It appears that the dependence liability of inhaled nicotine is also influenced by other constituents of tobacco smoke, such as chemicals that inhibit monoamine oxidase , an enzyme that degrades neurotransmitters released by nicotine, discussed in more detail later. Furthermore, dependence on nicotine from medications that deliver nicotine slowly appears to be low. On average, smokers absorb 1 to 1.5 mg of nicotine from a cigarette . Nicotine has an average half-life of 2 hours, but the half-life can be affected by genetic and environmental factors. With regular smoking, nicotine levels rise in the blood over 4 to 6 hours, plateau throughout the day, and then decline overnight. Thus, although each cigarette produces a spike of arterial nicotine with a rapid decline between cigarettes, in a regular daily smoker, the brain is exposed to nicotine for 24 hours each day. This duration of expo sure has implications for the development of tolerance and withdrawal symptoms, as discussed later. Nicotine is primarily metabolized by the liver enzyme, CYP2A6 . The main proximate metabolite is cotinine, which has been widely used as a biomarker of nicotine exposure. CYP2A6 activity is strongly influenced by genetic and environmental factors. Genetic variants associated with a slow rate of nicotine metabolism are more common in people of Asian and African descent compared to Caucasians. Environmental influences on nicotine metabolism include estrogen: Premenopausal women metabolize nicotine faster than men; women taking estrogen containing birth control pills metabolize nicotine faster than women who do not; and pregnant women metabolize nicotine fastest of all.
Various foods and medications can also affect nicotine metabolism. The rate of metabolism affects smoking behavior,pot drying with faster me tabolizers smoking more cigarettes per day . Brain mechanisms. Nicotine acts on nicotinic acetylcholine re ceptors that are found throughout the nervous system. Acetylcholine is a neurotransmitter that acts on nearly every organ in the body, and similarly, nicotine affects nearly every organ in the body. Many subtypes of nAChRs are present in the brain. Each receptor is composed of five subunits.When nicotine binds to the outside of a nAChR, an ion channel opens, allowing entry of calcium, sodium, or potassium ions. Initially, the receptor is activated, which is then followed by desensitization. nAChRs can exist in three conformational states: closed, in the resting state; open, allowing ion entry and membrane depolarization; and desensitized, where the receptor is unresponsive to nAChR agonists . The sensitivity to nicotine and the pharmacodynamics of response vary based on the particular receptor type, which translates into differential development and time course of tolerance to different nicotine effects. Mood, cognitive, and relaxation effects of smoking are thought to occur via nicotine’s stimulation of presynaptic nAChRs . Activation of these receptors results in facilitation of release of various neurotransmitters, including dopamine, which is known to signal pleasure and is released by all drugs of abuse; norepi nephrine and acetylcholine, which enhance vigilance and cognitive function; glutamate, which enhances memory and learning; serotonin, which affects mood; and g-aminobutyric acid and endorphins, which ameliorate stress and anxiety. The neural connections involving nicotine actions are complex. Nicotine affects the mesolimbic dopamine system, which is central in the neurobiology of addiction.
Nicotine binds to nAChRs in the ventral tegmental area, which then activate dopamine neurons in the nucleus accumbens. The firing of dopamine neurons is modu lated by GABAergic and glutaminergic neurons such that glutami nergic neurons enhance firing, while GABAergic neurons inhibit firing. This up regulation has been thought to be a response to nAChR desensitization, but more recent studies suggest that up-regulation occurs by a chaperoning mechanism . That is, nicotine appears to bind to nAChRs in the cell to facilitate assembly and chaperoning the receptors to the cell membrane. Up-regulation of nAChRs is thought to be related to the development of physical dependence, including the withdrawal symptoms that occur when nicotine exposure stops. Presumably, the up-regulated receptors that are inactive in the presence of nicotine become sensitive again during nicotine abstinence. Two other neurotransmitter systems appear to play important roles in nicotine dependence. Hypocretins are neuropeptides that regulate the effects of nicotine on reward centers in the brain, found to influence nicotine self-administration in animals . The insular cortex contains a high density of hypocretin-1–containing neurons. Immediate and sustained reduction in craving and withdrawal symptoms has been observed in hospitalized smokers following stroke damage to the insular cortex compared to hospitalized smokers without brain lesions .In time, the brain adapts to the persistent effects to normalize brain function and related behavior. When nicotine exposure is stopped, brain function is disrupted and put in a state of with drawal. Nicotine withdrawal results in activation of the corticotropin releasing factor system involved in the hypothalamus pituitary adrenal stress response.
Withdrawal symptoms, such as anxiety and stress, are thought to be mediated, at least in part, by a relative underactivity of the dopaminergic system and hyperactivity of the CRF system. Antagonists of the CRF receptor reduce the anxiogenic effects of nicotine withdrawal and reduce self-administration of nico tine in the withdrawal state . Dependence on nicotine appears to be augmented by other chemicals in cigarette smoke. Acetaldehyde, for example, increases self-administration of nicotine in animals. Particular chemicals in cigarette smoke inhibit the activity of the enzyme MAO in the brain . MAO catalyzes the breakdown of dopamine, norepinephrine, and serotonin, which are neurotransmitters that mediate nicotine reward. In animals, administration of drugs that inhibit MAO enhances nicotine self-administration. MAO-inhibiting medications have been used to treat depression. As discussed later, people with psychiatric illness, including depression, are more likely to smoke and to be more highly dependent. One theory is that MAO inhibition from smoking may have beneficial effects in depressed smokers. However, while acute smoking abstinence is associated with depressive symptoms and anxiety, prolonged quitting generally improves mood, including among smokers with psychiatric disorders such as depression .Positive psychoactive effects of nicotine include pleasure, stimulation, and mood modulation, with reduced anxiety and stress . A smoker often reports pleasure and stimulation with the first cigarette of the day,cannabis drying stimulation and increased concentration from smoking during repetitive tasks during the day, and relaxation at times of stress and at bedtime. However, tolerance develops to many of nicotine’s effects such that even within the day, the pleasure experienced from each cigarette diminishes. As nicotine levels decline, withdrawal symptoms develop, reversing nicotine’s positive effects. Thus, an abstinent smoker may feel anxious, irritable, and depressed and have problems concentrating. Hedonic dysregulation may be experienced, presumably related to a relative deficiency of dopaminergic activity. Nicotine increases metabolic rate and suppresses appetite, resulting in smokers, on average, weighing less than nonsmokers. During nico tine withdrawal, smokers typically experience hunger and gain weight. Some of the perceived benefits of nicotine are mediated by the reduction of adverse effects of nicotine withdrawal . Thus, the pharmacologic role of nicotine in addiction is a combination of providing positive and negative reinforcement . For daily smokers, there is a daily cycle during which nicotine levels rise in the blood, substantial tolerance develops during the day, and smoking occurs to relieve withdrawal symptoms.
