine, chlordiazepoxide, in the case of anxiety) were sub-optimal in important ways As a result, the period following the advent of these initial psychoactive medications, from 1960 to the present, was defined by a concerted and systematic effort to develop new and better medications for schizophrenia, depression, anxiety, and to a lesser degree, addictive disorders.

Answer 210

There are two basic ways in which the existing medications were sub-optimal. First, they did not always do what they were intended to do. For example, certain schizophrenic symptoms or certain individuals with schizophrenia did not respond to chlorpromazine. Second, even if the medications worked as intended, their short- and long-term side effects could be extremely difficult to tolerate. For example, in the short-term, chlorpromazine caused intense sedation, confusion and weight gain. In the long-term, this medication often produced a syndrome of involuntary muscle spasms or tics, facial grimacing, and shuffling gait. As noted in previous modules, these symptoms were referred to as tardive dyskinesia, literally "delayed-onset disturbance of movement." The symptoms reflected damage to dopamine neurons caused by long-term blockade of dopamine receptors by chlorpromazine. Sadly, these symptoms which resemble those of Parkinson's disease, appear to be irreversible. In the case of depression, the MAOI's required the patient to adhere to a strict diet. Failure to do so could result in a toxic reaction that may be lethal. Clearly, this was a major concern for depressed patients, who might deliberately eat forbidden foods in order to commit suicide. Even if a patient adhered to the dietary restrictions agitation was a common side effect of MAOI's, which could offset the mood-enhancing effects of the medication. Thus, pre-1960 psychoactive medications could be made "new and better" by enhancing their intended effects (efficacy), and by decreasing their unintended effects (side effects, toxicity).

Answer 211

The 1960's has been described as the era of the "Drug Revolution" because of the widespread use of non-medicinal psychoactive drugs that characterized this decade. In terms of psychoactive medication, however, this decade represents the beginning of the "Drug Evolution" - the systematic adaptation and refinement of existing chemicals to produce more effective and tolerable medications. Two key tools made the Drug Evolution possible: Organic Chemistry and Animal Models of Mental Illness.

Answer 212

Prior to 1950, there were no effective chemical treatments for most forms of major mental illness. When the first medications were discovered (by chance) around this time, they provided a template or a standard by which to refine and evaluate new chemicals that may also have therapeutic potential. For example, of the many neurotransmitters affected by chlorpromazine, its ability to block dopamine receptors was determined to be the primary feature responsible for its therapeutic effects in schizophrenia. This discovery enabled organic chemists to synthesize chemicals with similar chemical structures to chlorpromazine and to test their ability to block dopamine receptors in samples of brain tissue cultured from animals (dopamine receptors are very similar in all vertebrate organisms). A similar process of chemical refinement applied in the case of antidepressants and anti-anxiety agents, as discussed later in the module.

Answer 213

The second critical tool for the development of new and better psychoactive medications was the development of animal models of mental illness. Why should animal models of mental illness influence the refinement of psychoactive medications? Yes. It is possible. Drugs of this type are better described as "poisons." For example, para-methoxy-amphetamine (PMA; street name "death") has psychoactive effects similar to MDMA (Ecstasy). Sadly, the dose that will produce these effects will almost certainly kill the person who takes it. There are dozens (if not hundreds) of animal models of human behaviour. Several of these models are directly designed to reflect pathological behaviour or mental illness. Three of these models are discussed below. They were chosen because they are commonly used and illustrate features of the disorder that can be appreciated without an in-depth knowledge of mental illness.

Answer 214

Clinical anxiety involves fear and avoidance of situations that are disproportionate to their real threatening potential. For example, phobias can cause people to avoid elevators, airplanes, or in extreme cases, even social situations (e.g., parties). This avoidance is distressing because the individual would like to be able to enter these situations but the anxiety is too unpleasant. Thus, anxiety can be characterized as a Conflict between Approach (going into a situation) and Avoidance (not going into the situation). A medication for the treatment of phobic anxiety should therefore be able to increase approach behaviour and decrease avoidance, when the situation is itself desirable (i.e., going to a party). Approach-avoidance conflicts can be modeled in animals using a procedure called punished responding. In this procedure, the animal (usually a rat) learns to cross a metal platform to get a reward (usually a food pellet). Once the animal has mastered this behaviour, a low level electrical current is transmitted through the platform, at random intervals. As a result, the rat receives a mild electric shock while it is en route to the food reward. Moreover, because this electric shock is delivered randomly (i.e., it is unpredictable) the rat cannot learn to cross when he knows the current is turned off. The random shock of an animal that has learned to approach a food reward is a form of punishment. This punishment is usually very effective at stopping the rat from crossing the metal platform, even when it is very hungry. Here we have a situation that the animal would like to enter (food reward at the other side of the platform) but is too afraid to do so because of fear of some unpredictable unpleasant event (shock). This situation closely mirrors the phobic individual who would like to go to a party, but does not do so because of a vague fear that something terrible will happen. Chlordiazepoxide (the first consistently effective medication for the treatment of anxiety) restores approach behaviour in this model. In other words, animals that have learned to get the food pellet, and stopped doing so after the shock was introduced, will resume their attempts to walk across the metal platform when they get a dose of chlorpromazine. This "fearless" behaviour is called Punished Responding. Drugs that cause Punished Responding in this animal model are very good candidates as anti-anxiety medications.

Answer 215

A cardinal feature of depression is loss of motivation - or giving up. If a depressed person is having difficulty at school (as we all do at one time or another), they are likely to drop the course, or quit altogether. They lack the confidence, mental toughness, energy or motivation to bounce back to these setbacks. The depressed person is not just being lazy, or childish or "weak." He or she is actually impaired in fundamental ways from fighting back against adverse circumstances. Chronic stress or a severe loss (e.g., death of a loved one) can produce this type of impairment, leading to its clinical description, "learned helplessness." There are many ways to model learned helplessness in animals. A variant of learned helplessness that has proved especially useful in the development of antidepressant medication is called the Milk Maze. In this procedure, a rat is put into a vat of opaque white liquid (hence the name, "Milk Maze" - in fact the liquid is coloured water). The rat is first placed on a platform that is submerged just below the surface of the water. This tells the rat that there is a way to escape from the water to safety. Once the rat is aware that there is a way out, it is removed from the vat, and placed in at a later time. However, this time, the rat is put into the water. The vat is designed to have no cues to help guide the rat to the platform. Nor can it see the platform submerged beneath the opaque liquid. The only way to escape is to swim steadily and systematically around the vat in order to "discover" the location of the platform. Most rats placed in this situation will panic at first and begin to swim furiously without direction. After a period of time these animals get tired and lose their ability to stay afloat. At this point the experimenter removes the animal from the vat. The loss of ability and/or motivation to escape successfully from this highly aversive situation is a form of learned helplessness - the animal cannot go on, neither can it find a way out, so it resigns itself to death (i.e., drowning). Drugs like MAOI's will increase swim time and focused exploration of the vat in the Milk Maze. As a result, rats treated with an MAOI are much more likely to successfully find the platform than rats not treated with such a drug. Moreover, this is not simply a matter of increased energy; amphetamines and other stimulants will produce a burst of energy but not the steady, organized exploratory behaviour necessary to carefully survey the vat and thus find the way out. In short, drugs that have antidepressant potential will increase the duration and organization of swimming behaviour as well as the likelihood of finding the platform in the Milk Maze procedure.

Answer 216

Impulsiveness is a core symptom of many psychiatric disorders, including Tourette's syndrome, bulimia, attention deficit hyperactivity disorder (ADHD), childhood conduct disorder, and Borderline Personality Disorder. A fundamental feature of impulsiveness is an inability to put off responding to an instigating stimulus. This can result in aggressive reactions to provocation, bingeing on tasty food, or shouting/swearing when the appropriate response would be to remain quiet. The procedure known as delayed responding provides a reward to an animal ONLY when it responds at a specified slow rate. When it exceeds this rate or does not respond at all, it gets no reward. For example, a hungry animal will run very quickly to a food basket when a food pellet is dispensed. In the delayed responding procedure access to the food pellet is only provided when the animal either waits for a specified period of time or performs some other intervening behaviour (e.g., pressing a bar several times) prior to approaching the food basket. In a variation of this procedure, the animal may be given a choice between a small immediate reward (1 food pellet dispensed immediately) and a large delayed reward (10 food pellets dispensed after a 30-second delay). If it opts for the large delayed reward it has demonstrated delayed responding. Drugs that enhance serotonin are particularly effective in improving delayed responding. Note: serotonin-enhancing drugs, like Prozac, are also effective in the Milk Maze (as antidepressants). However, drugs that enhance norepinephrine can also improve performance in the Milk Maze (i.e., have antidepressant effects), whereas serotonin-enhancing drugs appear to have a unique advantage compared to other types of drugs in the Delayed Responding Procedure. Thus, drugs that are effective in increasing Delayed Responding may well be effective in the treatment of impulsive behaviour.

