Nicotinic Receptors & Nicotine addiction

The nicotinic cholinergic receptor consists of five subunits.

The brain expresses nine α subunits (α2 through α10) and three β subunits (β2 through β4). The most abundant receptors are α4β2, α3β4, and α7, the latter of which are homomeric.

The α4β2* is the principal mediator of nicotine dependence.

In mice, disruption of the β2 subunit gene eliminates the behavioral effects of nicotine; reinserting the gene into the ventral tegmental area restores behavioral responses to nicotine.

The α4 subunit is an important determinant of sensitivity to nicotine.

A mutation affecting a single nucleotide in the receptor gene increases the hypersensitivity to the effects of nicotine.

The presence of α5 subunit combined with α4β2 increases calcium conductance seven times; α5 gene variants also alter nicotine responsiveness in cultured human cells.

Theα3β4 subtype probably mediates the cardiovascular effects of nicotine.

The α7 homomeric receptors are involved in rapid synaptic transmission and long-term potentiation to dopaminergic neurons at excitatory inputs and have a role in learning and sensory gating.

Smoke particles carry the nicotine into the lungs, where it is rapidly absorbed into the pulmonary venous circulation. The nicotine then enters the arterial circulation and moves quickly from the lungs to the brain, where it binds to nicotine cholinergic receptors (ligand-gated ion channels that normally bind acetylcholine).

The binding of nicotine between two subunits of the receptor opens the channel, allowing the entry of sodium or calcium.

The entry of these cations into the cell further activates voltage-dependent calcium channels, allowing more calcium to enter.

One of the effects of the entry of calcium into a neuron is the release of neurotransmitters.

Nicotine and Neurotransmitter Release

Stimulation of nicotinic cholinergic receptors releases a variety of neurotransmitters in the brain.

One of them, dopamine, signals a pleasurable experience and is critical for the reinforcing effects (effects that promote self-administration)of nicotine and other drugs of abuse.

Experimentally induced lesions in dopamine-releasing neurons prevent self-administration of nicotine in rats.

Nicotine releases dopamine in the Mesolimbic area, the corpus striatum, and the frontal cortex.

The dopaminergic neurons in the ventral tegmental area of the midbrain and in the shell of the nucleus accumbens are critical in drug-induced reward (both regions have a role in perceptions of pleasure and reward).

Nicotine also augments both glutamate release, which facilitates the release of dopamine, and γ-aminobutyric acid (GABA) release, which inhibits dopamine release.

With long-term exposure to nicotine, some nicotinic cholinergic receptors become desensitized but some do not.

As a result, GABA-mediated inhibitory tone diminishes while glutamate-mediated excitation persists, increasing excitation of dopaminergic neurons and enhancing responsiveness to nicotine.

Nicotine lowers the threshold for electrical stimulation in reward system, leading to increased responsiveness to rewarding stimuli an effect that can last for more than 30 days.

It also increases activity in the prefrontal cortex, thalamus, and visual system, reflecting activation of the reward network), and releases dopamine in the striatum.

Other neurotransmitters that may be involved in nicotine addiction are the hypocretins, neuropeptides produced in the lateral hypothalamus that regulate the stimulatory effects of nicotine on reward centers in the brain and modulate self-administration of nicotine in rodents.

The Biology of Nicotine Addiction

Nicotine acts on nicotinic cholinergic receptors, triggering the release of neurotransmitters that produce psychoactive effects that are rewarding.

With repeated exposure, tolerance develops to many of the effects of nicotine, reducing its primary reinforcing effects and inducing physical dependence (i.e., withdrawal symptoms in the absence of nicotine).

Smoking behavior is influenced by pharmacologic feedback and by environmental factors such as smoking cues, friends who smoke, stress, and product advertising.

Levels of nicotine in the body in relation to a particular level of nicotine intake from smoking are modulated by the rate of nicotine metabolism, which occurs in the liver largely by means of the enzyme CYP2A6.

Other factors that influence smoking behavior include age, sex, genetics, mental illness, and substance abuse.

Neuroadaptation

With repeated exposure to nicotine, neuroadaptation (tolerance) to some of the effects of nicotine develops

As neuroadaptation develops… the number of binding sites on the nicotinic cholinergic receptors in the brain increases, probably in response to nicotine-mediated desensitization of receptors.