Some highly addicted smokers wake at night to smoke because of withdrawal symptoms. In contrast, some light and intermittent smokers smoke in response to particular cues, without experiencing withdrawal symptoms, and are thought to smoke just for positive reinforcement. Nicotine dependence severity is best measured by the number of cigarettes smoked per day and the time to first cigarette upon wakening. The two items make up the heaviness of smoking index . Number of cigarettes smoked per day is a measure of both daily nicotine intake and the frequency of nicotine self-administration. Time to first cigarette is a measure of physical dependence and the intensity of withdrawal symptoms after overnight abstinence. The two HSI items significantly correlate with biomarkers of tobacco exposure, accounting for 20 to 30% of the variance in measures of alveolar carbon monoxide, nicotine, and urinary cotinine . Research conducted by Altria with funding from Philip Morris USA concluded that the HSI items were the most important factors correlating with biomarkers of exposure . The HSI is associated with smoking-induced deprivation, measured as prioritization of cigarettes over household essentials such as food . Both items are used for dosing nicotine replacement medications, discussed in the “Tobacco Control Population Based and Policy Approaches” section, with higher doses for heavier smokers and those who smoke within 30 min of waking. HSI scores predict difficulty with quitting smoking and the likelihood of developing tobacco-related diseases, such as heart disease, COPD, and lung cancer . Smoking affects gene expression, and the two HSI items correlate with candidate genes previously associated with cocaine, alcohol, and heroin addiction . The rate of nicotine metabolism also correlates significantly with the HSI . The HSI items have demonstrated very good test-retest reliability among adolescents and adults . The HSI items come from the longer Fagerström Test for Cigarette Dependence . A similar instrument has been developed to assess severity of dependence on e-cigarettes with demonstrated validity, including among adolescents . While nicotine is necessary for tobacco dependence, conditioned behavior is also an important factor and has strong implications for behavioral treatment. When a person quits smoking, cravings for cigarettes persist long after nicotine withdrawal symptoms have resolved . A smoker typically associates smoking with particular situations, moods, or environmental factors that become cues to smoke. Thus, smokers often smoke after a meal, with coffee or alcohol, while driving, and/or with friends who smoke. Smoking a cigarette reverses the negative mood, anxiety, and irritability of nicotine withdrawal . This repeated experience can generalize to a condition in which anxiety or depression from any cause becomes a cue to smoke. The act of smoking, with the handling, hit to the throat, and taste and smell of cigarettes, which are often associated with the neurochemical effects of smoking, signals reward and becomes a cue to smoke. Exposure to tobacco advertising, particularly prevalent at point-of-sale retail and in popular media , and exposure to others smoking can also elicit craving and smoking behavior .Not all smokers become regular, daily, or addicted users. The younger a person starts smoking cigarettes, the greater the risk of stronger physiological addiction to nicotine. Smoking co-occurs with mental illness and other addictive disorders, suggesting greater vulnerability, and research suggests the potential for a gateway effect. Genetic factors also influence the risk of nicotine dependence. Adolescents and the developing brain. Nearly all individuals who smoke started by the age of 18. Adolescence is a critical window for brain development, with the brain not reaching full maturity until the mid-20s. Adolescence is a period of enhanced neuroplasticity during which the underdeveloped neural networks necessary for adult-level judgment cannot yet properly regulate impulses and emotion . As a consequence, adolescents are highly vulnerable to drug experimentation and addiction . Nicotine exposure during adolescence may have lasting adverse consequences for brain development. In animals, nicotine exposure during adolescence produces permanent changes in brain structure and function, including enhanced self-administration of nicotine and other drugs as adults . In humans, adolescents experience symptoms of dependence at lower levels of nicotine exposure than adults . Earlier onset of daily smoking is associated with higher nicotine dependence scores and heavier and longer smoking careers compared to late-onset smokers . Individuals who begin smoking as teens are more likely to become lifelong smokers than those who start smoking in their 20s or later . In a study of 1200 individuals, those who initiated smoking before age 13 had the lowest likelihood of quitting, followed by those who initiated between ages 14 and 17, while adult initiators had the highest likelihood of quitting . A number of studies have yielded similar results . The findings have implications for policy interventions aimed at preventing initiation in youth. Smoking among people with mental illness. Mental illness com monly co-occurs with tobacco addiction , including major depression, bipolar disorder, post traumatic stress disorder , and schizophrenia. Evidence that nicotine may improve cognitive function and sensory gating and reduce psychotic symptoms has led to the self-medication hypothesis, which posits that people with psychiatric disorders smoke to lessen their symptoms .