The anhedonic 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 β2
nicotinic acetylcholine receptor (nACh receptor) subunits in
nicotine withdrawal-induced
anhedonia using β2 nACh receptor subunit knockout (β2(-/-)) and wildtype (β2(+/+)) 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 β2(+/+) mice compared with saline-treated β2(+/+) mice and
nicotine-treated β2(-/-) mice. Spontaneous
nicotine withdrawal similarly resulted in significant elevations in thresholds in
nicotine-withdrawing β2(+/+) mice compared with saline-treated β2(+/+) and
nicotine-treated β2(-/-) mice, which remained at baseline levels. These results showed that precipitated and spontaneous
nicotine withdrawal-induced
anhedonia was attenuated in β2(-/-) mice. The reduced expression of anhedonic signs during
nicotine withdrawal in β2(-/-) mice may have resulted from the lack of neuroadaptations in β2 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 β2 nACh receptor subunit may experience less
anhedonia during
nicotine withdrawal, which may facilitate smoking cessation.