Answer 217

to see if a drug alters a behaviour that is involved in a psychiatric disorder in humans to see if a drug will achieve this effect without harming or killing the animal Protecting human beings while at the same time verifying therapeutic potential are the two benefits of animal models

Answer 218

Anti-psychotics are drugs that reduce thought disorder (i.e., psychosis). Psychosis involves beliefs that are not based in reality (i.e., delusions such as the belief that people are trying to kill you or the belief that you are Napoleon or someone other than who you are). It also involves hallucinations (i.e., sensory experiences not based in reality, like hearing voices in your head). Delusions and hallucinations are sometimes referred to as "Positive" symptoms, not because they are good, but because they represent an excess (a positive deviation) relative to normal. Psychosis can also involve negative symptoms (deficits from normal). Some examples include lack of affect (no emotion), lack of speech, or lack of social interest (isolation from others without feelings of loneliness). Both positive and negative symptoms are common in schizophrenia. Anti-psychotic medication treat these symptoms with varying degrees of efficacy.

Answer 219

Chlorpromazine was the prototype of this first generation of anti-psychotics. Drugs of this class are effective in treating positive psychotic symptoms but not negative symptoms. They also had severe side effects including sedation, weight gain, and most importantly, tardive dyskinesia (a movement disorder characterized by uncontrollable, abnormal, and repetitive movements of the face, torso, and/or other body parts) In addition, large doses of these drugs were required to prevent breakthrough symptoms (i.e., return of psychosis) during times of stress. This in turn increased the rate and severity of side effects. The discovery that dopamine receptor blockade was the key therapeutic feature of phenothiazines led to the development of drugs that had more potent anti-dopamine effects, without the same impact on other neurotransmitter systems (acetylcholine, histamine) that were markedly disturbed by phenothiazines.

Answer 220

These drugs are the second generation of anti-psychotics. They are generally much more potent than phenothiazines (e.g., 10 times or more). They are also more selective in their blockade of dopamine relative to other neurotransmitters. Haloperidol is the prototype medication of this class. Unfortunately, long-term blockade of dopamine receptors (particularly D2 receptors) appears to underlie tardive dyskinesia. Because butyrophenones have this effect, they are also very likely to give rise to tardive dyskinesia. Thus, although these drugs were more efficacious than phenothiazines, they were equally toxic when given chronically.

Answer 221

In the 1990's a major shift in anti-psychotic medication was achieved. A set of drugs called atypicals were introduced that treated schizophrenic symptoms without the same high rates of tardive dyskinesia. These drugs appeared to reduce dopamine transmission by means other than D2 blockade and thereby achieved a reduction in schizophrenic symptoms indirectly. Clozapine was one of the earliest atypical anti-psychotics. This drug blocked dopamine D4 receptors, and also enhanced norepinephrine. The enhancement of norepinephrine not only helped to moderate dopamine, it also appeared to restore cognitive function (i.e., clear thinking) in patients who had experienced fuzzy thinking and confusion on typical anti-psychotic medication. Despite these major advantages of clozapine, not every patient showed a therapeutic response to this drug. In addition, there was a danger of an acute toxic reaction if blood levels got too high. For this reason, patients taking clozapine must have weekly blood assessments to confirm that levels of the drug are safe. Risperidone was another atypical anti-psychotic medication. Like other atypicals, it had lower risk for tardive dyskinesia. In addition, this drug was distinctive for its ability to reverse the negative symptoms of schizophrenia (social withdrawal, lack of speech and emotion) as well as the more obvious positive symptoms. The reversal of negative symptoms appeared to be related to the drug's effects on serotonin receptors, which seemed to interact with dopamine in complex ways. Olanzapine is one of the most recent atypical anti-psychotics. It too has lower incidence of tardive dyskinesia. In some ways this drug is like a more potent version of clozapine. However, olanzapine also appears to have some distinct advantages in terms of side effects. Specifically, people treated with anti-psychotic medication smoke cigarettes at much higher rates than individuals who do not. This appears to be directly related to the medication they take, because unmedicated schizophrenics do not show this propensity. Blockade of a particular type of acetylcholine receptors is a side effect of many anti-psychotic medications that has been implicated in smoking. It seems that schizophrenics use nicotine to restore optimal levels of activation of the acetylcholine receptors blocked by their anti-psychotic meds. (A good example of cybernetic drug use). Research shows that schizophrenic patients who are switched from a typical anti-psychotic medication to olanzapine, can often quit smoking without difficulty, reflecting a restoration of normal acetylcholine transmission by olanzapine. Given the extreme toxicity of cigarettes, this feature of olanzapine is a powerful advantage of the medication. Clozapine, risperidone, and olanzapine represent the state of the art for anti-psychotic medications. Different patients will respond to different drugs depending on the unique nature of their symptoms. As of the 1990's there are finally a range of medications for long-term treatment of schizophrenia that are both effective and (reasonably) safe.

Answer 222

increased potency; lowered risk of tardive dyskinesia

Answer 223

As in the case of the anti-psychotics, there have been three major "generations" in the evolution of antidepressant medication. Also like anti-psychotics, each succeeding generation of antidepressants improved upon the preceding one, while at the same time leaving some issues unresolved. Because of the creative research that contributed to the refinement of antidepressants, the evolution of this class of drugs not only led to improved treatment of this disorder, but also to major insights in to the workings of the brain.

Answer 224

As you know, the first generation of antidepressants was the MAOI's. These drugs exerted a non-specific effect on the three neurotransmitters implicated in emotion and motivation: 1. Dopamine, 2. Serotonin, and 3. Norepinephrine Collectively, these transmitters are called "mono-amines" because of a shared feature of their chemical structures. In process terms these transmitters are all regulated by a common enzyme, mono-amine oxidase (chemicals that end in "-ase" are usually enzymes), which breaks down residual transmitter molecules in the synapse following exocytosis. (Recall this refers to the release of transmitters from the terminal buttons of the neuron due to an action potential). By inhibiting the activity of this enzyme, mono-amine oxidase inhibitors prevented the residual transmitter molecules from being broken down, allowing more of them to bind with the receptors on the receiving neuron. The result was a net increase in mono-amine transmission across the synapse. As noted earlier, MAOI's were sub-optimal for at least two reasons. 1. patients taking them had to adhere to a strict diet that excluded dairy foods and other products like red wine. 2. the MAOI's caused a particularly unpleasant side effect in many patients, namely agitation. As a result, the patient may stop being depressed only to become chronically anxious.

Answer 225

Dopamine. Dopamine is, among other things, the stimulant neurotransmitter. Therefore, activation of dopamine by a drug or medication might be expected to lead to agitation. A fruitful approach to refining the MAOI's therefore would appear to identify a drug that did not activate dopamine to the same degree. After several years of trials by organic chemists and behavioral scientists, an agent was identified that did precisely that.

Answer 226

The medications that (largely) replaced the MAOI's were termed Tricylic Antidepressants (TCA's). This reflected the fact that these drugs shared a common molecular structure that looked like 3 rings, hence the name "tri-cyclic." The protoype TCA was a drug called Imipramine (Trade Name: Tofranil). This medication strongly enhanced serotonin and norepinephrine, but had relatively little impact on dopamine. Whereas the MAOI's enhanced neurotransmission by inhibiting enzyme-induced degradation of residual transmitter molecules, the TCA's enhanced transmission by blocking the reuptake transporter for serotonin and norepinephrine. Recall that the reuptake transporter or pump is a recycling station where excess transmitter in the synapse is pumped back into the sending neuron for re-use. By blocking the reuptake transporter, TCA's prevented this recycling process, leaving more residual transmitter in the synapse after each action potential. The residual transmitter in turn would bind with receptors on the receiving neuron, leading to a net increase in neurotransmission. The TCA's varied in their relative impact on serotonin vs. norepinephrine. The drug, amitriptyline (trade name: Elavil) strongly enhanced norepinephrine transmission, but had only modest effects on serotonin. Conversely, the drug clomipramine (trade name: Anafranil) had potent enhancing effects on serotonin and comparatively modest effects on norepinephrine. Individuals with "classic" depressive symptoms, (sadness, lethargy, loss of motivation, loss of appetite) tended to respond well to Elavil. In contrast, individuals who displayed more intense cognitive symptoms like worrying or ruminating tended to respond well to Anafranil. Most individuals had a mixture of these symptoms and thus responded to the drug with the most even profile, Tofranil. Like the MAOI's there were two major concerns with the TCA's. First, although there were no dietary restrictions with TCA's, a person could still kill him or herself by deliberate overdose with these drugs. This reflected the fact that TCA's caused some cardiac irregularities which (a) made them inappropriate for depressed cardiac patients, and (b) could lead to cardiac arrest in overdose. The second concern with the TCA's was the side effect of blocking acetylcholine transmission. This contributed to their sedative effect but more importantly led to extreme drying of the mucous membranes. People taking TCA's would complain of intolerable dry mouth, as if it were full of cotton. This anti-acetylcholine effect also led to severe constipation and bloating which was another deterrent to taking them. Thus, both the safety and tolerability of TCA's was sub-optimal, even though their efficacy was very good.

