Lecture 6

Question 1

Serotonin

Answer 1

Serotonin (5-HT) is important for many aspects of behavior such as mood, anxiety, sleep, and digestion. At least 19 different serotonin receptors. Serotonin hypothesis of depression: psychiatric medications, in particular antidepressants, target serotonin. Effects of medication are contingent on the particular receptor type targeted. This is well-known in the public, most misunderstood and misrepresented neurotransmitter because of the press. It’s not a homogeneous agent, and its psychological functions are moderated by the receptors it binds to. Midbrain raphe nuclei connect to forebrain. Brainstem raphe nuclei connect to spinal cord.

Question 2

Glutamate and GABA

Answer 2

Most common neurotransmitters in the brain are amino acids. Glutamate is excitatory (EPSP), GABA is inhibitory. Glutamate is important in LTP (dendritic remodeling of the brain, learning/memory). Glutamatergic transmission employs AMPA and NMDA receptors (learning, LTP). GABA is a target of anxiolytic medications. Inhibiting is also important.

Question 3

Neuropeptides

Answer 3

Peptides (small proteins) act as neurotransmitters at some synapses, or as hormones. Opiod peptides mimic opiate drugs such as morphine and reduce perception of pain - enkephalins, endorphins, dynorphins. Endogenous opiods reduce pain perception (implicated in placebo response). Opiod receptors are the target of many narcotics. Peptide hormones include oxytocin and vasopressin (pituitary hormones). Synapse action - precise localized. Hormones - distal effects. These tend to be exictatory (most things except GABA are). Oxytocin - lactation, biological mechanism, but also psychological things like attachment and warmth. More distancing and increase of prejudice towards outgroup, tribalistic attachment, distancing from non-family.

Question 4

Neurotransmitters and drugs

Answer 4

Neurons process information through electrical responses and release a chemical into the synapse to inform the next cell. Neurochemistry focuses on the basic chemical composition and processes of the nervous system. The presynaptic neuron releases an endogenous ligand - a chemical neurotransmitter. Neuropharmacology is the study of chemical compounds that selectively affect the nervous system. Exogenous substances from external sources, such as drugs and toxins, have been used for ages to alter brain functioning. Certain molecules happen to by chance have a relationship to our brains and bind with the brain to create effects.

Question 5

Drugs as molecular locks

Answer 5

Ligands are molecules that fit into a receptor protein and activate or block it. Endogenous ligands: neurotransmitters or hormones made inside the body. Exogenous ligands: drugs and toxins from outside the body. Receptor agonist - exogenous molecule (drug, toxin) that fits into a receptor and acts like a neurotransmitter. Receptor antagonist - drug, toxin that fits into a receptor and blocks the action of a neurotransmitter. Endogenous molecules that activates a receptor is an agonist. Exogenous molecules are receptor agonists, and exogenous blockers are antagonists. These aren’t excitatory or inhibitory, they’re just opening or blocking. Some drugs modulate neurotransmission too.

Question 6

Synthetic drugs can target specific receptors

Answer 6

Many different receptor subtypes for a given neurotransmitter. Nature of the receptor determines the action of the ligand. Synthetic drug development targets specific receptors. Serotonin agonist of 5-HT2 has a different effect than serotonin 5-HT3 receptor. Because receptor subtypes have different localizations and functions, drugs can have varying effects. Not all drugs interact with receptors, e.g. SSRIs block serotonin transporters (but serotonin theory of depression is under question because SSREs also help depression). Pharmacology can target any part of neurotransmission.

Question 7

Routes of drug administration

Answer 7

Look in book for chart - ingestion, inhalation, peripheral injection, central injection. Inhalation is fast because of the capillaries in the olfactory system. Rate of effect is essentially how quickly it gets into the bloodstream. Fastest is injecting it right into the cerebrospinal fluid. Blood brain barrier - tight junctions between the cell walls of blood vessels that inhibit movement of larger molecules out of bloodstream and into brain. Makes sense because you don’t want toxins in your brain. Poses a challenge for neuropharmacology.

