Lecture 17 - Nicotine 1 Flashcards
(21 cards)
What was cigarette advertisement like during WW2?
Advertisements promoted cigarettes as a product aimed to help soldiers cope with the stresses of the war
What is cigarette packaging like now?
Awareness of health hazards
Introducing barriers to access to younger people (minimum of 20 cigarettes)
Unappealing e.g. larger health warnings, prominent graphic images, pantone 448C (least appealing colour), ‘smoking clogs your arteries’, ‘get help to stop smoking’
Increased duty
What health and economic impact does nicotine have?
Smoking is a health hazard and leading cause of premature death e.g. stroke, CV disease, lung cancer
UK government spends up to £17 billion per year on treating tobacco-related illness and promoting abstinence/prevention
Whole-body PET scans illustrating reduced MAO-B activity in smokers (Fowler et al., 2003)
Describe the tobacco plant
Tobacco cultivation requires mild, sunny climate
Top producers: China, India, Indonesia, Zimbabwe, Brazil
Nicotine biosynthesis takes place in the roots of tobacco plant and accumulates in the leaves
Nicotine is an insect-targeting neurotoxin, was used as an insecticide
Nicotine constitutes around 0.6-3% of dry weight of tobacco
Describe the pharmacology of nicotine
A cigarette contains 6–11 mg of nicotine, but only 1–3 mg is absorbed
Nicotine attaches to tar molecules of cigarette smoke
Tar is acidic and making conditions more suitable for nicotine absorption across lung alveoli into blood stream
Absorption profile is fast and spiked (within minutes)
Arterial nicotine (travelling away from heart/lungs) rose more rapidly and reached higher peak relative to venous blood, suggesting that nicotine is rapidly delivered to target sites in central nervous system
This fast ‘hit’ leads to stronger reinforcement (key factor in habit formation and substance dependence)
Which form of nicotine reaches the brain fastest?
Compared to oral forms (e.g., gum, patch), inhaled nicotine (smoking and inhalators) reaches the brain much faster due to rapid lung absorption, direct arterial transport
Pure nicotine in inhalators (with no tar) has to be at an extremely high dose to achieve the same level of absorption as a cigarette
This difficulty in replicating the fast, spiked, absorption profile of cigarettes was a significant hurdle for the nicotine replacement industry
What are the neural mechanisms of nicotine?
Nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs)
The neurotransmitter acetylcholine (ACh) is a ‘neuromodulator’ which can influence activity in target cells
ACh plays an important role in learning and intellectual function; degeneration in this system is seen in Alzheimer’s disease
Describe acetylcholine receptor activity
Nicotine activates ACh neurons in the pedunculopontine nucleus (PPT)
These neurons excite dopamine-producing cells in the ventral tegmental area (VTA)
→ This occurs indirectly via a branching pathway
As a result, nicotine increases dopamine release in the mesolimbic pathway
→ Specifically, from the VTA to the nucleus accumbens
This dopamine surge is believed to play a central role in the development of addiction
What is dopamine activity like in the VTA?
Rats were administered tobacco smoke (Fa et al., 2000)
Dopamine activity was measured by microelectrode placed in ventral tegmentum (‘VTA’)
Increased activity observed following tobacco administration, but reduced with administration of nicotinic receptor (nAChRs) antagonist - Mecamylamine
How is nicotine related to brain stimulation reward?
Rats learn to press a lever to obtain electrical brain stimulation reward of the mesolimbic dopamine pathway
Unlike natural reward, such behaviour does not require deprivation (Panksepp & Trowill, 1967)
Can displace other rewards, rats choosing stimulation reward over food to the point of starvation (Routtenberg & Lindy, 1965)
What has been found about nicotine self-administration?
Rats self-administered nicotine directly into the VTA → indicates nicotine has rewarding effects
Blocking dopamine receptors (SCH 23390) stopped self-administration → suggests nicotine’s effects depend on dopamine.
Conclusion: Nicotine stimulates ACh receptors → Increases dopamine activity in the VTA → increased activity mediates the addictive properties of nicotine
Blocking acetylcholine (ACh) receptors (using DHBE) also stopped self-administration → Nicotine acts through ACh receptors -> dopamine receptors
What is dopamine activity like in the ventral striatum?
Increased activity in the target cells, particularly dopamine, is thought to drive the rewarding/reinforcing effects of nicotine (in humans as well as rats)
How does nicotine metabolism act as a susceptibility factor?
Differences in nicotine metabolism due to genetic variations may account for differences in susceptibility across individuals
Slower metabolizers of nicotine need to smoke fewer cigarettes per day, thus reduces the likelihood of becoming dependant
How is adolescence a susceptibility factor?
One vulnerability factor is age of first exposure
Tobacco usage is higher in smokers adopting the habit earlier (18-25 years) rather than later (over 26 years of age)
What has been shown about smoking in adolescent rats?
Rats given the opportunity to self-administer (lever press for) nicotine
Adolescent rats worked harder for nicotine and took a larger amount of nicotine than adults (Levin et al., 2003)
Conclusion: adolescents are more vulnerable to nicotine addiction
What is clinical dependence according to the DSM?
Diagnostic and statistical manual of mental disorders (DSM)
Tolerance: Find that you had to use much more tobacco than you once did to get the effect you want?
Withdrawal: Often use tobacco just after getting up or shortly after getting up in the morning?
Escalation of dose: Have a period when you often used tobacco more than you intended to?
Difficulty cutting down: More than once wanted to stop or cut down on your tobacco use?
Reduce other activities: Give up or cut down on activities that you were interested in or that gave you pleasure because tobacco use was not permitted at the activity?
Use despite problems: Continue to use tobacco even though you knew it was causing you a health problem or making a health problem worse?
Describe nicotine dependence
High proportion of users become dependent - 60% of current smokers meet the DSM criteria for nicotine dependence (Donny and Dierker, 2007)
Tobacco highest % of ever-users who became dependent (Anthony et al., 1994)
However, not all smokers become dependent. At least 10% of current smokers are long term low-rate smokers (Hyland, 2005)
Conclusion: tobacco dependence is not the inevitable consequence of exposure to tobacco, but an interaction between exposure and individual vulnerability
What are the withdrawal effects of nicotine?
ACh receptors become desensitised through chronic coupling after prolonged exposure
This leads to withdrawal effects when nicotine is stopped: urges and cravings, irritated, anxious, restlessness, concentration difficulties, sleeping difficulties
Smokers adjust their cigarette use to maintain nicotine levels sufficient to avoid withdrawal effects
When do lapses occur?
Long-term smoking cessation is challenging
Smokers who had just quit recorded the situations in which they lapsed in diary studies
Almost 100% of lapses occurred when cigarettes were available and smoking was allowed
These data suggest situational cues for drug availability/acceptability play a critical role in maintaining drug use
What is nicotine replacement therapy?
Provides nicotine in an alternative form, helps reduce cravings and withdrawal effects, making it easier to quit smoking
Alleviate withdrawal symptoms by maintaining acetylcholine (ACh) receptor occupancy
However, it may lead to a transfer of dependence rather than completely eliminating nicotine addiction
How may Bupropion be used to prevent nicotine relapse?
Bupropion (an antidepressant marketed as Zyban) is thought to reduce the negative emotional effects of withdrawal, helping to prevent relapse. It works by inhibiting the reuptake of dopamine and noradrenaline
The 12-month sustained abstinence success rate is relatively low, with approximately 2% of individuals achieving long-term abstinence using a placebo
The success rate increases to about 5% for those using either NRT or bupropion (Wang, 2008; Wu, 2006)
