Molecular Mechanism of Action

Nicotine Withdrawal

As with other drugs of abuse, such as opiates and alcohol, the nicotine withdrawal syndrome in nonhuman animals has both somatic and affective signs. The somatic syndrome associated with nicotine withdrawal has been modeled in rats (Table 7.4). The somatic signs of nicotine withdrawal after exposure to 3.16 mg/kg nicotine base via a minipump implanted under the skin for 6 days resemble those seen in opiate withdrawal in rats, including abdominal constrictions, facial fasciculation, and ptosis. These signs are called somatic because they are expressed as responses of the body (e.g., gasps and writhes). This syndrome has been observed after spontaneous nicotine withdrawal (in which access to nicotine is simply removed) and when withdrawal is induced by a nicotinic acetylcholine receptor antagonist.

Affective and motivational measures of nicotine withdrawal have been modeled in animals using intracranial self-stimulation. Nicotine produces a pronounced elevation in brain reward thresholds, similar to the elevations seen during withdrawal from all drugs of addiction, including cocaine, amphetamine, morphine, ethanol, and Δ9-tetrahydrocannabinol (Figure 7.24). One remarkable aspect of nicotine withdrawal is the pronounced and prolonged elevation in brain reward thresholds that is in marked contrast to its efficacy as a reinforcer and the lack of intensity of somatic withdrawal signs. The magnitude of the elevation in reward thresholds produced by nicotine withdrawal depends on the nicotine dose, with higher doses producing greater elevations, and continuous drug administration producing longer-lasting reward elevations during withdrawal than intermittent administration, even when the total dose administered is the same. This parallels the human condition, in which the predominant symptoms of nicotine withdrawal are high irritability, malaise, and high craving. One hypothesized neurochemical basis of the dramatic elevations in brain reward thresholds during nicotine withdrawal includes effects in systems known to mediate acute nicotine reward, including alterations in nicotinic receptor function, decreased dopamine activity, alterations in dopamine-glutamate and dopamine-GABA interactions, changes in serotonergic function, and changes in opioid peptide function.

Figure 7.23 Mean nicotine intake in rats that self-administered nicotine under a fixed-ratio 1 (FR1) schedule in either 21 h (long access [LgA]) or 1 h (short access [ShA]) sessions. LgA rats increased their nicotine intake on an intermittent schedule with 24–48 h breaks between sessions. (left) Total number of nicotine infusions per session when the intermittent schedule included 24 h breaks between sessions. (right) Total number of nicotine infusions per session when the intermittent schedule included 48 h breaks between sessions. These data show that rats that were allowed to self-administer nicotine intravenously showed a compulsive-like pattern of escalation in nicotine intake, similar to other drugs of abuse when nicotine access was intermittent. Given that this is a pattern of nicotine use in human adolescents who initiate smoking behavior, this animal model has face validity with the human condition. [Taken with permission from Cohen A, Koob GF, George O. Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence. Neuropsychopharmacology, 2012, (37), 2153–2160.]

Decreases in the extracellular levels of dopamine in the nucleus accumbens and amygdala have been observed during precipitated nicotine withdrawal in rats chronically exposed to nicotine (Figure 7.25). Decreased neuronal firing in the ventral tegmental area has also been reported during chronic continuous nicotine infusion.

TABLE 7.4

Frequencies of Individual Categories of Abstinence Signs (mean ± SEM) Observed in Rats Over 15 min, 16 hours after the End of Nicotine Infusion

* p < 0.01 vs. saline-infused controls (Dunnett’s t test).

† p < 0.05 vs. saline-infused controls (Dunnett’s t test).

‡ 0.05 < p < 0.10 vs. saline-infused controls (Dunnett’s t test).

[Taken with permission from Malin DH, Lake JR, Newlin-Maultsby P, Roberts LK, Lanier JG, Carter VA, Cunningham JS, Wilson OB. Rodent model of nicotine abstinence syndrome. Pharmacology Biochemistry and Behavior, 1992, (43), 779–784.]