Question 8

Drug tolerance

Answer 8

Repeated treatments over the long term can reduce the effectiveness of drugs as drug tolerance develops. Metabolic tolerance - organ systems become better at eliminating the drug. Functional tolerance - target tissue may show altered drug sensitivity by changing the number of receptors. Neurons down-regulate receptors in response to an agonist drug (fewer receptors available). Neurons up-regulate receptors in response to an antagonist drug (more receptors are available). Cross tolerance - tolerance to a drug is generalized to other drugs in its class.

Question 9

Mechanisms of drug action

Answer 9

Drugs can target many aspects of presynaptic and postsynaptic processes. Presynaptic - Production: inhibition of synthesis, blockade of axonal transport, interference with storage. Release: prevention of transmission, alteration of the synaptic transmitter release, modulation of transmitter release by presynaptic receptors. Clearance: inactivation of transmitter reuptake, blockade of transmitter degradation. Postsynaptic - receptors - blockade of receptors, activation of receptors. Cellular processes - alteration of number of postsynaptic receptors, modulation of second messengers.

Question 10

Psychiatric Drugs

Answer 10

Depression is the most burdensome illness in the world. Psychiatric symptoms seem to be on the rise (awareness but also failure being on you), antidepressants aren’t really treating depression. Despite spending about 15 billion per year on antidepressants, rates of it have increased over the past 25 years. Similar profiles for other disorders.

Question 11

Antipsychotics and Antidepressants

Answer 11

Traditional antipsychotics act as selective antagonists of the dopamine D2 receptor (initially developed as an antihistamine - lots of psychiatric medications are developed by chance). More recent atypical antipsychotics target both dopaminergic and serotonergic receptors. Antidepressants increase synaptic transmission of monoamines. MAOIs block enzymatic degradation of serotonin, dopamine, and norepinephrine. Tricyclic antidepressants block reuptake of serotonin and norepinephrine. SSRIs (prozac, zoloft) act specifically at serotonergic synapses. SSRIs have the same efficacy as the older ones, but they have fewer side effects.

Question 12

Placebo

Answer 12

Much of antidepressant efficacy is placebo. In more severe depression, you can differentiate the placebo and the more pharmacological effect. However, in mild to moderate depression, maybe there is not a serotonergic mechanism. It may be targeting neurogenesis in the hippocampus.

Question 13

Recreational drugs

Answer 13

They all elevate dopamine transmission in the nucleus accumbens, and this drives their pleasurable effects. This is critical for understanding addiction.

Question 14

Alcohol

Answer 14

Has biphasic effects. Initial stimulant phase involves stimulation of the dopamine pathways (euphoria, pleasure). Has a more prolonged depressant phase involving increase in GABAergic activity (social disinhibition, motor control, attentional myopia). Chronic alcohol abuse damages the brain. Cells of superior frontal cortex (personality), cerebellum (balance), and hippocampus (memory) show particularly prominent pathological changes. Excessive bingeing suppresses neurogenesis in the hippocampus. Korsakoff syndrome - chronic memory disorder caused by deficiency of thiamine (vitamin B1) secondary to alcohol abuse.

Question 15

Quitting alcohol

Answer 15

Increases in anterior cortical gray matter, decrease in the size of the lateral ventricles. Example of neuroplasticity.

Question 16

Marijuana

Answer 16

Derived from cannabis sativa plant - main ingredient is THC. Variable effects: relaxation, mood alteration - stimulation, hallucination, and paranoia in some cases. Brain contains cannabinoid receptors that mediate the effects of THC (there are more cannabinoid receptors than any other receptors, and these are all over the brain). This is the highest concentration of any receptor in the brain. Endocannabinoids are analogs of THC produced in the brain that activate CB receptors, such as anandaminde. Endocannabinoids are critical for many functions, including brain development. Look at book for chart. Biggest predictor of addiction is age of use. Adolescents who use marijuana are more likely to develop psychosis in adulthood. People with a certain variant of the COMT gene are more likely to develop psychosis in response to marijuana use (gene x environment, COMT involved in enzymatic degradation of catecholamines). Persistent marijuana use is associated with profound reduction in brain connectivity and volumetric reduction in limbic areas of the brain involved in emotion and memory. Persistent cannabis users show cognitive decline from childhood to midlife (ruling out preexisting deficits).

