Nicotine addiction

Question 1

give an overview on tobacco

Answer 1

• Leaves of Nicotiana tobacum cured and (usually) smoked and sometimes chewed (potent poison for bugs/keeps them away).
• Indigenous to North America - given to C Columbus when landed in San Salvador in 1492.
• Smoked by natives for medicinal, ceremonial purposes (~1 B.C.) (enhancing fertility, predicting weather, conducting war councils, enabling vision quests, making peace).
• No society that has adopted tobacco has ever given it up!

Question 2

what are some facts on smoking?

Answer 2

• Tobacco addiction is the LEADING preventable cause of death in Western societies.
• 1.3 Billion smokers worldwide and contributes to appx 5 million death a year (WHO).
• Half of all smokers die prematurely as a consequence of their addiction.
• WHO data shows that Europe still has the highest overall smoking rates.
• UK rates have fallen to 16.9% (2015).
• Service cost over £61 million last year (UK).
• Smoking prevalence is linked to socio-economic status and vulnerable populations.
• Non-smokers exposed to environmental tobacco smoke (passive smokers) have a significantly higher risk of developing cancers and pulmonary diseases. Children exposed to second hand smoke develop a variety of respiratory disorders and morbidity.
• Only 3-5% of smokers who want to quit succeed without NRT and only 1/3 succeed with them.

Question 3

what is the main compound in cigarettes that are involved in addiction?

Answer 3

The major if not sole compound responsible for driving the addiction to smoking and thus a formidable obstacle to the prevention of tobacco related deaths is NICOTINE.

Nicotine mimics some of the actions of acetylcholine.

It exerts its effects on nicotinic receptors (nAChR) – ion channel receptors for which acetylcholine is the endogenous ligand.

Question 4

describe nicotine absorption

Answer 4

Nicotine is readily absorbed across intact skin. This allows for transdermal administration of nicotine as a therapeutic adjunct to tobacco cessation.

Conversely, the bioavailability of nicotine in the gastrointestinal tract is limited. Absorption across the gastric mucosa is poor as a result of low gastric pH. In the small intestine, nicotine is well absorbed due to increased pH; however, the systemic bioavailability is low (30%) because it undergoes significant first-pass hepatic metabolism. Oral nicotine formulations (e.g., sublingual tablets and lozenges) are not subject to first-pass hepatic metabolism.

Nicotine is rapidly absorbed across respiratory epithelium in the lungs.
Passes freely through the BBB and reaches brain in 11 secs.

Question 5

describe nicotine metabolism

Answer 5

Nicotine is metabolized extensively in the liver and to a lesser extent in the kidney and lung.
Approximately 70–80% of nicotine is metabolized to cotinine, an inactive metabolite, and about 4% is metabolized to nicotine-oxide.
The metabolism of nicotine to cotinine is a two-step process likely involving CYP2A6 and aldehyde oxidase.
Cotinine is further metabolized to 3′-hydroxycotinine, which undergoes renal elimination. However, nicotine, cotinine, and 3′-hydroxycotinine also undergo glucuronidation.
A small fraction (10–20%) of an administered dose of nicotine is excreted as unchanged drug in the urine.

Question 6

what is the half life of nicotine?

Answer 6

The half-life of nicotine in the body is approximately 2 hours. This rapid metabolism of nicotine to inactive compounds underlies tobacco users’ need for frequent, repeated administration of nicotine. With regular tobacco use, significant nicotine levels accumulate during waking hours.

Question 7

what is the half life of cotinine (nicotine’s major metabolite)?

Answer 7

The half-life of cotinine (nicotine’s major metabolite) is much longer (18–20 hours). For this reason, cotinine can be used as a more reliable biomarker of tobacco use and exposure to second-hand smoke.

Question 8

How can the daily intake of nicotine be estimated?

Answer 8

The daily intake of nicotine can be estimated from a measured plasma cotinine level using the following equation:
Daily dose of nicotine (in mg) = plasma cotinine concentration (ng/ml) x 0.08

Example: A smoker absorbs, on average, approximately 1 mg of nicotine per cigarette. A person with a plasma cotinine concentration of 300 ng/ml would be expected to smoke approximately 24 cigarettes per day:
300 ng/ml x 0.08 = 24 mg = 24 cigarettes (1 mg = 1 cigarette)

Question 9

describe nicotine excretion

Answer 9

Nicotine and other metabolites are excreted in the urine. Urinary excretion is pH dependent; the excretion rate is increased in acidic urine. Nicotine accumulates in breast milk and can be detected in the blood and urine of infants of nursing smokers.