Desensitization — ligand-induced closure and unresponsiveness of the receptor —is believed to play a role in tolerance and dependence: the symptoms of craving and withdrawal begin in smokers when desensitized α4 β2* nicotinic cholinergic receptors become responsive during periods of abstinence, such as nighttime sleep.

Nicotine binding of these receptors during smoking alleviates craving and withdrawal.

Cigarette smoking maintains near-complete saturation — and thus desensitization — of theα4 β2* nicotinic cholinergic receptors.

Thus, smokers are probably attempting to avoid withdrawal symptoms when maintaining a desensitized state By sustaining sufficient levels of plasma nicotine to prevent withdrawal symptoms, they also derive rewarding effects from the conditioned reinforcements associated with smoking, such as the taste and feel of smoke.

Nicotine withdrawal causes anxiety and stress, both of which are powerful incentives to take up smoking again.

The negative affect that typifies the response to nicotine withdrawal probably results in part from a cascade of events involving increased levels of extra hypothalamic corticotrophin-releasing factor (CRF) and increased binding of CRF to corticotropin-releasing factor 1 (CRF1) receptors in the brain, thereby activating the CRF–CRF1 receptor system, which mediates responses to stress.

Anxiety-like behavior and the release of CRF in the central nucleus of the amygdala occur during nicotine withdrawal.

CRF causes anxiety, whereas the pharmacologic blockade of CRF1 receptors inhibits the anxiogenic effects of nicotine withdrawal. The blockade of CRF1 receptors also prevents the increase in self-administration of nicotine that occurs during abstinence from nicotine.

Thus, both underactivity of the dopaminergic system and activation of the CRF–CRF1receptor system contribute to the symptoms of nicotine withdrawal that often precipitate relapse.

Clinical Aspects of Nicotine Addiction

Psychoactive Effects of Nicotine

Nicotine induces pleasure and reduces stress and anxiety. Smokers use it to modulate levels of arousal and to control mood. Smoking improves concentration, reaction time, and performance of certain tasks.

Relief from withdrawal symptoms is probably the primary reason for this enhanced performance and heightened mood.

Cessation of smoking causes the emergence of withdrawal symptoms: irritability, depressed mood, restlessness, and anxiety.

The intensity of these mood disturbances is similar to that found in psychiatric outpatients.

Anhedonia — the feeling that there's little pleasure in life — can also occur with withdrawal from nicotine, and from other drugs of abuse.

The basis of nicotine addiction is a combination of positive reinforcements, including enhancement of mood and avoidance of withdrawal symptoms.

In addition, conditioning has an important role in the development of tobacco addiction.

Conditioned Behavior

When a person who is addicted to nicotine stops smoking, the urge to resume is recurrent and persists long after withdrawal symptoms dissipate.

With regular smoking, the smoker comes to associate specific moods, situations, or environmental factors — smoking-related cues —with the rewarding effects of nicotine. Typically, these cues trigger relapse.

The association between such cues and the anticipated effects of nicotine, and the resulting urge to use nicotine, constitute a form of conditioning.

Studies show that nicotine exposure causes changes in the protein expression of brain cells and in their synaptic connections— a process termed neural plasticity —which underlie conditioning. Nicotine also enhances behavioral responses to conditioned stimuli, which may contribute to compulsive smoking.

The desire to smoke is maintained, in part, by such conditioning. Smokers usually take a cigarette after a meal, with a cup of coffee or an alcoholic drink, or with friends who smoke, when repeated many times; such situations become a powerful cue for the urge to smoke

Aspects of smoking itself — the manipulation of smoking materials, or the taste, smell, or feel of smoke in the throat — also become associated with the pleasurable effects of smoking. Even unpleasant moods can become conditioned cues for smoking: a smoker may learn that not having a cigarette provokes irritability and that smoking one provides relief. After repeated experiences like this, a smoker can sense irritability from any source as a cue for smoking.

