Lecture 9 - Nicotine

Behaviour and the Brain Part I: Addiction - Nicotine

Outline

  • Brief history of tobacco use
  • Pharmacology
  • Acute effects of nicotine
  • Smoking behaviour
  • Quitting
  • Smoking and health

History

  • Before 1492: Inhabitants of America
  • 1492: Columbus received tobacco leaves, Rodrigo de Jerez became the first known European smoker
  • 16th century: Tobacco introduced in Europe (1560)
  • 17th century: James I (England) condemned smoking in 1604: "He that taketh tobacco saith he cannot leave it, it doth bewitch him"
  • After initial resistance, tobacco use began to spread worldwide

18th Century

*Snuffing in Europe
*Chewing in America

Early 20th Century – Smoking Becomes Mainstream

  • End of 19th century / beginning of 20th century: Smoking tobacco became popular, and tobacco became an important addictive substance.
  • Important developments responsible:
    • New way of drying the leaves, better suited for smoking
    • Mechanization of cigarette production in the 1880s
    • Invention of the match in the mid-19th century
    • New possibilities for advertising
    • Smoking became acceptable for women

Late 20th Century – Smoking in (Slow) Decline

  • US Surgeon General 1957: "Causal relationship between smoking and lung cancer"
  • 1964: Report “Smoking and Health”
  • 1988: “Addictive like heroin and cocaine”

Share of Men and Women Who Smoke (2016)

  • The share of men and women who smoke varies across different regions.
  • The graph shows a comparison of smoking prevalence among men and women in different countries, categorized by region (Africa, Asia, Europe, North America, Oceania, and South America).

Tabak Figures

  • In 2023, 18.1% of young people (12-25 years old) smoked monthly.
  • In 2023, 2.8% of young people used nicotine pouches monthly.

Administration and Absorption

  • Nicotine is primarily administered by sniffing, chewing, and smoking tobacco leaves.
  • Smoking is the most used method due to very rapid absorption and effects (within 10 seconds for cigarettes).
  • Cigar and pipe smokers: shallow inhalation leads to primary absorption through mucosal membranes of mouth and nose.
  • Cigarette smokers: deep inhalation and keeping smoke in lungs before exhaling, leading to absorption through lung membranes.
  • Nicotine patches: absorption through skin is slower but provides extended release for those who want to quit.
  • Half-life of nicotine = 30 minutes (short, broken down quickly).

Nicotine Composition

  • Nicotine is only 1 of 4000 components.
  • Composition of tobacco smoke is influenced by:
    • Exact composition of tobacco
    • The tightness with which tobacco is packed in the cigarette
    • The length of the tobacco column
    • The characteristics of the filter (if one is used)
    • The paper that is used
    • The temperature at which tobacco is burned
  • The harmful effects of tobacco smoke are mostly derived from other tobacco components than nicotine.

Vaping and E-cigarettes

  • Liquid nicotine gets heated by a battery-powered heating element.
  • Similar administration actions as smoking.
  • Fewer non-nicotinic toxic substances (including in secondhand smoke) (?)
  • Poorly regulated, dosages and ingredients vary widely.

Tabak Figures for E-Cigarettes

  • In 2023, 18.1% of young people (12-25 years old) smoked monthly
  • 10.3% of young people used an e-cigarette monthly
  • 69.1% of young people who used e-cigarettes monthly also smoked cigarettes montly.
  • In 2023, 2.8% of young people used nicotine pouches monthly.

Pharmacology

  • Nicotine is carried in smoke on small particles (tar) – in cigarette 8 to 10 mg nicotine, 20% is absorbed.
  • Nicotine in high dose is toxic (lethal dose may be as low as 60 mg), but smokers have good control over nicotine administration via:
    • Depth of inhalation
    • Time of smoke in lungs
    • Time between cigarettes / number of smoked cigarettes
  • Metabolized (80 to 90%) by enzyme in liver (CYP2A6) to cotinine (HL 2hrs).
  • Cotinine often used as an indicator for nicotine use (HL 24h).
  • Lethal dose could be reached if one ingests e-cig liquids because e-cig fluid is very concentrated.
  • Cotinine has a half-life of 24 hours.

Neurotransmitter Families

  • Nicotine binds to nicotinic acetylcholine receptors.
  • Several neurotransmitter families exist, including:
    • Amines (e.g., Acetylcholine)
    • Monoamines (e.g., Norepinephrine, Dopamine, Serotonin)
    • Amino Acids (e.g., GABA, Glutamate)
    • Neuropeptides (e.g., Enkephalins, Endorphins, Dynorphins)
    • Peptides (e.g., Oxytocin, Substance P)
    • Purines (e.g., Adenosine)
    • Lipids (e.g., Endocannabinoids)
    • Gases (e.g., Nitric Oxide)

Nicotine Receptors

  • Two kinds of cholinergic receptors in body
    • Muscarine: muscarine = stimulation, atropine = blockade
    • Nicotine: nicotine = stimulation, curare & mecamylamine = blockade
  • Nicotine attaches to nicotinic acetylcholine receptors (nAChRs) at presynaptic membranes
  • nAChRs are everywhere in brain, including in cortex, basal ganglia, VTA, and nucleus accumbens.
  • Everywhere including very much the reward pathway