Answer 227

The efficacy of TCA medications implied that deficits in serotonin and norepinephrine transmission were involved in the symptoms of depression. However, what was unclear was the relative contribution of these two transmitters to the therapeutic response to TCA's. To address this question, a scientist called Pedro Delgado developed a safe procedure for inducing a transient and selective reduction in brain levels of serotonin in human beings. If serotonin were selectively reduced, the TCA would have nothing to "keep in the synapse, " so that serotonin transmission between neurons would essentially shut down. Delgado reasoned that if patients taking TCA's showed a resurgence of depressive symptoms after undergoing this procedure, it would suggest that serotonin is critical (perhaps even necessary) for the beneficial effects of TCA's. The procedure Delgado used involved administering a beverage that rapidly depleted the body's supplies of an amino acid called Tryptophan. This amino acid was the raw material that was eventually synthesized into serotonin. Depletion of tryptophan thus led to a reliable decrease in serotonin in the brain and a concomitant decline in serotonin transmission across the synapse. When Delgado used tryptophan depletion in formerly depressed patients who were successfully being treated with a TCA, he found that these patients displayed a full resurgence in depressive symptoms, that is, they relapsed. The fact that this occurred despite the fact that their norepinephrine levels were unchanged, suggested that enhancement of serotonin was the vital feature of TCA drugs. By implication, a deficit in serotonin appeared to be the vital problem in depression.

Answer 228

This module will examine the evolution of medications for the treatment of anxiety, attention deficit hyperactivity disorder (ADHD), and addictions. The focus of this module will be learning the relation between psychoactive drugs and medications. If you were born 50 years ago and suffered from anxiety, you may have been prescribed a barbiturate, like pentobarbital. You almost certainly would have become addicted to it, necessitating increasing doses with an increasing risk of overdose, particularly if you drank alcohol. If you were born 40 years ago and suffered from attention deficit hyperactivity disorder (ADHD) you may have been prescribed a TCA antidepressant or even an anti-anxiety drug. These medications would likely have not helped and possibly worsened your ADHD symptoms. If you were born 30 years ago, and became addicted to cigarettes or alcohol, you would have had no effective pharmacological treatments for your problem. Today, safe and effective medications exist for anxiety, ADHD, and to a lesser extent, addictions.

Answer 229

Sedatives are drugs that put you to sleep. Tranquilizers alleviate anxiety. Most drugs that do one will also do the other. This is sometimes good and sometimes not good. For example, anxiety and insomnia are frequently present in a variety of psychiatric disorders, so a sedative-tranquilizer will be beneficial in such cases. However, some people just have difficulty sleeping but are not anxious. These people may become complacent on a drug that affects both these responses. Conversely, many people with anxiety disorders experience their symptoms during the day when they may encounter threatening situations, but have little difficulty sleeping in the safety of their homes. Such people may be unduly sedated or drowsy on a conventional sedative tranquilizer.

Answer 230

Until the 1960's, the only option for sleep disturbance or anxiety were the dual-action sedative-tranquilizer drugs known as barbiturates. These drugs were sub-optimal in numerous ways. (1) They caused sedation during the day. (2) They caused a disturbance in the restorative (REM) phase of sleep so that patients did not feel rested from their sleep. (3) They were highly addictive, leading to rapid tolerance and withdrawal. (4) They were highly toxic in overdose (depressing respiration), or at clinical doses when mixed with alcohol.

Answer 231

The advent of benzodiazepines, like chlordiazepoxide (Librium) and diazepam (Valium), made barbiturates largely redundant. Today there are few clinical uses for barbiturates outside of surgical anesthesia. Benzodiazepines are effective in the management of anxiety, as well as occasional insomnia. Chronic use of benzodiazepines often leads to tolerance to their sedative effects but interestingly does not appear to reduce their tranquilizing effects. This is good for patients with anxiety. Occasional insomnia, which may accompany a stressful period at work or when a person is bereaved (in mourning), is effectively treated by benzodiazepines. Chronic insomnia, particularly insomnia that involves awakening too early, is often better treated by a low dose of a TCA (e.g., Elavil). This is because tolerance does not appear to develop to TCA-induced nighttime sedation. There are 2 basic types of benzodiazepine: short-acting and long-acting. Short-acting drugs have half-lives of 4-8 hours, and are quickly eliminated from the body. These drugs are effective for insomnia, because they minimize drowsiness the next day. They are also effective for anxiety disorders that involve rapid onset of symptoms, like panic disorder. An example of short-acting benzodiazepine used for the treatment of panic disorder is alprazolam (trade name: Xanax). Long-acting benzodiazepines are useful for the management of chronic anxiety. For example, clonazepam is very effective in treating social phobia, which involves a pervasive fear and avoidance of social situations. Clonazepam has a half-life of 18-60 hours. Benzodiazepines can sometimes be abused (e.g., taken at too high a dose, or mixed with drugs or alcohol). They are dangerous (overdose) and addictive when used in this manner, despite their safety and low abuse liability when taken as prescribed. Anxiety and insomnia are common in problem drinkers and cocaine abusers. Such individuals may abuse benzodiazepines to take the edge off anxiety or to enhance the effects of their primary drug. To facilitate the management of anxiety and insomnia in these populations, alternative sedative-tranquilizers are needed.

Answer 232

Beta blockers can be used for the management of panic disorder which is a common complication in chronic alcoholics. Beta blockers reduce the heart's reaction to stress. Because panic involves an exaggerated response to bodily symptoms (e.g., a rapid pulse may be interpreted as a heart attack), beta blockers provide an indirect way to reduce panic symptoms with no risk of abuse. They also have the benefit of reducing high blood pressure which is another side effect of chronic heavy drinking. Zopiclone is a drug with sedative properties for the treatment of insomnia in patients who may abuse benzodiazepines. This drug is useful for short-term insomnia in this population. Because it produces a characteristic metallic taste, most patients will not take it more often or in higher doses than are absolutely necessary. Buspirone (trade name: Buspar) is a drug originally marketed for the management of generalized anxiety. This drug does not have sedative effects, but importantly does not appear to have any abuse potential. In contrast to benzodiazepines, patients do not appear to get "high" from Buspar even when taken in high doses. A number of studies have investigated the value of this drug for the treatment of anxiety in alcoholics. The good news is, it appears to reduce anxiety without interacting negatively with alcohol. The bad news is, it doesn't reduce drinking and may even increase drinking, by reducing the unpleasant anxiety that comes in the aftermath of a drinking binge. In sum, there are now a number of options for the management of clinical anxiety. Given the pervasiveness of anxiety, it is not surprising that benzodiazepines, collectively, are the most widely prescribed psychoactive medications in the world. However, when anxiety or insomnia co-exist with drug/alcohol abuse, benzodiazepines appear to be ruled out as a medication of choice.

Answer 233

diazepam (Valium) Individuals who abuse alcohol, are highly likely to abuse benzodiazepines like diazepam (Valium) which can produce feelings of euphoria when taken in high doses. Increased dosing in turn raises the risk of tolerance and withdrawal, leading to a secondary addiction to benzodiazepines. Co-administration of alcohol and Valium could lead to overdose (usually due to coma or respiratory failure).

Answer 234

Attention deficit hyperactivity disorder (ADHD) is a psychiatric syndrome that typically emerges in childhood. Children with ADHD have trouble concentrating on schoolwork, cannot sit still, and often behave in impulsive (poorly planned) ways. Prior to the 1970's kids with ADHD may have been prescribed a low dose of a TCA antidepressant with calming properties (e.g., amitriptyline, trade name Elavil). This medication would probably have had minimal benefits and may even have worsened their symptoms. Alternatively, they may have undergone cognitive-behavioral therapy to learn how to use "self-talk" to slow themselves down and plan their behaviors better. It was not until the mid-1970's that physicians began to try a controversial treatment for the management of ADHD, the stimulant drug, Ritalin. It had been recognized for a while that kids with ADHD are more likely to smoke cigarettes than kids without the disorder. This could simply reflect a deviant attitude resulting from doing poorly in school or other conventional areas of achievement. Alternatively, some investigators proposed, it may have reflected an effort to self-medicate their ADHD symptoms. Nicotine is a CNS stimulant drug. The fact that it calms ADHD symptoms is paradoxical given that these children appear to be too stimulated - i.e., hyperactive. If stimulants did alter their brain chemistry in a way that was therapeutic, perhaps a stimulant medication that was less toxic than cigarettes would also have this effect.

Answer 235

This medication is a highly selective psychomotor stimulant. It is a dopamine reuptake inhibitor - that is, it increases levels of dopamine in the synapse by preventing recycling of residual dopamine by means of reuptake. Many children with ADHD display a rapid and sustained decline in hyperactivity and increase in attentional focus when they take this medication. By the time they enter adolescence, the symptoms of the disorder often taper off, and they can be weaned from the medication without apparent difficulty. Why should a stimulant drug have a calming effect. The answer appears to lie in an imbalance in the regional activity of dopamine in the brains of children with ADHD. Specifically, ADHD appears to involve a deficit in frontal lobe dopamine activity (i.e., the cortex, where planning decision-making, and complex integration of psychomotor behaviour occur). As a result, the frontal lobe does not exert sufficient regulatory control on limbic dopamine activities - seeking and approach. When kids with ADHD take Ritalin, it appears to enhance dopamine activity in the frontal lobe, thereby restoring an optimal balance between limbic and frontal dopamine. Whereas children with ADHD usually display this effect with relatively few side effects, children who do not have bona fide ADHD (but display impulsive, rebellious or aggressive behavior) may display a worsening of symptoms when they receive Ritalin. They may also display a wide range in side effects including loss of appetite, insomnia, and irritability.