Question 10

what are the pharmacodynamics of nicotine?

Answer 10

Nicotine pharmacodynamics refers to the effects that nicotine has on the body. Nicotine is a potent agent that affects numerous organ systems, including the cardiovascular, endocrine, musculoskeletal, and neurologic system. Following absorption, nicotine binds to receptors in the brain and other sites in the body, inducing a variety of predominantly stimulant and, to a lesser extent, sedative effects.

Question 11

what are the pharmacodynamic effects of nicotine on the central nervous system?

Answer 11

• Pleasure: Tobacco users commonly report they find tobacco use pleasurable.
• Arousal, enhanced vigilance: Tobacco use may help with thinking, concentration, and mood elevation.
• Improved task performance: Nicotine has been shown to increase vigilance and performance for some types of tasks (e.g., repetitive/monotonous tasks).
• Relief of anxiety: Many tobacco users report reduced anger, tension, and stress after administration.

It is not known whether the improvements in mood or task performance are due to relief of nicotine withdrawal symptoms or a direct effect of nicotine on the brain.

Question 12

what are the pharmacodynamic effects of nicotine on the cardiovascular system?

Answer 12

Nicotine’s effects on the cardiovascular system include increased heart rate, cardiac output, and blood pressure as well as cutaneous and coronary vasoconstriction. After a cigarette is smoked, the smoker’s blood pressure rises by 5–10 mmHg for 15–30 minutes, and the heart rate increases an average of 10–20 beats/min for up to 60 minutes. Studies suggest there is a flat dose-response to the cardiovascular effects of nicotine. This so-called ceiling effect might be due to a rapid but partial development of tolerance to the cardiovascular effects of nicotine.

Question 13

what are some other pharmacodynamic effects of nicotine?

Answer 13

Nicotine is an effective appetite suppressant and causes modest acute increases in the metabolic rate. Most people who quit using tobacco will gain weight, although the average person will gain less than 10 pounds. Weight gain after tobacco cessation is a major concern for many patients, especially females. Nicotine also causes relaxation of some skeletal muscle. Withdrawal effects include vomiting, nausea and headache due to tolerance. Other effects of nicotine include slow stomach secretion, acting as a laxative and formation of wrinkles.

Question 14

what are the neurochemical and related effects of nicotine?

Answer 14

On a neurochemical level, nicotine induces a variety of central nervous system, cardiovascular, and metabolic effects. Nicotine stimulates the release of many neurotransmitters, which have been associated with the following effects…

• Dopamine–>Pleasure, reward
• Norepinephrine–>Arousal, appetite suppression
• Acetylcholine–>Arousal, cognitive enhancement
• Glutamate–>Learning, memory enhancement
• Serotonin–>Mood modulation, appetite suppression
• b-Endorphin–> Reduction of anxiety and tension
• GABA–>Reduction of anxiety and tension

Question 15

Nicotine induces a constellation of effects that reinforce tobacco use behavior.

Answer 15

mad

Question 16

describe the nicotinic acetylcholine receptors (nAChRs)

Answer 16

• Ligand-gated ion channels (mostly Na+/K+).
• Widespread in the CNS.
• Acetylcholine (Ach) is the endogenous ligand.
• The major role in mammalian CNS is to influence neurotransmitter release.
• Pentamer…
  • 5 polypeptide subunits
  • 9 subtypes (a1, a2, a3, a4..a7, b1, b2 etc)
  • Potential for 59 = 2 million different assemblies

• Nicotine is a potent agonist at the nicotinic a4b2 receptor.
• Nicotine dependence is modulated primarily through a4b2 nACh receptors.
In b2-subunit knock-out mice nicotine does not produce reinforcing effect (less dopamine is released and mice do not self-administer nicotine). Nicotine does not activate VTA neurons of b2 KO mice. In these mice nicotine does not promote DA release in striatum.

Question 17

name the two main diffuse modulatory cholinergic systems acetylcholines (monoamines) work on

Answer 17

Two main diffuse modulatory cholinergic systems – basal forebrain complex / septohippocampal pathway and nucleus basalis (cognitive function / Alzheimer’s disease) and motor control (striatal).