Action Potential

  • Nicotine binding causes ion channels to open, leading to an action potential across the membrane.
  • This results in the release of various neurotransmitters
    • Noradrenaline, dopamine, serotonin
    • Glutamate, beta-endorphin
    • Growth hormone, vasopressin, and prolactin
  • Different components of receptor build an ion channel together
  • Nicotine receptors cause them to open & enable ion influx --> depolarization & action potential across the membrane

Physiological Effects (1)

  • Fight-flight response – activation of the body
  • Direct stimulation of reticular activating system (RAS)
  • Increased respiration through effect on respiratory centre – high dose blocks this centre
  • Stimulation vomiting centre brain stem and sensors stomach
  • Arteries skin constrict

Physiological Effects (2)

  • Stimulates reward pathway – addictive
  • Serotonin release raphe nucleus – effect on depression
  • Weight reduction through decrease in appetite
  • Decrease insulin release – smoker somewhat hyperglycemic.
  • Stimulation release ADH, reduced urine production

Effects of Nicotine

  • Al’Absi, 2002
  • 15 male and 15 female smokers
  • 2 lab sessions on 2 days
  • Abstinence – 18 hr not smoking
  • Ad libitum smoking – normal smoking pattern
  • Overall, mood differs across abstinence and smoking
  • Higher depression, anger, anxiety, difficulty in concentration, lesser control, less calm

Increased Cognitive Function

  • Al’Absi, 2002
  • 8 min PASAT
  • Adding up consecutive numbers auditory presentation with increasing speed
  • 8 min mental arithmetic
  • Adding three-digit numbers consecutively
  • Better performance on memory task when smoking
  • NB. Tested in smokers!
  • Abstinent smokers perform worse but tested in smokers --> might be withdrawal effects that cause a decrease in cognitive performance

Nicotine and Task Performance

  • Smoking increases performance on:
    • Tasks that require attentiveness and prolonged concentration
    • Monotonous tasks (speed and accuracy)
    • Motor responses
    • Recall
  • Most studies in smokers who are deprived
  • Nonsmokers less strong effects – exception: strong increase in attention
  • Nicotine naive participants = not strange that something happens then after they get exposed to nicotine
  • Very rare studies, ethical issues

Nicotine and Subjective Effects

  • Effects on feelings and mood can be both stimulating and relaxing (Nesbitt’s paradox)
  • No ‘high’ but light euphoria is possible, especially after deprivation a user is likely to experience a ‘kick’.
  • Smokers respond that nicotine has both a stimulating & relaxing effect
  • Combination of 2 responses that seem to be working in opposite directions = Nesbitt's paradox

Stress and the Desire to Smoke

  • Al’Absi, 2002
  • Desire for a cigarette is increased in stress
  • More in women than in men
  • Stress increases the desire to smoke, especially in women.

Stress and Nicotine Effect on Physiology?

  • Corticosterone levels in rats were found to be lower in the nicotine withdrawal condition (Semba et al. 2004)
  • Al’Absi 2002 study
  • No effect for cortisol but there was an interaction for SBP – greater response during abstinence

Stress, Nicotine, and the Brain

  • (Dagher et al., 2009, Brain Research)
  • 15 smokers
  • 2 sessions, one with and one without stress
  • Stressor: Montreal Imaging Stress Task, followed by drug cues
  • Stress associated with decreased neural activity (hypoactivation) in limbic areas

Craving for Cigarettes

  • No differences in session - as time increases craving also increases.
  • The difference between smoking and control video is larger in stress situations
  • More brain activation during stress related to higher cue reactivity.

Smoking Behavior

  • Nicotine seems to control smoking behavior: variations in blood level lead to variations in smoking behavior
  • The duration of every puff decreases and the time between puffs increases when smoking a cigarette
  • Experienced smokers: keep nicotine in blood at one level (usually about 20 to 40 nanogram / millilitre plasma)
  • Smoking behavior can temporarily change under certain conditions – stress, cold or illness, pregnancy.

Blood Nicotine Levels

  • The figure shows blood nicotine levels of an inhaling smoker, smoking one cigarette an hour.

Chain Smoker

  • Peaks not so discernable from the valleys anymore as the level is quite high constantly
  • Hypothesis: we primarily see smoking out of negative reinforcement to prevent level from dropping
  • Could also be related to behavioral addiction (this is ritualized behavior)
  • People do this without thinking about it, they smoke unconsciously

Tolerance and Dependence

Tolerance
  • First time smoking a cigarette may lead to nausea and vomiting – tolerance for this effect develops rapidly
Dependence
  • Self-administration in humans and animals
  • Both physical and psychological dependence
  • 6 hours after last cigarette: decrease heart rate and blood pressure
  • Withdrawal syndrome (within 24 hours): intense craving, headache, concentration problems, irritation, drowsiness, tiredness, sleeplessness, anxiety, anger and increased appetite
  • Craving may last months or even years

Measuring Addiction - Fagerström Questionnaire

  • The Fagerström questionnaire is used to measure nicotine dependence. It includes questions such as:
    1. How soon after you wake up do you smoke your first cigarette?
    2. Do you find it difficult not to smoke in places where you shouldn't?
    3. Which cigarette would you most hate to give up?
    4. How many cigarettes do you smoke each day?
    5. Do you smoke more during the first few hours after waking up?
    6. Do you still smoke if you are so sick that you are in bed most of the day?
  • Scoring: 7-10 points = highly dependent; 4-6 points = moderately dependent; less than 4 points = minimally dependent.