Answer 236

1. First it is given to children (who by law cannot provide informed consent until age 16). 2. Second, the loss of appetite and alteration of normal metabolic processes led to concerns that children would suffer a disturbance in growth. 3. Finally, because Ritalin is a psychomotor stimulant with biochemical properties similar to cocaine, parents worried that their children would become addicted to Ritalin, or somehow be sensitized to other drugs of abuse later in life. Most research shows, however, that when Ritalin is given to children with bona fide ADHD, none of these effects appears to materialize. Because Ritalin, like cocaine, enhances dopamine, it should have high abuse liability. Indeed this is the case, among people who abuse cocaine or other stimulants. However, abuse (taking too much) and addiction (inability to stop taking it) appears to be rare in cases of bona fide ADHD. This provides some insight into a critical feature of "medications" as compared with drugs of abuse. That is, medications appear to reverse a deficit or abnormal state, whereas drugs of abuse appear to worsen deviations from normal. Thus, for children with ADHD, Ritalin is primarily a medication, whereas for children (and adults) without ADHD, Ritalin is a potential drug of abuse.

Answer 237

1. First it is given to children (who by law cannot provide informed consent until age 16). 2. Second, the loss of appetite and alteration of normal metabolic processes led to concerns that children would suffer a disturbance in growth. 3. Finally, because Ritalin is a psychomotor stimulant with biochemical properties similar to cocaine, parents worried that their children would become addicted to Ritalin, or somehow be sensitized to other drugs of abuse later in life. Most research shows, however, that when Ritalin is given to children with bona fide ADHD, none of these effects appears to materialize. Because Ritalin, like cocaine, enhances dopamine, it should have high abuse liability. Indeed this is the case, among people who abuse cocaine or other stimulants. However, abuse (taking too much) and addiction (inability to stop taking it) appears to be rare in cases of bona fide ADHD. This provides some insight into a critical feature of "medications" as compared with drugs of abuse. That is, medications appear to reverse a deficit or abnormal state, whereas drugs of abuse appear to worsen deviations from normal. Thus, for children with ADHD, Ritalin is primarily a medication, whereas for children (and adults) without ADHD, Ritalin is a potential drug of abuse. Recent statistics show that many young people are abusing Ritalin in the context of Rave parties, where other stimulant-like drugs (e.g., Ecstasy) are used, to increase energy and enable dancing for long periods of time. In cases where this persists despite consequences (e.g., fines or other legal penalties), the situation of abuse has clearly emerged. The general lack of abuse of Ritalin by kids with ADHD mirrors the general low abuse rates of morphine abuse by cancer or post-operative patients given free access to morphine to manage pain. In both these cases, excessive use and addiction are extremely rare, despite the fact that morphine has heroin-like properties and is generally considered to posses high abuse liability.

Answer 238

Evidently, the heroin use was serving a medicinal purpose (management of stress or pain) that was situation specific (being in a war). The situation represented a gross deviation from "normal" and the heroin reversed this deviation. At home, no such deviation from normal existed, there was no need to use heroin to restore stress levels to normal, and hence use of heroin stopped.

Answer 239

In each of these cases a drug with high "abuse liability" did not give rise to abuse when it was used strictly to restore normal functioning. Thus, an important difference between medicinal and non-medicinal psychoactive drug use is whether or not the drug primarily restores normalcy or increases the deviation from normal. It should be pointed out that alcohol and cigarettes can be used in order to self-medicate deviations from normal. For example, anxious individuals often use alcohol to reduce anxiety, whereas individuals with ADHD or depression often use cigarettes to offset the symptoms of their disorders. In these cases, abuse and addiction of these drugs will often arise due to the after-effects of the drug. For example, the after effect of alcohol tends to be worse anxiety, particularly in anxious individuals. The after-effect of cigarettes is poorer concentration and more susceptibility to stress/sadness in people with ADHD and depression respectively. Thus, it should be noted that individuals who initially used alcohol or cigarettes to "self-medicate" symptoms often start to abuse these substances to counter the after-effects of the drug. It is possible that an anxious person who only drank 1 glass of alcohol, or a depressed person who only smoked half a cigarette to manage their symptoms would not experience the powerful rebound symptoms caused by these drugs. They could then continue to use alcohol and cigarettes to manage their symptoms without the escalation in dose that leads to addiction. It is easy to drink or smoke more than is needed for purely medicinal (i.e., negative reinforcement) purposes. Consequently, people who start using a drug for self-medication ultimately wind up abusing the drug to manage the rebound loss of reward caused by taking a bit too much in the first place (i.e., loss of "positive reinforcement"). This is a good illustration of the cybernetic model of drug use, and the cycle of abuse that results when a drug increases rather than decreases the deviation from the internal optimum.

Answer 240

stimulation of an underactive frontal cortex The frontal cortex acts as a governor on the limbic system. When it is underactive, it does not govern or inhibit limbic activity as well as it should, resulting in excessive approach and motor behaviour (limbic dopamine effects). Ritalin appears to selectively enhance dopamine transmission in (i.e., stimulate) the frontal cortex of children with ADHD, restoring its ability to inhibit excessive motor and approach behaviour. In normal children and adults without this underactive frontal cortex, Ritalin causes the familiar increase in behavioral activation associated with other psychomotor stimulants (e.g., cocaine, amphetamine), an effect that may lead to its being abused by these people.

Answer 241

The idea that a psychoactive drug may serve as a medication when it is strictly used to restore optimum functioning (negative reinforcement) rather than to get high (positive reinforcement) has led to a search for medications for the treatment of addiction. People who abuse drugs or alcohol do so for the positive and negative reinforcing effects. The negative reinforcing effects may involve pre-existing symptoms (e.g., anxiety, depression). However, they will also likely involve drug-induced effects (withdrawal). To successfully treat a person for an addictive disorder, it is necessary to find a medication that will not be abused, that is, used to get high rather than to stop feeling bad (withdrawal, craving).

Answer 242

One of the earliest efforts to treat alcoholism was a drug called disulfiram (trade name: Antabuse). This drug prevented the proper metabolism of alcohol leading to a build-up of acetaldehyde in the body. The build-up of acetaldehyde led to nausea and vomiting, which effectively prevented further alcohol use. Although some individuals found they were able to stop their drinking with antabuse, most alcoholics did not benefit from it. The reason can be given in a single word: Non-compliance. Alcoholics simply did not benefit from the medication because they did not take it as prescribed. Whenever they felt the craving for alcohol, they would simply skip their dose of Antabuse, enabling them to drink without getting sick. As a result, the alcohol abuse continued. To circumvent the problem of non-compliance a long-acting form of Antabuse was developed in the form of a pellet that was surgically implanted under the skin near the stomach. When drinking rates did not decline in alcoholic patients treated in this way, doctors were surprised to learn that the patients had in fact cut the pellets out of their bodies in order to be able to drink. This example of self-mutilation demonstrates the incredible power of addictive motivation.

Answer 243

1. The first medication was known as naltrexone (trade name: Revia). This drug works by blocking endogenous opioid receptors in the brain. As a result, the person tends not to experience the pleasurable high caused by alcohol, and is therefore better able to curb the desire to drink more. Like Antabuse, naltrexone relies on compliance with the prescribed regimen for it to work. Patients can therefore skip their dose and continue drink. In addition, naltrexone appears to work best when the patient takes the medication AND continues to drink, at least initially. The reason for this apparent contradiction, is that drinking while taking naltrexone enables the alcoholic to repeatedly experience alcohol without its pleasurable effects. As a result, a substance that had been highly reinforcing acquires a new association - no reinforcement. In learning terms, this is called "extinction." This strategy may work reasonably well while the patient is under close supervision. However, once the formal treatment program ends, close supervision of drinking stops and the individual often begins to not use the drug as intended (i.e., taking only when not drinking, not taking it when drinking). Under these circumstances, relapse to alcohol is very likely. Although some individuals have benefited from naltrexone, recent research has questioned its overall efficacy, when effects are averaged across individuals. Under these circumstances, average rates of alcohol use/relapse under naltrexone do not appear to differ significantly from rates seen in alcoholics given a placebo. A third drug currently being used for the treatment of alcoholism is acamprosate. This drug is a glutamate enhancer, and appears to block both the craving and subjective effects of alcohol. Research in Europe has found some promising evidence. No comparable research has been undertaken in North America, so the jury is still out. In sum, pharmacological treatment of alcoholism has a rather poor record of success. This is due largely to problems of compliance. In other cases, e.g., where an alcoholic used alcohol to manage anxiety and was given a benzodiazepine as a substitute, use of prescription medication often escalates into positive reinforcement use, and eventual abuse (i.e., a transfer of addiction). Thus, alcohol abusers tend to abuse drugs that could be helpful to them if used correctly. This likely reflects a chronic pattern of using drugs for reward rather than solely for restoring normal functioning.

Answer 244

The issue of compliance has compromised successful treatment of alcoholism. Heroin addicts however, have benefited from a treatment that involves daily administration of a heroin-like drug, methadone, under circumstances that prevent non-compliance. Heroin addicts in methadone treatment must provide daily urine samples to confirm that they are heroin-free. They then receive a standard dose of methadone which is taken under a doctor's supervision. The methadone effect will last for 24 hours at which point the patient must return for another dose. Methadone maintenance appears to be very effective in keeping heroin addicts from using heroin. The methadone binds with the same receptors (endogenous opioid) that heroin does and activates them (albeit more less strongly than heroin). This prevents the cravings and withdrawal that would cause relapse to heroin. However, at the same time, the person has essentially switched their dependence from heroin to methadone. If they stopped taking methadone all the same symptoms of withdrawal and craving for heroin would re-emerge. That is why methadone treatment is typically described as Maintenance, because maintains the addict without curing him or her of his/her dependence.

