Nicotine and Caffeine Notes

• Nicotine

  Nicotine and Caffeine Notes

  • Nicotine is an alkaloid found in tobacco leaves.

  • It was unknown to Europeans until Columbus's expedition but quickly became popular.

• Cigarettes became popular in the mid-19th century.

• E-cigarettes heat and vaporize a nicotine solution for inhalation.

Nicotine Pharmacokinetics

• Cigarettes contain 6 to 11 mg of nicotine, with 1 to 3 mg reaching the bloodstream, depending on smoking behavior.

• Nicotine enters the lungs on tiny particles called tar, a complex mixture of hydrocarbons, some carcinogenic.

• It's rapidly absorbed through the lungs, reaching the brain within 7 seconds of the first puff.

• Absorption is less efficient when chewing or snorting snuff.

E-cigarettes

• Many designs have been introduced.

• Most flavorings regulated or banned to reduce attractiveness to children.

• Nicotine concentrations in e-liquids vary.

Nicotine Metabolism

• Elimination half-life is about 2 hours.

• The principal metabolite is cotinine, catalyzed by cytochrome P450 2A6 (CYP2A6), and excreted in urine.

• Estrogens increase CYP2A6 expression, leading to faster nicotine metabolism in women.

• Menthol inhibits CYP2A6 activity, slowing conversion to cotinine.

• Genetic variation in CYP2A6 activity affects smoking behavior and quitting success.

Nicotinic Receptors

• Subunit composition determines receptor features like affinity, ionic selectivity, allosteric binding sites, and channel kinetics.

Mechanism of Nicotine Action

• Nicotine activates nicotinic cholinergic receptors (nAChRs), which are ionotropic and produce rapid excitatory responses.

• Receptor subunit composition affects affinity for agonists and antagonists.

• nAChRs containing α7 subunits enhance neurotransmitter release presynaptically.

• High-affinity nAChRs desensitize rapidly in the presence of nicotine, reducing ACh transmission.

Behavior and Physiological Effects

• Smoking-related mood changes involve both pharmacological (nicotine) and nonpharmacological factors.

• In smokers, nicotine produces a calm or relaxed state, partly relieving withdrawal symptoms.

• Nicotine administration to nonsmokers can cause heightened tension, arousal, lightheadedness, dizziness, and nausea.

• Expectations significantly influence subjective effects.

Cognitive Function

• Nicotine enhances cognitive function, with ACh playing an important role.

• Enhancement of attention task performance is most evident in people with a low baseline level of attention.

• Research uses subunit-selective antagonists and knockout mice to determine which subunit combinations mediate cognitive enhancement.

• High-affinity nAChRs play a more important role than low-affinity nAChRs in mediating nicotine’s enhancement of hippocampal-dependent tasks.

Reinforcements

• Nicotine exerts both reinforcing and aversive effects.

• Reinforcement can be influenced by many factors, including sex and age; females and adolescents are more sensitive.

• The mesolimbic DA pathway from the VTA to the NAcc plays a key role.

• Research using knockout mice: high-affinity nAChRs subunits β2, α4, and α6 are involved in reinforcement; polymorphisms in human genes for these subunits are linked to subjective effects of smoking and risk of dependence.

• Brain imaging shows nicotine occupancy of high- affinity α4β2 subunit–containing nAChRs.

Aversion

• Aversive effects: nausea, dizziness, sweating, headache, palpitations, stomach ache, and clammy hands

• Aversion is dependent on nAChRs containing the α5 subunit

• Knocking out the α5 subunit enhances nicotine self-administration at high doses

• Genes for the nAChR α5, α3, and β4 subunits are on human chromosome 15; a mutation in the α5 gene results in less aversion to nicotine and heavier smoking behavior

Physiological Effects

• Nicotine produces a wide range of physiological effects

• Smoking can activate both sympathetic and parasympathetic systems, causing a wide range of physiological effects

• Tachycardia and elevated blood pressure can increase risk of cardiovascular disease.

• Release of NE and EPI from adrenal glands contributes to arousing effects of nicotine

• Reduces appetite and increases metabolic rate, resulting in weight loss; also affects GI tract.

Toxicity

• Nicotine is a toxic substance that can cause severe distress or even death at high doses

• Accidental poisoning can result from swallowing (mostly by children), contact with tobacco in the field, or insecticides.

