Role of alpha7- and beta4-containing nicotinic acetylcholine receptors in the affective and somatic aspects of nicotine withdrawal: studies in knockout mice.

To assess which nicotinic acetylcholine receptors (nAChRs) are involved in the aversive aspects of nicotine withdrawal, brain reward function and the somatic signs of nicotine withdrawal were assessed in mice that lack alpha7 and beta4 nAChR subunits. Brain reward function was assessed with the intracranial self-stimulation (ICSS) procedure, in which elevations in ICSS thresholds reflect an anhedonic mood state. At 3-6 h of spontaneous nicotine/saline withdrawal, thresholds were elevated in nicotine-withdrawing alpha7(+/+) and beta4(+/+), but not alpha7(-/-) or beta4(-/-), mice compared with saline-withdrawing mice, indicating a delay in the onset of withdrawal in the knockout mice. From 8 to 100 h of withdrawal, thresholds in alpha7(+/+) and alpha7(-/-) mice were equally elevated, whereas thresholds in beta4(+/+) and beta4(-/-) mice returned to baseline levels. Somatic signs were attenuated in nicotine-withdrawing beta4(-/-), but not alpha7(-/-), mice. Administration of a low dose of the nAChR antagonist mecamylamine induced threshold elevations in alpha7(-/-), but not alpha7(+/+), mice, whereas the highest dose tested only elevated thresholds in alpha7(+/+) mice. Mecamylamine-induced threshold elevations were similar in beta4(-/-) and beta4(+/+) mice. In conclusion, null mutation of the alpha7 and beta4 nAChR subunits resulted in a delayed onset of the anhedonic aspects of the spontaneous nicotine withdrawal syndrome. Previous findings of attenuated somatic signs of nicotine withdrawal in beta4(-/-), but not alpha7(-/-), mice were confirmed in the present study, indicating an important role for beta4-containing nAChRs in the somatic signs of nicotine withdrawal. The mecamylamine-precipitated withdrawal data suggest that compensatory adaptations may occur in constitutive alpha7(-/-) mice or that mecamylamine may interact with other receptors besides nAChRs in these mice. In summary, the present results indicate an important role for alpha7 and beta4-containing nAChRs in the anhedonic or somatic signs of nicotine withdrawal.