Answer 245

These medications do not require the patient to come to the clinic as often to get their dose, so this tends to increase compliance a bit. Methadone maintenance is beneficial relative to heroin primarily because the person does not need to inject the drug. Injection use of heroin is associated with the spread of disease (HIV, AIDS, and hepatitis). It is also more likely to result in overdose due to uncertain potency of a given batch of heroin. Because heroin itself does not damage body tissue, the primary benefit of methadone over heroin has to do with its oral method of administration vs. the risks inherent in IV administration of heroin. Because heroin is difficult to procure, and easy to detect in the urine, compliance with methadone maintenance has been quite good. In contrast, the fact that alcohol (the drug of choice for alcoholics) is easily procured and difficult to detect in urine, comparable once-a-day maintenance programs with anti-drinking medications (e.g., naltrexone) have not been very successful.

Answer 246

direct agonist Methadone binds directly with endogenous opioid receptors, activating them (weakly) in a manner similar to heroin.

Answer 247

The percentage of regular smokers who remain abstinent one year after they quit is 1-3%. This reflects the extreme addictive potential of nicotine. As noted in previous modules, part of the addictive power of nicotine is its route of administration and frequency of dosing. Each puff of a cigarette has an almost immediate effect (6-8 seconds), thus each cigarette effectively administers 15-20 mini-doses of nicotine. Multiply this by 20 cigarettes per day and the average number of mini-doses ranges from 300-400 per day. It is not surprising therefore that cigarette addiction is so difficult to quit. In the 1980's, awareness of the dangers of secondhand smoke made smoking in public places taboo. By the 1990's a very large number of regular smokers were attempting to quit, creating a huge demand for products to facilitate this process. The nicotine patch is the first-line intervention for smoking cessation. This treatment administers a slow steady flow of nicotine into the bloodstream by a transdermal (across the skin) route of administration. Quitters typically start at a high dose (e.g., 21 mg) and taper down to a low dose (e.g., 7 mg). In many cases, the slow steady flow of nicotine provided by the patch is sufficient to allay cravings. In cases of very heavy cigarette use, the patch does not adequately approximate the pulsatile infusion of nicotine provided by smoking. Such individuals may require stronger nicotine replacement therapies (NRT's), such as the nicotine nasal spray or the puffer. The nasal spray gets the nicotine to the brain in a minute or so, while the puffer, which resembles an asthma inhaler, essentially equals the cigarette in terms of speed of delivery to the brain from the lungs. Typically the person is weaned from the puffer to the nasal spray to the patch and so on. However, even if a former smoker remained on an NRT indefinitely it would still be a great improvement over cigarettes. This is because the toxic effects of smoking lie in the tobacco not the addictive compound, nicotine. Tobacco contains numerous carcinogens and poisons whose toxic effects are magnified by the burning process. Thus, delivery of nicotine without these carcinogens removes the risks associated with these toxins, even if the individual remains addicted to nicotine (which itself is not toxic in the doses administered by the typical smoker). Nicotine has important stress modulating effects and also improves attention and concentration in habitual smokers. Some individuals have difficulty with stress management during nicotine withdrawal; others simply cannot concentrate. Such individuals are prone to relapse to restore these basic functions. There is now a medication for these individuals which may provide more potent anti-stress and cognitive enhancing effects than NRT's.

Answer 248

The medication, Bupropion (Zyban) was originally developed as an antidepressant. This drug enhances norepinephrine and to a less extent dopamine. These effects have been implicated in the cognitive and anti-stress effects of nicotine. At the same time, bupropion appears to block acetylcholine receptors that mediate the rewarding effects of nicotine. As a result, smokers do not enjoy cigarettes as much when they are taking the medication. Thus, like naltrexone for alcoholics, bupropion appears to promote extinction of smoking behaviour by blocking the biochemical mechanism of reinforcement from smoking. Bupropion is an interesting example of a drug whose therapeutic effects rely greatly on the body's metabolic processes. Indeed, the metabolite of bupropion (the compound into which the drug is converted by enzymes in the body) is a much stronger norepinephrine and dopamine enhancer than bupropion itself. Both bupropion and its metabolite exert their effects by blocking reuptake of norepinephrine and dopamine, leaving more of these transmitters remaining in the synapse to bind with their receptors on the receiving neuron. Bupropion can be taken indefinitely by former smokers, thereby reducing the risk of relapse at a later time It should be noted that bupropion has been implicated in some serious side effects particularly, seizures. Adherence to the specific dosing regimen appears to be especially important to preventing these dangerous effects. Pharmacological treatment of addictive behaviours has been attempted for years. The goal of these efforts has been to either block the pleasurable effects of the abused drug (e.g., naltrexone, bupropion), or to substitute for the reinforcing effects in a manner that did not allow escalation of dose or toxicity (e.g., methadone). Increased sophistication in organic chemistry and molecular biology in the last 10 years has enabled pharmaceutical companies to develop new and better medications that mimic or negate the reinforcing effects of abused drugs. The evidence from naltrexone and bupropion suggests that the benefits of these medications vary greatly across individuals. Therefore, scientists and clinicians who evaluate the effects of such treatments may do well to assess the characteristics of individuals who respond favorably to a given medication and rather than just assess the average overall response across individuals.

Answer 249

toxicity and abuse liability Barbiturates were more toxic and more prone to abuse than benzodiazepines, which in turn were more toxic and prone to abuse than buspar and zopiclone.

Answer 250

risk of drug interactions poor compliance risk of secondary addiction Unlike other patients with other psychiatric disorders, people with addictions are often extremely ambivalent about getting cured of their disease. This is because drug use brings powerful reinforcement that is forfeited when the person chooses to stop their addictive behaviour. Compliance is therefore a major obstacle to any kind of treatment. Further concerns raised by pharmacological treatment are the risk that the addictive substance will interact dangerously with the medication (i.e., overdose) or that the Person will begin to abuse the medication (if it has abuse liability). For these reasons, pharmacological treatment of addictive disorders remains a very difficult clinical issue for health care providers and scientists attempting to isolate potential medications.

Answer 251

it is absorbed slowly and has a long half life

Answer 252

This module will examine current issues in non-medicinal psychopharmacology. The focus of this week is how to minimize harm associated with non-medicinal psychoactive drug use. An alcoholic woman becomes pregnant. Like many alcoholics, she is unable to curb her drinking, although she knows that it is bad for the developing fetus. The baby is born with a number of birth defects. It also fails to develop normally in several ways. The Children's Aid Society eventually takes custody of the child and charges the mother with child abuse due to her failure to adequately care for the needs of her child while it was inside her womb. Wracked with guilt, the mother takes her two other children to their grandmother's house, and then kills herself. This scenario is made up. However, it illustrates the terrible cost exacted by drugs and alcohol not only on the users of these substances, but also on their children and loved ones. The issues of addiction and personal responsibility clash head on when the unborn child is exposed to drugs that can cause birth defects. There are few good remedies once the damage is done, highlighting the importance of new and better strategies for prevention.

Answer 253

The term "teratogen" comes from Greek. It literally translates to "monster maker." In practice, it refers to any agent that can cause birth defects. Alcohol consumption by a pregnant mother can cause birth defects in her unborn child. These defects are irreversible and manifest themselves over the course of the child's development. Alcohol thus qualifies as a teratogen. How alcohol causes birth defects has not been categorically determined. However, current evidence shows that alcohol (small molecule) passes through the placental barrier (the mesh of densely packed cells that protects and nourishes the fetus). Once inside, alcohol appears to disturb the complex signalling process by which DNA is used to create the various structures in the body and CNS of the fetus. Alcohol may even disturb the DNA code itself, compromising the eventual development of the child, long after it is born. Fetal alcohol syndrome (FAS) refers to a specific set of neurological, morphological, and behavioral deficits that emerge in children who were exposed to alcohol while they were in their mother's womb. It occurs in approximately 0.3 - 1.9 out of every 1,000 (i.e., about 0.1 %) live births. This rate likely underestimates the number of fetuses damaged by alcohol because these cases often end in spontaneous abortion or miscarriage. This is an example of nature taking care of its own.

Answer 254

For example, the ratio of FAS in black Americans vs. the general population is about 6:1. The ratio of FAS in Native Americans (aboriginal peoples) vs. the general population is about 30:1. These differential risk rates likely reflect differences in education about the risks of maternal drinking as well as rates of alcoholism (particularly in the Native community) in pregnant women. The features of FAS can be categorized into neurological, morphological and behavioral deficits. Neurological Deficits include problems in spatial and verbal learning, problems in psychomotor co-ordination and execution of skilled motor acts. The higher functions of planning and abstract reasoning are also likely to be impaired. These impairments sometimes translate into overall deficits in IQ, but sometimes may only emerge on tests specifically designed to assess cognitive executive function. These deficits likely derive from structural brain damage to regions that co-ordinate complex psychomotor function ("basal ganglia) and nerve tissues that connect the two hemispheres of the brain and co-ordinate their activities ("corpus callosum").

Answer 255

The most common physical indicator of FAS is a pronounced 'flattening' of the face and lack of the normal notch between the upper lip and base of the nose. Some children may also display inadequate muscular development and not achieve their normal height.