Functional imaging studies have shown that exposure to drug-associated cues activates cortical regions of the brain, including the insula. Smokers who sustain damage to the insula (e.g., brain trauma) are more likely to quit smoking soon after the injury, and to remain abstinent, and are less likely to have conscious urges to smoke than smokers with brain injury that does not affect

The Tobacco Addiction Cycle

The first cigarette of the day has a substantial pharmacologic effect, primarily arousal, but at the same time, tolerance to nicotine begins to develop

A second cigarette is smoked later, at a time when the smoker has learned

That there is some regression of tolerance. With subsequent smoking, there is an accumulation of nicotine in the body, resulting in a greater level of tolerance, and withdrawal symptoms become more pronounced between successive cigarettes. Transiently high levels of nicotine in the brain after individual cigarettes are smoked may partially overcome tolerance, but the primary (euphoric) effects of nicotine tend to lessen throughout the day.

Abstinence overnight allows considerable resensitization to the actions of nicotine.

Genetics of Nicotine Addiction

Studies in twins have shown a high degree of heritability of cigarette smoking (≥50%), including the level of dependence and the number of cigarettes smoked daily. these studies have also revealed the heritability of the particular symptoms that occur when a smoker stops smoking.

Numerous attempts have been made to identify genes underlying nicotine addiction.

Candidate genes coding for nicotine receptor subtypes, dopamine receptors and dopamine transporters, GABA receptors, opiate and cannabinoids receptors, and other types of receptors have been associated with different aspects of smoking behavior.

Vulnerability to Addiction

Tobacco use typically begins in childhood or adolescence— 80% of smokers begin smoking by 18years of age. Although two thirds of young people try cigarette smoking, only 20 to 25% of them become dependent daily smokers, usually as adults.

Risk factors for smoking in childhood or adolescence include peer and parental influences, behavioral problems (e.g., poor school performance), personality characteristics (rebelliousness, risk taking, depression, and anxiety), and genetic influences.

The risk of dependence increases when smoking begins early. Studies animals suggest that nicotine can induce permanent changes that lead to addiction. Brain changes in adolescent rats exposed to nicotine are greater than those in exposed adult rats.

Adolescent rats that have been exposed to nicotine have higher rates of nicotine self-administration as adults, which is consistent with the idea that early exposure to nicotine increases the severity of dependence.

Tobacco addiction is highly prevalent among persons with mental illness or substance-abuse disorders. The mechanisms of this association are likely to include a shared genetic predisposition, the capacity of nicotine to alleviate some psychiatric symptoms, and the inhibitory effects of tobacco smoke on monoamine oxidase.

Smoking behavior in women is more strongly influenced by conditioned cues and negative affect; men are more likely to smoke in response to pharmacologic cues, regulating their intake of nicotine more precisely than women.

On average, women metabolize nicotine more quickly than men, which may contribute to their increased susceptibility to nicotine addiction and may help to explain why, among smokers, it is more difficult for women to quit. those who metabolize nicotine rapidly take in more cigarette smoke per day than those who metabolize nicotine slowly. Nicotine is metabolized to cotinine primarily by the liver enzymes.

Persons with a genetic basis for slow metabolism smoke fewer cigarettes daily than persons with faster metabolism.

Rapid metabolism of nicotine is associated with more severe withdrawal symptoms and a lower probability of success in quitting during nicotine-patch treatment.

Conclusions

Nicotine sustains tobacco addiction, a major cause of disability and premature death, by acting on nicotinic cholinergic receptors in the brain to trigger the release of dopamine and other neurotransmitters.

Release of dopamine, glutamate, and GABA is particularly important in the development of nicotine dependence, and CRF may play a key role in withdrawal. Neuroadaptation and tolerance involve changes in nicotinic receptors and neural plasticity. Nicotine addiction occurs when smokers come to rely on smoking to modulate mood and arousal, relieve withdrawal symptoms, or both. Light smokers smoke mainly for positive reinforcement in specific situations. Genetic studies indicate that nicotinic receptor subtypes and the genes involved in neuroplasticity and learning play a part in the development of dependence. People with psychiatric or substance-abuse disorders, who account for a large proportion of current smokers, have an increased susceptibility to tobacco addiction. Nicotine is metabolized in liver, and variation in the rate of nicotine metabolism contributes to differences in vulnerability to tobacco dependence and the response to smoking-cessation treatment.