Fagerström Questionnaire

  • (Min Park, Drug and Alcohol Dependence, 2004)
  • Scores are related to cotinine levels and are higher in those who inhale deeply, smoke for more years, and started at a young age.

Smoking Cessation

  • In general: 5 to 10% of those who attempt to quit smoking are still abstinent after one year
  • New Year's resolution study in the Netherlands:
    • 1 January 2000 – more than 600,000 smokers quit smoking
    • 6 out of 10 lasted more than one week
    • 12% had not smoked yet by January 1st, 2001

Therapy

  • Most stated reason for smoking cessation is concern about own health
  • About 2/3 of smokers who attempt to quit do so without any help
  • Remaining: courses, advice GP, nicotine replacement (patches, chewing gum, tablets), acupuncture or hypnosis, or other method
  • Medication to counteract craving and withdrawal are nicotine replacements (1st choice), partial agonists (reduce withdrawal but block effect nicotine) and anti-depressants (bupropion).
  • Psychological treatment
  • Vaccine: long-term effects not yet favorable

Effect of Drug Therapy

  • Abstinence rates were higher with bupropion + patch compared to bupropion alone, nicotine patch alone, or placebo.

Abstinence

  • Varenicline had a higher percentage of smokers maintaining abstinence over a 52-week period compared to Bupropion SR and placebo.
  • Though adverse effects may prevent general use and often long-term results are less promising.

The Effects of Smoking

  • Nicotine binds to nicotine receptors on dopamine neurons in the ventral tegmental area, increasing dopamine release in the nucleus accumbens.

Smoking and Health

Health Risks

  • WHO projects 2020-2030: 10 million deaths per year due to smoking.
  • Every cigarette removes 14 minutes of life
  • 2 packs per day during 20 years means loss of 8 years.

Mechanisms by Which Smoking Leads to Heart Disease

  • Smoking leads to the release of catecholamines, increasing heart wall tension and contraction velocity.
  • Contributory factors include atherosclerosis, platelet stickiness, increased carboxyhemoglobin, and modulation of oxygen affinity for hemoglobin.
  • This disparity between the needs for and availability of oxygen can lead to angina, infarct, and death.
  • Chronic obstructive lung disease is also associated with smoking.

Carotid Artery Thickness

  • Smoking effects on thickness of the lining of the carotid artery (Howard et al. 1998).
  • N: Nonsmoker, P: Past Smoker, C: Current Smoker (+/- E): Environmental tobacco smoke.

Cancer

  • No doubt about relation with lung cancer.
  • Smoking is most important cause of lung cancer in men and women
  • One explanation: BPDE (metabolite) leads to damage to a cancer suppressor gene
  • Also more cancer of mouth, vocal cords, throat, pancreas, bladder, cervical cancer

Lung Disease (Non-Cancer)

  • Chronic smoking causes smoker’s syndrome:
    • Problems in respiration,
    • Wheezy breathing,
    • Pain in chest,
    • Lung obstruction,
    • More infections of the airways.
  • Increased risk for emphysema
  • 70% of lung disease is tobacco-associated
  • Non-smokers exposed to second-hand smoke have an increased risk of heart and lung disease

Comorbidity

  • Smoking often co-occurs with other addictions and psychiatric disorders.
  • Depression scores in depression patients who get treatment with nicotine patches (Salin-Pascual et al., 1996)
  • Anti-depressants do help in some cases to quit smoking.
  • Possibility of smoking as self-medication for depression

Smoking, Depression, and the HPA-Axis

  • (Rao et al., 2009)
  • 151 adolescents (48 no depression, 48 at risk for depression and 55 with depression)
  • 5-year follow-up, at intervals measurement of smoking, depression, and life events
  • Both HPA-axis and life events were associated with smoking initiation.
  • Relation smoking and depression was reduced after controlling for HPA-axis and life events

Nicotine and Personality

  • Walther et al. 2012:
  • Cross-sectional data 2553 German students (12-25 yrs)
  • Clear differences in most personality traits
  • Not all associations remain when adjusted for age, gender, migration background, SES, and parental monitoring

Smoking, Comorbidity and Cognition

  • Alzheimer’s: Conflicting results regarding cognitive improvement with nicotine in AD patients. Research continues into therapeutic possibilities of nicotinic drugs.
  • Schizophrenia: Results are inconsistent.
  • ADHD: Studies with adults who have ADHD are slightly more positive in supporting a cognitive effect from nicotine, consistent with the high rate of smoking in this population.
  • Parkinson’s: Stronger evidence suggesting a protective role for nicotine receptors in Parkinson’s disease.