Answer 256

In addition to the neurological deficits outlined above, children with FAS display poor affect regulation (i.e., proneness to tantrums), and tendency to develop Pica (tendency to eat inedible objects that extends past the infant stage). During adolescence and adulthood, these individuals are more likely to abuse drugs and alcohol themselves. This may represent an effort to mask their cognitive deficits, which may emerge in the form of impaired memory or poor speech fluency. Although no safe level of alcohol use has been defined, FAS is much more common in problem drinkers and alcohol dependent women than in social drinkers. This suggests that the dose required to induce FAS is not trivial. Research with animals shows a direct relationship between the volume of alcohol consumed and the severity of the FAS symptoms. Furthermore, high blood alcohol levels are more likely to cause impairment than low, steady elevations in blood alcohol. This indicates that binge drinking may be a particular risk factor for FAS. Other things being equal, FAS is more likely to occur and the symptoms to be more severe, when alcohol is consumed during the first trimester of pregnancy as opposed to later in the pregnancy. This is because the first trimester is the time when much of the vital hardwiring of the CNS is occurring in the fetus. Disturbance of this hardwiring by alcohol will therefore have more debilitating and more lasting effects than after the basic wiring has already been established (after the first trimester). Tragically, many mothers do not know they are pregnant until well into their first trimester, so that even if they were able to curtail their drinking, the damage may already have been done.

Answer 257

Subtle deficits in cognitive and behavioral functions have been identified in as many as 20% of all children whose mothers drank heavily during pregnancy. These milder spectrum of disorders (called Fetal Alcohol Effects, FAE) is typically only detectable on specialized tests rather than in gross motor, academic, or social functioning. In addition, children with this disorder cannot be recognized based on their appearance. The high prevalence of FAE among children of heavy drinking mothers has led to a general advisory against consumption of any alcohol by the mother during pregnancy. In practice, however, it is highly unlikely that one or two drinks, even if they were consumed before pregnancy was confirmed, would result in any effects whatsoever.

Answer 258

Although the mother has often taken the blame for the teratogenic effects of drinking while pregnant, recent evidence suggests that drinking by the father may also play a role. It appears that heavy paternal drinking can damage the sperm or its genetic contents (DNA), and thereby transfer these deficits to the fetus following conception. Fortunately, fertility in heavy drinking males is often low, reducing the chances that a damaged sperm will successfully fertilize an otherwise healthy egg.

Answer 259

FAS and FAE highlight the issue of pharmacological toxicity and the importance of education and prevention efforts. Toxicity is also the critical concern in the case of so-called "designer drugs." Designer drugs are chemical knockoffs of regular drugs of abuse. These drugs are typically developed by slightly modifying the chemical structure of a known substance thereby preserving many of its subjective and behavioral effects. The motivation to produce designer drugs is twofold: It enables the developer to create his or her own supply for marketing purposes. It circumvents laws against banned substances, which are defined based on a substance's specific chemical structure. Thus, until authorities detect the designer drug and implement laws against the chemical, the developer can technically distribute the drug without criminal repercussions. Three infamous examples: MPPP, MPTP, and Para-methoxy-amphetamine (PMA). Two drugs that exist both as street drugs ("cooked" in clandestine labs) and pharmaceuticals manufactured under standardized conditions by pharmaceutical companies: Fentanyl and MDMA.

Answer 260

This designer drug was developed in the 1940s and emerged as a street drug in the 1980's and went by the name "China White." MPPP was a heroin analogue (chemical derivative) but its potency ranged from 10 to 10,000 times that of heroin,.and went by the street name, "China white." MPPP has since been identified and its manufacture controlled. This synthetic opiate is considered to be the most potent psychoactive chemical known to humankind (replacing LSD, which formerly held this dubious distinction). Because of its extreme potency only physicians trained to manipulate minute doses of drugs (anesthesiologists) typically use the drug, typically in the context of surgery.

Answer 261

Since the potency of any given batch of MPPP on the street could not be established beforehand, users ran the risk of administering a fatal dose with every injection, much like the more recent situation with street versions of the potent pharmaceutical opioid, fentanyl, which is not usually considered a designer drug. Under controlled conditions, including rigorous production control to standardize and verify potency and purity, fentanyl can be a highly valuable treatment for severe acute pain (e.g., post-operative, burns) or chronic (e.g., cancer) pain. Control of dosing of prescription fentanyl is further enhanced by employing slow routes of administration (e.g., trans-dermal/patch)

Answer 262

MPTP is a toxic by-product of faulty production of MPPP. MPTP initially emerged on the street in San Francisco in the 1970's. Extreme and unpredictable potency and potential overdose are not the only dangers of this drug. Doctors first became alarmed when they noticed a spate of cases of heroin users arriving in emergency rooms with a characteristic profile of extreme Parkinson-like symptoms. The muscular rigidity and lack of ability to respond to environmental stimuli led doctors to describe these individuals as "frozen addicts" Although some patients would recover, many did not. Post mortem analysis of the brains of these frozen addicts revealed extensive damage to the dopamine neurons in the same brain regions now implicated in Parkinson's disease.

Answer 263

This amphetamine derivative first emerged in the 1970's when "speed" was a popular street drug pedaled by biker gangs like the Hell's Angels. More recently, PMA has resurfaced in clubs where it is sold as Ecstasy to naïve consumers. During the early stages of intoxication, its effects may be hard to differentiate from Ecstasy. However, by the time the drug has reached peak concentrations in the blood, the individual will likely have experienced a seizure and or cardiac arrest. It is not surprising given this profile of effects that PMA has earned the street name, "death."

Answer 264

A new old designer drug is methylene-dioxy-methaphetamine (MDMA, Ecstasy) MDMA was first synthesized as a blood clotting agent in 1912. At that time, this amphetamine analogue failed to demonstrate its intended effects. Later in the 20th century, MDMA was re-examined along with PCP and LSD as potential tools of mind control (or mind disturbance) by the US armed forces during the cold war. However, MDMA also failed in this regard. In the 1970's a number of psychiatrists began to experiment with the drug as a tool in marital therapy. The powerful empathic effects of the drug were believed to enable trust and communication between spouses whose relationship had deteriorated so significantly that they were unable to connect in any other way. By the 1980's MDMA had resurfaced in Britain where its combined stimulant, mild hallucinogenic and sensory enhancing effects made it popular at dance clubs. In North America this trend emerged with the advent of the Rave culture in the late 1980's and early 1990's. By the turn of the century, MDMA had become the fastest growing drug of abuse in adolescents and young adults. Initial reports from animal studies had shown that MDMA caused damage to serotonin neurons in the brain. However, the doses used were often much larger than would be taken by a human being. By the 1990's the evidence was much more clear: Animals and humans exposed to moderate doses of MDMA (enough to get "high") displayed deficits in serotonin transmission as well as structural damage to serotonin neurons and functional deficits in faculties mediated by serotonin. Two specific forms of deficit that emerge in Ecstasy users are memory impairment and increased impulsivity (loss of control or lack of planning). Recent studies show that this impairment may be irreversible and can emerge after a single dose of the drug. A remaining issue is the contribution of other drugs of abuse to the deficits found in human Ecstasy users. Because it is unethical to administer a potentially toxic drug to human beings in the laboratory, a direct causal link between MDMA and structural or functional toxicity cannot be established. Instead, investigators must assess individuals who have already used Ecstasy and attempt to rule out alternative causes. A major obstacle in this regard is the use of other potential neurotoxins (e.g., meth-amphetamine) by human MDMA users. A major aim of future research therefore is to identify and test individuals who have not used drugs other than MDMA to determine the effects of this drug alone. Despite the lack of unequivocal evidence, the findings from animals and from humans should serve as a warning to any one thinking of trying Ecstasy. Moreover, use of Ecstasy in the context of dancing has the added risk of leading to acute hyperthermia (overheating), organ failure, and death. While rare, this circumstance does occur, confirming that Ecstasy is not at all the benign drug that users assume it is.

Answer 265

Anabolism means the "process of building up." Anabolic steroids are drugs that enable the body to rebuild damaged tissue rapidly and effectively. They are commonly used in the case of athletic injury. In addition, because athletic training involves the break down of muscle fibers during exercise, anabolic steroids are used to speed recovery and facilitate intense training schedules. Considerable evidence also shows that these drugs not only facilitate structural recovery. They also improve function. That is, muscles grow stronger and performance gets better when people take anabolic steroids. Anabolic steroids are chemical derivatives of the male sex hormone, testosterone. Like testosterone, these drugs can alter neurotransmission in the brain. Testosterone is critically involved in libido and associated feelings such as confidence. However, the brain and body are designed to respond to variations in testosterone levels within a given range. Anabolic steroids fool the brain and body into thinking they have more circulating testosterone than they actually do. As in the case of other drugs, this can lead to compensatory processes by the body, which themselves are negative. Prior to the 1980's anabolic steroids were restricted to a small group of elite athletes. By the 1980's they began to be used as tools for enhancing the muscularity of body builders as this sport made its way into the mainstream. By the 1990's anabolic steroid use was common at the high school level, primarily among athletes intent on winning scholarships. At the turn of the century, anabolic steroids were one of only two drugs whose rates of use were on the rise among teens and young adults (the other being Ecstasy). Anabolic steroid use by teenagers and young adults reflects an increasing concern with body size and muscular definition among males. Like cigarettes for females, anabolic steroids appear to facilitate achievement of the body ideal for males. This illustrates the pathogenic effects of media images and unrealistic standards of beauty. As a result, a syndrome called megorexia has emerged that parallels anorexia in females. Megorexics are males who have a distorted perception of their bodies as being too small or too undefined. Such individuals are more likely to use anabolic steroids in conjunction with weight training to restore their shape to what they perceive is normal (which is usually abnormally muscular). Unfortunately, chronic use of anabolic steroids has important health consequences, and can even lead to addiction. Among the physical consequences of anabolic steroid use in males are a decline in spontaneous testosterone production, shrinkage of the genitals, growth of breasts (all reflecting the body's compensation to perceived elevations in testosterone). In females, anabolic steroids can lead to enlargement of the clitoris, emergence of facial hair, and a syndrome referred to as "lantern jaw" (exaggerated growth of the chewing muscles in the jaw). In both genders, anabolic steroids have been linked with tendon injury, loss of bone mass, hypertension, and cancer.