Question 17

Opiates

Answer 17

Operate on mu-opiod receptors. Highly addictive, come from poppy flower. Morphine is the psychoactive substance in opium - analgesic. Heroin, Oxycontin, and Vicodin are derivatives of morphine. Opiod receptors in the periaqueductal gray (pain perception, homeostasis, has the mu-opiod receptors) are central to the analgesic effect. The brain generates its own morphine like compounds - endogenous opiods. Ventral striatum and nucelus accumbens also have mu-opiod receptors. There are differential rates of tolerance in different parts of the brain. Nucleus accumbens - quick, want it more, tolerance happens. Periaqueductal gray - slow, risk of overdose. People want more but aren’t tolerant enough yet.

Question 18

Cocaine

Answer 18

Stimulant. It blocks monamine transmitters, thus slowing reuptake of these. They accumulate in synapses in the brain (like dopamine). Cocaine generates a strong increase in dopamine transmission in the mesolimbocortical reward circuit, especially the nucleus accumbens. Crack is a smokable form of cocaine, it enters the blood stream faster and thus is more effective. Rats who self-administer (tested through microdialysis), see increase in dopamine in nucleus accumbens when using cocaine.

Question 19

Amphetamine and Methamphetamine

Answer 19

Also stimulants. They have multiple mechanisms of action on monoamines (especially dopamine). They work first in the axon terminals, causing larger than normal release of neurotransmitter as well as release in the absence of an action potential. Then they interfere with the reuptake and degradation of monamine neurotransmitters in the synaptic cleft. Tolerance develops quickly. Leads to symptoms resembling psychosis (dopamine salience model). This is also an L-Dopa side effect.

Question 20

Caffeine

Answer 20

Adenosine is typically co-released with other neurotransmitters (catecholamines) as a negative feedback mechanism. When activated, presynaptic adenosine autoreceptors reduce subsequent neurotransmitter release. Caffeine blocks adenosine autoreceptors for catecholamines, resulting in elevated and sustained release of catecholamines (dopamine, epinephrine, norepinephrine). Same thing as cocaine but milder.

Question 21

Hallucinogens

Answer 21

First research at Harvard in the 1960s. Hallucinogens alter sensory perceptions in dramatic ways. The structure of LSD resembles serotonin, and LSD evokes visual hallucinations by activating serotonin (5-HT2A) receptors in the visual cortex. Ecstasy/MDMA is a hallucinogenic amphetamine derivative. Stimulates those same receptors as LSD. Also changes the level of dopamine and of the hormone prolactin (wanting to touch people, released in childbearing, after orgasm, why there’s a tactile component to the drug), explaining the sensory component of drugs. Dissociative drugs produce feelings of depersonalization and detachment from reality. Phencyclidine or PCP/angel dust and ketamine/Special K are both MDMA glutamate receptor agonists.

Question 22

Neural correlates of LSD

Answer 22

LSD used to be considered untouchable from a scientific perspective. Now using LSD to understand consciousness. LSD gets stuck in receptors sometimes, why it wears off slowly, flashbacks. Operates on the serotonin system, visual cortex and other networks. Elevated resting state functional connectivity associated with ego dissolution.

Question 23

Ketamine

Answer 23

Depression treatment. Works on glutamate, glutamate modulates dopamine (depression), also spotlight on self in depression, so depersonalization may help. Dissociating from reality is terrifying for a lot of people.

Question 24

Neuroscience of addiction

Answer 24

All forms ultimately hijack the mesolimbocortical dopamine pathway. Down regulation of D2 receptors in the nucleus accumbens leads to wanting (midbrain dopamine - it’s a habit oriented circuit, so addiction is also related to habit learning) and craving. They don’t get pleasure out of the drug anymore, just attenuating the craving. Opponent process - needs substance to stay at homeostasis. Reward-deficit model of addiction - people go out to maximize positive emotion, the risk factor is low reward-related brain function, depresssion has low, and these covary. PET - down-regulation of dopamine in ventral striatum with addicts (is it pre-existing or a consequence?). Reward-hypersensitivity model - too much sensitivity causes sensation seeking. Both are probably part of it or are different roads to addiction.