Question 18

nAchRs:

• Used a self-administration model and mice
• Put nicotine inside the container and look at the self-administration behaviour of the of WT mouse and alpha4-beta2 KO mouse
• In normal mouse: increased lever pressing activity for nicotine to be injected into the brain
• In KO mouse: no reward at all–> this is because it requires alpha4-beta2 receptor for nicotine to bind and cause a rewarding effect

Answer 18

Also wanted to investigate if the receptor was associated with an increase in dopamine release from the nucleus accumbens.
• Therefore, they did a microdialysis experiment: probe in nucleus accumbens of mouse= measured dopamine releasing in KO mouse and WT mouse —>
• WT mouse: increasing dose of nicotine= increase in dopamine
• KO mouse: nothing
• nicotine acts on these receptors= activates them= increased dopamine in nucleus accumbens= rewarding effect

Question 19

describe the reinforcing effect of nicotine- “Reward” pathway

Answer 19

• Nicotine interacts with the ‘reward’ pathway.
• Nicotine releases dopamine in the nucleus accumbens and dorsal striatum in vitro and in vivo.
• nAChRs are found on both cell bodies and axon terminals of dopamine neurones but they can also modulate GABA and glutamate release.

Question 20

describe nicotine regulation of the DA system

Answer 20

Nicotine acts both presynaptically and postsynaptically to activate the mesolimbic pathway and cause the release of dopamine.

Question 21

what are the three states of the nAChR ion channels?

Answer 21

1. Closed (at rest) – not activated by any ligand.
2. Open (cations flow into the cell) – in response to ligand binding.
3. Desensitised (closed and not responsive to agonists) – after being bombarded with ligand – NEURADAPTIVE MECHANISM.

Question 22

describe nAchR activation

Answer 22

• Ach (or nicotine) binds to the receptor and stabilises the open state of the ion channel for several milliseconds.
• Cations (Na+ and K+) enter and depolarise the cell initiating cellular response.
• A variety of neurotransmitters are released in the CNS as presynaptic nAChRs are present on various types of neurons.
• ACh is rapidly broken down by acetylcholine-esterase.
• Nicotine has much longer duration of effect than Ach.
• Receptor becomes de-sensitised and unresponsive for a period of time.

Question 23

what happens to nAChRs with repeated smoking?

Answer 23

Between cigarettes nAChRs are mainly desensitised (acute tolerance).
Next cigarette activates a small pool of receptors that are still responsive, producing pleasurable effects.
In chronic smokers (e.g. with daily smoking for 6 months or longer):
• Tolerance.
• Withdrawal syndrome on cessation of smoking.
• Long-term desensitisation of nAChRs.
• Increase in receptor density (upregulation of nAChRs) as a compensatory response to desensitisation of the large proportion the total number of nAChRs receptors – autopsy studies comparing smokers to nonsmokers reveal up to 400% increases in brain nicotine receptors. Reversibility extent, time course, and variability is unclear. Increased receptors associated with tolerance and dependence.

Question 24

outline the cycles of pleasure and withdrawal

Answer 24

Cycles of pleasure and withdrawal:

1. Initial activation causes pleasure response.
2. However, dopamine falls quickly over the next 2 hours.
3. As levels fall the smoker feels displeasure or withdrawal.
4. The next cigarette reduces the cravings and other withdrawal symptoms and produces some positive effects.
5. This reinforces the compulsion to smoke.

Environmental cues are also important in producing addiction.

Question 25

outline nicotine’s plasma concentration

Answer 25

• Each cigarette delivers 1.2-2.9mg of nicotine.
• A typical pack-a-day smoker absorbs 20-40mg of nicotine each day.
• Half-life is ~ 2hours.
• During a typical day, nicotine accumulates over 6-8 hours (3-4 half-lives).
• The increment is 5-30ng/ml after each cigarette (depending on how the cigarette is smoked).
• More frequent smoking reduces fluctuations in nicotine plasma concentration.
• The plateau (10-50ng/ml) is usually reached in the early afternoon.

Question 26

LOOK AT THE NICOTINE ADDICTION CYCLE GRAOH.

describe it

Answer 26

To alleviate the symptoms of withdrawal, smokers re-dose themselves throughout the day. This figure depicts the typical nicotine addiction cycle a cigarette smoker experiences on a daily basis.
• The jagged line represents venous plasma concentrations of nicotine as a cigarette is smoked every 40 minutes from 8 am to 9 pm.
• The upper solid line indicates the threshold concentration for nicotine to produce pleasure or arousal.
• The lower solid line indicates the concentrations at which symptoms of abstinence (i.e., withdrawal symptoms) from nicotine occur.
• The shaded area represents the zone of nicotine concentrations (neutral zone) in which the smoker is comfortable without experiencing either pleasure/arousal or abstinence symptoms.