• Green tobacco illness: nicotine exposure in field workers

• Toxic to insects and other animals

• An extremely high overdose may end with convulsions and fatal respiratory failure due to depolarization block of the respiratory muscles

Tolerance and Dependence

• Chronic exposure to nicotine induces tolerance and dependence

• Acute tolerance: brief; due to desensitization of central nAChRs

• Smokers undergo acute tolerance during the course of a day; after overnight abstinence, smokers awaken more sensitive to nicotine than at the end of the previous day.

• Chronic tolerance from long-term exposure: Smokers show an up-regulation of nAChR levels in many brain areas, may be a response to chronic receptor desensitization associated with repeated nicotine exposure

Tolerance and Dependence

• Nicotine is a highly addictive drug.

• Compulsive cigarette use is characterized by successive stages of wanting, craving, and finally needing a cigarette

• Withdrawal when trying to quit has three kinds of symptoms: affective (mood related), somatic, and cognitive

• Animal models given continuous exposure to nicotine show withdrawal symptoms; a stronger response occurs if a nicotinic receptor antagonist such as mecamylamine is given

Cigarette Smoking and Vaping

• What percentage of the population are current users of tobacco and/or e-cigarettes?

• Smoking in the U.S. increased up to the 1960s; cigarette smoking in films was a major influence

• Declines since then are related to Surgeon General’s reports on health consequences, antismoking ads, high cigarette taxes, and societal disapproval of smoking.

• Overall, cigarette smoking is gradually declining across the population; e-cigarettes are gradually replacing tobacco cigarettes.

Cigarette Smoking and Vaping

• Nicotine users progress through a series of stages in their pattern and frequency of use

• Most smokers begin in adolescence; many theories as to why adolescents start

• Significant predictors: poor academic performance, rebelliousness, sensation seeking, receptivity to marketing, smoking by family and/or friends

• Intermittent smokers: develop a habit of non-daily smoking; daily smokers score much higher on standard test of nicotine dependence

Cigarette Smoking and Vaping

• Adolescents now use more e- cigarettes than tobacco cigarettes.

• e-cigarette users have less parental support/monitoring, more parental conflict, less academic involvement, poorer behavioral and emotional self- control and regulation

• Several hypotheses have been proposed to explain the initial choice of e-cigarettes over tobacco cigarettes; many e- cigarette users undergo a transition to tobacco cigarette smoking

The Why?

• Why do smokers smoke and vapers vape?

• Conditioning: sensory and environmental cues associated with smoking

• Stress and negative affective states, especially anxiety

• Nicotine resource model: mood control and enhanced concentration are dual motivation

• Deprivation reversal model: alleviation of irritability, stress, and poor concentration in withdrawal; having a smoking habit increases overall stress, which then must be countered by repeated smoking

• Other chemicals in cigarettes – flavor additives; chemicals that inhibit MAO

Dual Motivation

• Nicotine consumption can affect both reward/reinforcement and cognitive enhancement

• Activation of both mesocoritcal and mesolimbic DA pathway regulates two distinct responses

Health Hazards

• Smoking is a major health hazard and a cause of premature death

• Cigarette smoking increases long-term risk for several kinds of cancer, cardiovascular disease, respiratory disease, and many others.

• Contributing factors: carbon monoxide and tar which contains toxic compounds and carcinogens

• There is a very strong relationship between smoking and cardiovascular disease

• Epigenetic effects; may increase disease risk even if smoker has quit

• Smoking may increase risk of contracting COVID-19 and severity of the illness

E-Cigarette Safety

• There are fewer toxic chemicals and lower levels of these chemicals in e- cigarette vapor than in cigarette smoke

• But e-liquids do have toxic chemicals: aldehydes like formaldehyde and metals, generated by pyrolysis of constituents such as glycerin.

• Health effects have been studied using human and animal models, cell culture, and epidemiological research

• e-cigarette, or vaping, product- associated lung injury (EVALI): a novel disease identified in 2019

Health Hazards

• Smoking is a major health hazard and a cause of premature death

• Smoking during pregnancy: chemicals in cigarette smoke pass through the placenta

• Animal studies: prenatal nicotine results in abnormal brain development, hyperactivity, cognitive deficits, increased anxiety, diminished lung function, hypertension, increased risk for obesity and cancer

• Human clinical studies: increased incidence of stillbirth, SIDS and low birth weight

• Developmental origins of health and disease hypothesis: characteristics of the intrauterine environment “program” the fetus in a way that determines subsequent vulnerability for developing chronic diseases

Health Hazards

• During adolescence the brain is still developing

• Animal and human studies: nicotine leads to long-term changes in neurotransmission, altered dendritic branching, deficits on various behavioral tasks, and increased risk for developing depression, anxiety disorders, and addiction

• Use of vaping products by young people may pose a hazard to their neurobehavioral development.