Answer 266

Testosterone can create feelings of confidence. An exaggeration of this state is a form of psychosis that involves delusions of grandeur (beliefs that one is better, more important, or more special, than one really is). This can be accompanied by extreme intolerance for frustration, a syndrome referred to as "Roid Rage." Less severe but more common among steroid users are general increases in aggression and hostility. It is noteworthy that individuals who try to come off steroids after a period of chronic use often report feelings of decreased confidence and depression, which may reflect a compensatory rebound by the body when the drugs are removed (i.e., withdrawal). These feelings may be compounded by the real decline in musculature that accompanies the cessation of steroids. Together, these effects have led some steroid users to report cravings, one of the symptoms that characterizes "psychological" dependence on a substance (the belief that one cannot function without it). Surveys of high school students have found that roughly 25% of steroid users would not stop using them despite the evidence of their harmful effects. While evidence of tolerance to steroids is less clear, the findings on anabolic steroids certainly indicate that these drugs possess the potential for psychological if not physiological dependence. Given their dangerous side effects, this is an important issue to highlight for young athletes, particularly males, who may be at risk of abusing them.

Answer 267

HIV and AIDS are often associated with the homosexual community. However, in terms of the percentage of individuals affected, intravenous drug users represent a much more serious "high risk" group. In North America, roughly 25% of all AIDS cases (55% of female AIDS cases) were contracted through intravenous drug use (sharing dirty needles to inject heroin). Looking at the IV drug use community alone, we find that more than half of all its members are HIV-positive. Thus, in contrast to heroin itself, which is not toxic except in overdose, blood-borne agents like HIV are highly likely to eventually kill individuals who inject heroin. Hepatitis B and C are other infectious diseases that are spread by sharing dirty needles. These diseases attack the liver and impair its ability to cleanse other toxins from the body. These diseases are difficult to treat and, like HIV, often fatal.

Answer 268

The policy of harm reduction acknowledges that it is extremely difficult to stop using heroin and rather than promoting abstinence, aims instead to reduce the negative consequences of heroin use. To this end, institutions that advocate harm reduction typically provide education on the safe use of IV drugs (bleach to disinfect needles) as well as programs to facilitate implementation of safe strategies. These programs include needle exchange, where users can deposit their dirty needles in exchange for clean ones, and free distribution of contraceptives, since unsafe sex can act as a point of first contact in the IV drug use community. In addition, practitioners of the Harm Reduction approach often get involved in outreach programs to access IV drug users who may not otherwise become aware of their risks and options. Although Harm Reduction took root in the IV drug use community, its basic themes of tolerance for drug use and focus on treatment and prevention rather than punishment, have resonated with health care providers in Canada and around the world. Indeed, one of the first legal heroin clinics opened recently in Australia. This is the next step beyond methadone maintenance in acknowledging that heroin itself is far less toxic than the consequences of non-sterile heroin administration. Non-sterile heroin administration in turn is a by-product of criminal sanctions against heroin use.

Answer 269

By the end of the 21st century more than one half billion people worldwide will have died prematurely as a direct result of smoking cigarettes. More than three quarters of these people will have smoked their first cigarette during adolescence. Current statistics show that approximately 2/3 of all adolescents try cigarettes and one third to one half of these eventually become regular smokers. For this reason, some investigators have described adolescent smoking as a "pediatric epidemic." Whereas marijuana has been described as a gateway drug to "hard drug" use, evidence from animals suggests that nicotine is more likely to fit this profile. Specifically, administration of nicotine to animals during the adolescent phase of their lifecycles increases subsequent consumption of alcohol and other drugs of abuse when the animals reach maturity. This appears to result from long-term alterations in dopamine transmission due to adolescent nicotine exposure. Unfortunately, adolescents are experimenters by nature and far less receptive to educational messages about the healthy consequences of smoking than adults. Indeed, developmental elevations in dopamine during the teenage period may contribute to this kind of risk-taking behavior as well as to the vulnerability to become addicted to cigarettes during adolescence. Research shows that symptoms of nicotine dependence (e.g., tolerance and withdrawal) can begin to emerge before the individual is smoking on a daily basis. This reflects the extremely rapid trajectory to dependence in the case of nicotine as compared with other psychoactive drugs. Peer pressure appears to be more important than parental role models as a social factor in starting smoking. However, persistence in smoking after the initial experimental phase may be more related to factors within the individual. For example, depression and attention deficit disorder are two variables that predict the development of nicotine dependence. That is, people who have these disorders before they start smoking are more likely to progress to regular smoker status. Once regular smoking has begun, it is extremely difficult to quit. Moreover, initial studies using conventional anti-smoking strategies (e.g., nicotine patch) have proven ineffective in adolescent smokers, although the reasons for this are unclear. What is clear is that prevention efforts must be improved to stem the epidemic. Primary prevention refers to stopping the behavior before it starts. Based on the finding that a substantial minority of current smokers had their first cigarette before age 10, such prevention efforts must begin in kindergarten. Secondary prevention refers to stopping the escalation of the behavior once it has started. Strategies of zero tolerance, peer counseling, and mentoring by respected adults are now in use to help novice smokers quit before they become addicted. Tertiary prevention refers to stopping relapse in individuals who have already engaged in the behavior extensively. This involves providing support systems for adolescents who have quit smoking (e.g., teenage Addictions Anonymous). These measures have all shown some success, but the problem is far from solved. Creative strategies are needed to address the extremely complex needs of adolescents who are both more sensitive to the reinforcing effects of nicotine and at the same time less sensitive to messages designed to deter smoking.

Answer 270

According to Wechsler and colleagues at Harvard roughly 45% of university undergraduates in North America will have engaged in binge drinking (> 5 standard drinks in a sitting) in any given month. This reflects the strong social message that drinking alcohol is a rite of passage to adulthood. The rates of binge drinking have tripled in the past 30 years, perhaps reflecting increasing pressures or stresses of young adulthood or changing norms in university communities. Fraternities and sororities are major factors promoting binge drinking. The ritual element of heavy drinking is even more important in these institutions than it is in the general student community. In Canada, the correlation between rates of binge drinking on campus and rates of alcoholism in the graduates of different universities suggest that university communities act to socialize a new generation of problem drinkers. Even during the university years, the consequences of binge drinking are apparent. The more alcohol a person drinks, the lower his or her GPA will be. The more alcohol a person drinks, the greater his or her likelihood of dropping out before graduation. Serious non-academic correlates of binge drinking include: physical assault, sexual assault, impaired driving, accidents and suicide. As in the case of adolescent smoking, binge drinking by university students may hide more serious developmental difficulties. For example, social phobia (average age of onset: 16 years) is strongly implicated in the development of alcoholism (average age of onset: 25 years). Thus, alcohol may serve as a means to affiliate with others while at the same time medicating symptoms that would prevent social interaction. In general, drinking to cope with negative affect (depression, anxiety) is a consistent predictor of eventual problem drinking in university students, indicating that alcohol may be enabling some students to deal with the difficult problems of transition to adulthood. Perceptions also fuel university binge drinking. Surveys of undergraduates find that students consistently over-estimate the level of alcohol consumption of their peers. As a result, they may drink more than they otherwise would either to keep pace with others or because they believe that their levels of use are not excessive relative to others.' Primary prevention efforts include increased availability of alcohol-free alternatives at social events and educational efforts to sensitize vulnerable individuals. This is especially important during Frosh Week, where new students are first introduced to their new community. Secondary prevention includes alcohol-free residences as well as alcohol advertising bans on campus. Tertiary prevention includes routine screening for problem drinking at university health services, using questionnaire that are sensitive to incipient (i.e., just beginning) problem drinking. An example of such a questionnaire is the Alcohol Use Disorders Identification Test (AUDIT), which is often given at doctor's offices rather than at facilities that specialize in addiction treatment. The questions on the AUDIT are shown below. Notice how they differ in severity from the questions on the Alcohol Dependence Scale that you encountered in an earlier module. Take the audit to see where you range; this is audit is completely anonymous. Voting Card 0 never during the last year 1 less than monthly 2 monthly 3 weekly 4 daily or almost daily Audit 1. Found it difficult to get the thought of alcohol out of your mind. 0 1 2 3 4 2. Skipped meals because you were drinking. 0 1 2 3 4 3. Experienced that you were not able to stop drinking once you started. 0 1 2 3 4 4. Found it difficult to stop drinking before you became completely intoxicated. 0 1 2 3 4 5. Needed a first drink to get yourself going in the morning after a heavy drinking session. 0 1 2 3 4 6. Been unable to remember what happened the night before because you had been drinking. 0 1 2 3 4 7. Been in a situation where you drank more than your friends. 0 1 2 3 4 8. Been gulping drinks in order to speed up the effect of alcohol. 0 1 2 3 4 9. Failed to do what normally is expected from you because of drinking. 0 1 2 3 4 10. Stayed drunk for several days at a time. 0 1 2 3 4 11. Needed more alcohol than you previously did in order to get the desired effect. 0 1 2 3 4 12. Tried to reduce your alcohol consumption and failed. 0 1 2 3 4 13. Needed to drink alcohol at times of the day when you normally did not drink. 0 1 2 3 4 14. Have had your hands shake a lot in the morning after drinking. 0 1 2 3 4 A score of 8 to 11 = possible problem drinking and a score of 11 or greater = problem drinking. A score of 8 on the AUDIT is the cut-off for hazardous drinking (rate of use that could eventually lead to abuse). A score of 11 indicates alcohol abuse.