Question 27

After smoking the first cigarette of the day, the smoker experiences marked pharmacologic effects, particularly arousal. No other cigarette throughout the day produces the same degree of pleasure/arousal. For this reason, many smokers describe the first cigarette as the most important one of the day. Shortly after the initial cigarette, tolerance begins to develop. Accordingly, the threshold levels for both pleasure/arousal and abstinence rise progressively throughout the day as the smoker becomes tolerant to the effects of nicotine.

With continued smoking, nicotine accumulates, leading to an even greater degree of tolerance. As a result, the smoker experiences greater withdrawal symptoms between successive cigarettes. Late in the day, each individual cigarette produces only limited pleasure/arousal; instead, smoking primarily alleviates nicotine withdrawal symptoms.

Answer 27

Cessation of smoking overnight allows resensitization of drug responses (i.e., loss of tolerance). Most dependent smokers tend to smoke a certain number of cigarettes per day (usually more than 10) and tend to consume 10–40 mg of nicotine per day to achieve the desired effects of cigarette smoking and minimize the symptoms of nicotine withdrawal.

Question 28

describe nicotine addiction

Answer 28

Tobacco users tend to carefully titrate, or regulate, their tobacco intake to maintain a relatively constant level of nicotine in the body, in order to…
• Prevent withdrawal symptoms.
• Maintain pleasure/arousal.
• Modulate mood (e.g., to handle stress or anxiety).
Although many tobacco users might not think about it consciously, they are able to alter nicotine delivery in a number of ways, including
• By smoking or dipping more frequently.
• By smoking more intensely (e.g., inhaling deeper or longer, smoking cigarette down to the filter).
• By obstructing the vents (with fingers or lips) on “light” cigarettes, thereby increasing the amount of nicotine delivered to the lung.

Question 29

describe how withdrawal symptoms arise and what they are like

Answer 29

• Nicotine plasma concentration significantly drops overnight, which leads to withdrawal symptoms in the morning in chronic smokers.
• Withdrawal onset is usually within a few hours after last cigarette.
• Nicotine withdrawal syndrome includes: mood changes, dysphoria, depressive mood, irritability, frustration or anger, anxiety, restlessness, difficulty concentrating, impaired attention, hunger, increased appetite or weight gain, craving.

First morning cigarette produces the most pleasurable effect…
• After an overnight abstinence, more receptors become available for activation.
• It also relieves withdrawal symptoms.

The earlier the smoker begins to smoke after waking in the morning the more severe the dependence.
If abstinence continues, withdrawal symptoms peak at 24-48 hours and gradually subside over several weeks.
Some symptoms persist for months…
• Mild depression, dysphoria and anhedonia.

Question 30

name the factors contributing to tobacco use

Answer 30

Nicotine is a powerful drug capable of inducing a variety of pharmacologic effects, including an alteration in brain chemistry. However, tobacco addiction is more than just a brain disease. It is a complex process involving the interplay of many factors (pharmacologic, environmental, and physiologic) that influence an individual’s decision to use tobacco. As such, treatment of addiction requires a multifaceted approach.

• environmental factors
• social interactions
• pharmacologic factors
• physiologic factors

Question 31

describe the environmental factors contributing to tobacco us

Answer 31

• Tobacco industry advertising: For years, the tobacco industry has engineered major marketing plans to design more addictive cigarettes and to defy the public regarding the hazards of smoking. Their multibillion-dollar marketing effort is an important contributor to tobacco use.
• Conditioned stimuli: All drug-taking behavior is learned, a result of conditioning. Drug-taking behavior is reinforced by the consequences of the pharmacologic actions of the drug. At the same time, smokers begin to associate specific moods, situations, or environmental factors with nicotine’s reward effects. The association between such cues and anticipated drug effects and the resulting urge to smoke is another type of conditioning. For example, people often smoke cigarettes in specific situations, such as after a meal or with coffee or alcoholic beverages. The association between smoking and these other events, repeated many times, causes the environmental situations to become powerful cues for the urge to smoke. A nondrug example of this type of conditioning is the desire to eat popcorn at the movies.
• Other aspects of smoking (e.g., manipulation of smoking materials, taste, smell, feel of smoke in the throat) become associated with the pleasurable effects of smoking. Even unpleasant moods can become conditioned cues for smoking. For example, a smoker may learn that not having a cigarette provokes irritability, a common nicotine withdrawal symptom. Smoking a cigarette relieves withdrawal symptoms. After repeated similar experiences, a smoker may come to regard irritability from any source, such as stress or frustration, as a cue for smoking.