Treatments

• Behavioral and pharmacological strategies are used to treat tobacco dependence

• Self-help materials

• Cessation advice: 5As, Ask-Advise-Refer (AAR); refer to cessation programs such as SmokefreeTXT or quit-START app

• Individual or group counseling

• Medications

• Addiction to nicotine is so powerful that quitting success rate is quite low, even with medication

Treatments

• Nicotine replacement therapy (NRT): relieves withdrawal symptoms with nicotine gum and lozenges, transdermal patch, nasal spray and inhalers; e- cigarettes are potential NRT

• Non-nicotine drugs – most effective with behavioral intervention: Bupropion (Zyban), a DA and NE reuptake inhibitor and weak nAChR antagonist

• Varenicline (Chantix), a partial agonist at high- affinity α4β2 nAChRs.

• Nicotine vaccine – no efficacy in clinical trials

Caffeine

• Seeds of the plant Coffea arabica are the major source of caffeine; one of the most widely used drugs in the world

• Tea contains caffeine and theophylline

• Other sources: cocoa beans, kola nuts, yerba mate, and guarana berries

Energy Drinks

• Energy drinks contain high levels of caffeine plus sugar and specialty ingredients – amino acids, ginseng, sodium, vitamins

• There is evidence that they can boost energy and alertness, alleviate fatigue, counteract effects of sleep deprivation, improve athletic endurance and performance, increase concentration

• Side effects: elevated heart rate and palpitations, jitteriness, headache, GI upset and abdominal pain, insomnia, mood changes, depression, feeling stressed

Caffeine Pharmacology

• Basic pharmacology of caffeine

• Normally consumed in drinks; completely absorbed from the GI tract in 30 to 60 minutes; plasma half-life is about 4 hours

• Converted to metabolites in the liver: first to paraxanthine, a CNS stimulant just like caffeine

• Further breakdown of paraxanthine leads to metabolites that are mostly excreted in the urine.

Beahvioural Effects

• Animal studies: caffeine has biphasic effects – a stimulant at low doses, effect is reversed at high doses

• Caffeine is taken to stimulate arousal, increase concentration, and reduce fatigue

• There are significant individual differences in sensitivity to caffeine but in general, doses > 400 mg cause tension, jitteriness, and anxiety

• Caffeine enhances muscle strength and power, and it facilitates athletic performance, particularly in endurance sports

Beahvioural Effects

• Behavioral and physiological effects of caffeine

• Regular caffeine use leads to tolerance and physical dependence.

• Symptoms of withdrawal include headache, drowsiness, fatigue, impaired concentration, reduced psychomotor performance, sometimes mild anxiety or depression

• Relief from withdrawal is a major factor in chronic coffee drinking

Caffeine Disorders

• Behavioral and physiological effects of caffeine

• Consumption of high doses associated with two psychiatric disorders:

• Caffeine intoxication – restlessness, nervousness, insomnia, tachycardia, muscle twitching, GI upset

• Extremely high doses (3 to 5 g or more) can produce severe toxicity and even death

• Caffeine use disorder – 3 criteria: difficulty in reducing caffeine use, continued caffeine use despite knowledge of effects, and withdrawal symptoms upon abstinence

Psotivie/Negative Effects

• Behavioral and physiological effects of caffeine

• Caffeine use during pregnancy dose- dependently increases the risk of miscarriage, stillbirth, and low birthweight.

• Medical uses: analgesic, apnea in newborns, pediatric asthma,

• Epidemiological studies: 3 to 5 cups of coffee per day reduces vulnerability to obesity, type 2 diabetes, liver cirrhosis, several kinds of cancer, Parkinson’s disease and age-related dementia; attributed mainly to antioxidant and anti-inflammatory substances in coffee

Mechanism of Action

• Caffeine acts through the adenosine receptor

• Adenosine is crucial for regulating sleep

• Caffeine keeps you awake by blocking adenosine receptors.

• Normally, when adenosine binds to its receptors, neural activity slows down and you feel sleepy.

• When caffeine binds to those receptors, it blocks their activity, allowing neural activity to speed up, so you feel alert!

Mechanism of Action

• Inhibition of cAMP phosphodiesterase, blockade of GABAA receptors, stimulation of Ca^{2+} release in cells, and blockade adenosine receptors

• A2A receptors form heteromeric complexes with DA D2 receptors in the striatum.

• Adenosine activation of striatal A2A receptors has a negative allosteric effect on D2 receptors

• Blockade of adenosine receptors, particularly A2A subtype, underlies caffeine- induced behavioral stimulation