Answer 271

1. A range of current problematic issues related to drug and alcohol use. These issues represent areas of special concern with respect to toxicity or addiction to non-medical psychoactive drugs. 2. The concept of "designer" drugs and the key consequence of designer drug use: Toxicity. 3. Sociological and psychological influences on increased rates of anabolic steroid and Ecstasy use. 4. Key concepts underlying the policy of Harm Reduction as it applies to IV drug use and prevention of communicable disease. 5. Impediments to change in adolescent smoking and university drinking behavior.

Answer 272

This article is discussing different drugs that can be used to treat schizophrenia, which is a mental illness that can cause problems with thinking, feeling, and behavior. The article says that there are many different drugs available, and it's important for doctors to choose the best one for each patient based on how well it works and what side effects it might cause. The article talks about studies that have been done to compare different drugs and see which ones work best and which ones have the most side effects. They found that some drugs work better than others, but all of them have some side effects. For example, some drugs might help with negative symptoms of schizophrenia (like lack of motivation or emotion), but might cause weight gain or heart problems. The article also talks about how doctors can use other drugs (like antidepressants) in addition to antipsychotics to help treat symptoms. They also mention that if a patient doesn't respond well to one drug, the doctor might switch to a different one with a different receptor profile (basically, a different way of working in the brain). Overall, the article is saying that there are many different drugs available to treat schizophrenia, and doctors need to consider a lot of factors to choose the best one for each patient. By looking at studies that compare different drugs, doctors can get a better idea of which drugs work best and what side effects to watch out for. Positive symptoms This passage is talking about different medications that are used to treat schizophrenia, a mental illness that can cause a range of symptoms such as hallucinations and delusions. The passage is specifically discussing positive symptoms, which are symptoms that involve the presence of something abnormal, such as hallucinations or delusions. The passage says that there have been studies comparing different medications and how effective they are at reducing positive symptoms. The medications that have been found to be more effective than older medications called FGAs (first-generation antipsychotics) are amisulpride, olanzapine, clozapine, and risperidone. These medications are all called SGAs (second-generation antipsychotics). The passage also mentions that there were few differences among the SGAs, except that olanzapine and risperidone were more effective than quetiapine or ziprasidone. However, the passage notes that these differences may be influenced by the fact that the effectiveness of placebo treatments has been increasing over time. Overall, the passage is summarizing research on which medications are most effective at reducing positive symptoms of schizophrenia. It suggests that SGAs are generally more effective than older FGAs, and that there may be some differences among SGAs, but more research is needed to fully understand these differences. Negative symptoms Negative symptoms in patients with schizophrenia refer to a lack of normal behavior or emotions, such as reduced speech, lack of motivation, or decreased ability to feel pleasure. Many antipsychotic drugs have been tested for their effectiveness in reducing these negative symptoms, but it's often unclear whether the effects seen are due to the medication's direct impact on these symptoms or its impact on other symptoms like depression or side effects. Studies have shown that certain antipsychotic drugs like amisulpride, clozapine, olanzapine, and risperidone are more effective than older antipsychotic drugs in treating negative symptoms in patients with schizophrenia. Recent meta-analyses have also shown that amisulpride and olanzapine may be effective in reducing negative symptoms in patients whose symptoms are characterized as predominantly negative (i.e. with low positive or depressive symptoms). One study even found that a new drug in development called MIN-101 showed promising results in reducing negative symptoms without affecting positive symptoms or depression. However, it's important to note that some studies have specific requirements, such as the need for negative symptoms to be both predominant and persistent, in order to ensure that the results are more reliable. Additionally, there are differences in effectiveness among different antipsychotic drugs, and more research is needed to determine which drugs are the most effective in treating negative symptoms in patients with schizophrenia. Weight and diabetes Some medicines used to treat certain mental health conditions can cause weight gain and problems with blood sugar and cholesterol levels. Different medications can have different effects on weight gain, with some causing more weight gain than others. Olanzapine, zotepine, clozapine, iloperidone, and chlorpromazine are among the medications that have been shown to cause more weight gain than others like haloperidol, ziprasidone, lurasidone, aripiprazole, and asenapine. Studies have also found that some medications like olanzapine and clozapine are associated with a higher risk of diabetes, but the specific risks vary depending on the medication. For example, a consensus statement from the American Diabetes Association in 2004 found that olanzapine and clozapine had the highest diabetes risk, while risperidone and quetiapine had a somewhat lower risk. A recent meta-analysis of various studies reported that all antipsychotics except aripiprazole and amisulpride were associated with increased diabetes risk, and quetiapine and clozapine were associated with higher risk than olanzapine. However, a direct comparison of different medications in patients with schizophrenia found no significant differences in glucose and lipid levels, except for an increase in triglycerides in patients treated with clozapine or olanzapine compared to those treated with risperidone. Extrapyramidal side effects and tardive dyskinesia Extrapyramidal symptoms (EPS) and movement disorders are side effects that were common with the older antipsychotic medications. Newer antipsychotic medications, called second-generation antipsychotics (SGAs), were developed to try and reduce these side effects. Studies have shown that most SGAs are slightly to moderately better than the older medications at reducing these symptoms. Clozapine is especially good at reducing EPS symptoms. Another side effect of the older medications was tardive dyskinesia (TD), which causes involuntary movements of the face and body. Studies have shown that patients who take SGAs have a lower risk of developing TD than those who take the older medications. It's important to note, though, that the studies didn't show whether some SGAs were better than others at reducing TD. Recommendations for maximizing first-line antipsychotic response Choice of first-line antipsychotic The paragraph is discussing different medications for treating symptoms of certain mental illnesses, like schizophrenia. It's comparing different medications and their effectiveness and potential side effects. The first sentence is saying that two medications, olanzapine and amisulpride, are very effective and have a high level of acceptance among doctors and patients. They work well for both positive and negative symptoms of the mental illness. Risperidone is also effective for treating positive symptoms. The paragraph goes on to say that olanzapine might be a good choice for patients where weight gain or diabetes isn't a big concern. Amisulpride is another good choice, as long as the patient isn't at high risk for overdose. However, amisulpride isn't available in the United States. Aripiprazole might be a better choice for patients who need to avoid weight gain and glucose-lipid abnormalities. It's also relatively new and doesn't cause a lot of anxiety-like side effects. The last sentence mentions two newer medications, brexpiprazole and cariprazine, which are also good options for patients who need to avoid weight gain and glucose-lipid abnormalities. These medications have been shown to have no significant effects on glucose-lipid changes and are similar to aripiprazole in terms of side effects.

Answer 273

3.3. How Do You Select an Antidepressant? This passage talks about how doctors and patients should choose the best medicine for treating depression. There are many types of medicine that can be used, but some are better than others. The most common and effective types of medicine are called SSRIs, SNRIs, agomelatine, bupropion, and mirtazapine. These are the ones that doctors will usually try first. However, some people may not respond well to these first-line medications, or they may experience side effects that make it difficult to continue taking them. In these cases, the doctor may recommend second-line medications, such as TCAs, quetiapine, trazodone, moclobemide, selegiline, levomilnacipran, or vilazodone. If these medications still do not work or cause side effects, then the doctor may recommend third-line medications, such as MAO inhibitors or reboxetine. However, these medications are not used as often because they have more side effects or do not work as well as the first- or second-line medications. When choosing a medication, doctors consider many factors, such as a person's symptoms, medical history, and potential side effects. It's important for patients to work closely with their doctor to find the right medication for them. 3.6. How Do Second-Generation Antidepressants Compare in Efficacy? The text is discussing different types of antidepressants and their effectiveness in treating depression. The text explains that there have been studies comparing different antidepressants to see which ones work better. The studies have found that some antidepressants work better than others, but the differences are usually small. The text also mentions a type of study called a network meta-analysis, which compares different drugs based on both direct and indirect comparisons. The studies have found that some antidepressants, such as agomelatine, citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, and sertraline, work better than others. However, there are not enough studies comparing all the different drugs to say which one is definitively the best. The differences in effectiveness between the drugs are usually small, only about 5-6%. Overall, the choice of antidepressant will depend on the individual needs of the patient and their particular case. The text suggests that an individualized needs assessment should be done for each patient to choose the best antidepressant for them. 3.9. Are Antidepressants Associated with Suicidality?

WEEK 1 - Flashcards

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