Question 32

describe the social factors contributing to tobacco use

Answer 32

Having family or peer-group members who smoke increases the likelihood of tobacco use and, therefore, addiction. Among adolescents, peer pressure is often a reason for initiating tobacco use.

Question 33

describe the pharmacologic factors contributing to tobacco use

Answer 33

As discussed previously, there is a pharmacologic basis for a nicotine-dependent individual’s decision to use tobacco.

Question 34

describe the physiologic factors contributing to tobacco use

Answer 34

Experts now believe that some individuals have a genetic predisposition for nicotine addiction. Additionally, the impact of coexisting medical conditions (especially psychiatric conditions) increases an individual’s likelihood of using and becoming dependent on tobacco.

Question 35

how to genetic play a part in nicotine addiction

Answer 35

Heritability ~50% (range 28-84%).
Effect of gene polymorphisms…
• People with defective alleles of CYP2A6 gene have slow metabolism of nicotine and lower rates of smoking and tobacco dependence.
• People with CHRNA4 gene polymorphism (gene coding for α4 subunit of the nicotinic Ach receptor) have higher rates of tobacco dependence.

Question 36

Genetic variation in CHRNA5, the gene encoding the alpha-5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was “Rescued” in knockout mice by re-expressing alpha-5 subunitS in the medial habenula (MHb) and recapitulated in rats through alpha-5 subunit knockdown in MHb.

Answer 36

Remarkably, alpha-5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems.

Increased nicotine intake in α5 knockout mice…

• Nicotine intake has bell-shaped concentration curve.
• Up-phase represents rewarding component, unaffected by deletion of a5.
• Down phase reflects the aversive effects of higher doses of nicotine, significantly greater responses in a5 KO.

Question 37

Identification of novel pathway (habenulo-interpeduncular) that transmits inhibitory motivational signal which limits nicotine intake (opposes mesoaccubens reward). This showed that nicotine acts both in the mesolimbic pathway to increase dopamine and in the habenulo-interpeduncular system to oppose the reward system. If this inhibition is removed, self-administration continues despite the toxic effects of high nicotine doses.

Answer 37

mad

Question 38

what are some facts regarding smoking and mental health?

Answer 38

• People with psychiatric disorders and substance use disorders have 2-4 times higher rates of smoking (range 41% and 67% respectively) than the general population.
• 40-88% of patients with schizophrenia smoke.
• Higher rates of depression in smokers.
• Higher rate of smoking in substance abusers.
• Suggests common mechanism underlying nicotine addiction and other psychiatric disorders.

Question 39

does smoking have any health benefits?

Answer 39

Possibly reduces symptom severity in schizophrenia (self-medication hypothesis)…
• There is deficient endogenous central nicotinic neurotransmission in schizophrenia, which causes a disruption of sensory gating (a possible mechanism for delusions).
• Exogenous nicotine partly compensates for this deficiency.
• Schizophrenic patients smoke larger amounts of cigarettes per day and extract more nicotine from them – significant health risk.
• Therapeutic use of safe forms of nicotine in schizophrenia has been proposed.

Reduces risk of Parkinson’s disease…
• Benefit correlates with the intensity and duration of smoking.
• Does not appear to be due to publication bias.

Does it reduce prevalence of Alzheimer’s disease?
• After controlling for tobacco industry affiliation, smoking has been found to increase the risk of Alzheimer’s disease, RR -1.72.

Question 40

how is tobacco dependence a two part problem?

Answer 40

Tobacco dependence is a chronic brain disease and is a condition that requires a two-prong approach for maximal treatment effectiveness.
Prolonged tobacco use of tobacco results in tobacco dependence, which is characterized as a physiological dependence (addiction to nicotine) and behavioral habit of using tobacco. Addiction can be treated with FDA-approved medications for smoking cessation, and the behavioral habit can be treated through behavior change programs, such as individualized counseling and group or online cessation programs.

Physiological: the addiction to nicotine…treatment: medications for cessation

Behavioral: the habit of using tobacco…treatment: behaviour change program