Another part of the neuronal circuit that drives nicotine reward during withdrawal may occur at the level of pedunculopontine tegmental nucleus cholinergic neurons that terminate on dopamine neurons. One hypothesis is that after nAChR desensitization and upregulation in the absence of sufficient agonist to stimulate the receptors, reduced cholinergic activation of dopamine neurons occurs. A reduction of the cholinergic input to dopamine neurons in the mesocorticolimbic dopamine system may result in decreased brain reward function.

These proposed neuroadaptations that involve dopamine, however, may only partially contribute to nicotine withdrawal symptomatology. Alterations in GABAergic, opioidergic, serotonergic, and corticotropin-releasing factor (CRF) systems may also contribute to the negative affective aspects of nicotine withdrawal. Pharmacological studies have implicated the opioid peptide systems in nicotine dependence. The somatic signs of nicotine withdrawal can be precipitated by the opioid receptor antagonist naloxone. Interestingly, acute injections of the opioid agonist morphine reversed the somatic signs of nicotine withdrawal. Naloxone administration in nicotine-dependent humans dose-dependently increases self-reported affective and somatic signs of nicotine withdrawal, providing evidence that long-term exposure to nicotine is associated with alterations in endogenous opioid peptide systems. Chronic nicotine exposure may release opioid peptides, thus leading to the downregulation of opioid receptor transduction mechanisms. During nicotine abstinence, the downregulation of μ opioid receptors or opioid receptor transduction mechanisms may contribute to some, but not all, aspects of nicotine withdrawal.

Figure 7.24 (A) Intracranial self-stimulation (ICSS) reward thresholds and (B) overall somatic withdrawal signs in rats during spontaneous withdrawal from chronic nicotine administration (9.0 mg/kg/day for 7 days; n = 8) or saline (n = 6). ∗p < 0.05, significant difference between nicotine and saline groups after removal of the minipumps. These data show that rats made dependent on nicotine show elevations in reward thresholds measured by intracranial self-stimulation during withdrawal from nicotine. These increases can be interpreted as “dysphoric-like” effects, last more than 4 days, and outlast any significant increases in the somatic signs of nicotine withdrawal. [Adapted with permission from Epping-Jordan MP, Watkins SS, Koob GF, Markou A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature, 1998, (393), 76–79.]

Alterations in serotonin neurotransmission may also be observed in nicotine withdrawal. Chronic nicotine treatment decreases serotonin concentrations in the hippocampus and increases the number of hippocampal serotonin 5-HT1A receptors in chronic smokers. This receptor upregulation may reflect a reduction of the activity of serotonergic neurons in the median raphe nucleus, which innervates the hippocampus, amygdala, and several other forebrain structures. Deficits in serotonin neurotransmission have been implicated in human depression and anxiety. One hypothesis is that decreases in serotonin function during chronic nicotine exposure and nicotine withdrawal play a role in negative affective withdrawal symptoms, including depressed mood, impulsivity, and irritability. nAChRs are located in the somatodendritic region in the median raphe nucleus and terminal fields in the forebrain and may facilitate serotonin release. Chronic nicotine treatment desensitizes nicotinic receptors, decreases serotonin release, and increases postsynaptic serotonin 5-HT1A receptors to maintain functional activity in the terminal regions. At the neuronal level, nicotine withdrawal increases the inhibitory influence of somatodendritic 5-HT1A autoreceptors in raphe nuclei, contributing to decreases in serotonin release in forebrain sites. Serotonergic antidepressant treatment can reverse the elevation in brain stimulation reward thresholds but not somatic signs in rats during nicotine withdrawal. During nicotine abstinence, decreases in serotonin, combined with upregulated postsynaptic 5-HT1A receptors, may contribute to the depressed mood often reported during nicotine withdrawal.

Alterations in brain stress systems also contribute to the negative affective symptoms associated with nicotine withdrawal (see Figure 7.25). Acute withdrawal from nicotine increases circulating corticosterone, and CRF is increased in the central nucleus of the amygdala. CRF receptor antagonist administration directly into the central nucleus of the amygdala or systemically blocks the increase in nicotine self-administration observed during nicotine abstinence. CRF antagonists also block the escalation in nicotine intake in rats with extended access to nicotine. A common thread between various drugs of abuse, including nicotine, is that CRF levels are increased during withdrawal. Thus, overactivity of brain CRF may underlie the anxiety, increased stress, and irritability often reported by abstinent smokers.

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