Molecular Mechanism of Action

Molecular Changes During Withdrawal from Chronic Nicotine

At the molecular level, the effects of nicotine on central nAChRs have been described as being paradoxical. Chronic nicotine exposure leads to receptor desensitization and inactivation, followed by an upregulation of nicotinic receptors during withdrawal. As mentioned above, acute nicotine administration stimulates nAChRs, leading to the brief opening of the ion channel (receptor activation). The receptor then becomes unresponsive to further agonist exposure (receptor inactivation and desensitization). Consequently, the desensitization process leads to an increase in the number of nAChRs (receptor upregulation). Nicotinic receptor activation, desensitization, and upregulation can be presumed to be a neuronal response that attempts to maintain the baseline level of synaptic activity within cholinergic and other neurotransmitter systems during chronic nicotine exposure. nAChRs may exist in many different functional states within the brain. Differential activation could be a driving force for the neuroadaptive changes associated with dependence. The α2, α4, and α7 subunits become inactive and desensitized with chronic nicotine exposure, but the α3 and α6 subunits do not show inactivation, suggesting that some nAChR subunits are more sensitive to nicotine than others. The differential effects of chronic nicotine exposure on the release of various neurotransmitter systems may be explained by a balance between receptor density, desensitization, and functionality.

During nicotine abstinence, changes in nAChR function may mediate some of the negative affective states and somatic symptoms associated with nicotine withdrawal. For example, nicotine abstinence leads to decreased plasma nicotine levels. The previously desensitized or inactive nAChRs may then begin to recover to their normal functional states at different rates, depending on the brain region and receptor subtype. During chronic nicotine exposure, nAChR upregulation may also occur along non-reward-related cholinergic pathways. nAChR dysregulation in both reward (desensitized) and non-reward (upregulated) circuits may contribute to the negative affective or somatic symptoms of withdrawal. The development and perpetuation of nicotine addiction may involve self-medication to effectively control the number of functional nAChRs along the various pathways affected by nicotine.

Smokers report that the first cigarette of the day is the most pleasurable, possibly because of nicotine-induced activation of recovered nAChRs in the ventral tegmental area, leading to greater dopamine release compared with later time-points during the day. Throughout the day, smokers maintain steady blood nicotine levels and are exposed to nicotine concentrations that cause nAChR desensitization in the ventral tegmental area. If different nAChRs in the ventral tegmental area are differentially sensitive to nicotine as suggested above, then periodic re-administration of nicotine engages nAChRs that are only activated by high nicotine doses once a steady-state of nicotine is reached.

Figure 7.25 Decreased dopamine release and increased CRF release in the central nucleus of the amygdala in nicotine-dependent rats. (A) The placement of a microdialysis probe in the rat central nucleus of the amygdala (CNA, left side) and a region where Fos-immunoreactive nuclei were counted (CNA, shaded area, right side). BLA, basolateral amygdala. (B) Temporal changes in extracellular dopamine concentrations in the central nucleus of the amygdala after systemic injections (indicated by the arrows) of saline and mecamylamine (1 mg/kg, s.c.) in animals infused for 14 days with nicotine (●, n = 5–6) and control animals (◯, Sham, n = 5–8). B1 indicates baseline 1, which is the sample that immediately preceded the saline injection (100% in the figure is the aver age of the two samples that preceded the saline injection). B2 indicates baseline 2, which is the sample that immediately preceded mecamylamine injection (100% is defined as the average of the two samples that preceded the mecamylamine injection [Taken with permission from Panagis G, Hildebrand BE, Svensson TH, Nomikos GG. Selective c-fos induction and decreased dopamine release in the central nucleus of amygdala in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome. Synapse, 2000, (35), 15–25.] (C) Effect of mecamylamine (1.5 mg/kg, i.p.)-precipitated withdrawal on extracellular levels of corticotropin-releasing factor in the central nucleus of the amygdala measured by in vivo microdialysis in chronic nicotine-treated rats (nicotine-dependent, n = 7) and chronic saline-treated rats (nondependent, n = 6). *p < 0.05, compared with nondependent rats. [Taken with permission from George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O’Dell LE, Richardson HN, Koob GF. CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proceedings of the National Academy of Sciences USA, 2007, (104), 17198–17203.] These data show that animals made dependent on nicotine show a decrease in dopamine release in the central nucleus of the amygdala and a concomitant increase in corticotropin-releasing factor release from the central nucleus of the amygdala during precipitated withdrawal measured by in vivo microdialysis.

In summary, the same neurotransmitter systems hypothesized to mediate the acute reinforcing effects of nicotine are compromised during the development of dependence, reflected by aberrant or decreased function during withdrawal. Dopamine and serotonin activity decreases during withdrawal. CRF activity increases during withdrawal. These changes appear to contribute to the negative affective state that drives negative reinforcement in nicotine dependence.

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