Null mutation of the β2 nicotinic acetylcholine receptor subunit attenuates nicotine withdrawal-induced anhedonia in mice

The ant-tectonic signs of nicotine withdrawal are predictive of smoking relapse rates in humans. Identification of the neurobiological substrates that mediate anhedonia will provide insights into the genetic variations that underlie individual responses to smoking cessation and relapse. The present study assessed the role of beta 2 nicotinic acetylcholine receptor (nACh receptor) subunits in nicotine withdrawal-induced anhedonia using beta 2 nACh receptor subunit knockout (beta 2(-/-)) and wildtype (beta 2(+/+)) mice. Anhedonia was assessed with brain reward thresholds, defined as the current intensity that supports operant behavior in the discrete-trial current-intensity intracranial self-stimulation procedure. Nicotine was delivered chronically through osmotic minipumps for 28 days (40 mg/kg/day, base), and withdrawal was induced by either administering the broad-spectrum nicotinic receptor antagonist mecamylamine (i.e., antagonist-precipitated withdrawal) in mice chronically treated with nicotine or terminating chronic nicotine administration (i.e., spontaneous withdrawal). Mecamylamine (6 mg/kg, salt) significantly elevated brain reward thresholds in nicotine-treated beta 2(+/+) mice compared with saline-treated beta 2(+/+) mice and nicotine-treated mice. Spontaneous nicotine withdrawal similarly resulted in significant elevations in thresholds in nicotine-withdrawing beta 2(+/+) mice compared with saline-treated beta 2(+/+) and nicotine-treated beta 2(-/-) mice, which remained at baseline levels. These results showed that precipitated and spontaneous nicotine withdrawal-induced anhedonia was attenuated in beta 2(-/-) mice. The reduced expression of anhedonic signs during nicotine withdrawal in beta 2(-/-) mice may have resulted from the lack of neuroadaptations in beta 2 nACh receptor subunit expression and function that may have occurred during either nicotine exposure or nicotine withdrawal in wildtype mice. In conclusion, individuals with genetic variations that result in diminished function of the beta 2 nACh receptor subunit may experience less anhedonia during nicotine withdrawal, which may facilitate smoking cessation. (C) 2014 Elsevier B.V. All rights reserved.