Sex Specific Alterations in α4*Nicotinic Receptor Expression in the Nucleus Accumbens

Background: The mechanisms leading from traumatic stress to social, emotional and cognitive impairment and the development of mental illnesses are still undetermined and consequently there remains a critical need to develop therapies for preventing the adverse consequences of traumatic stress. Research indicates nicotinic acetylcholine receptors containing α4 subunits (α4*nAChRs) are both impacted by stress and capable of modulating the stress response. In this study, we investigated whether varenicline, a partial α4β2*nAChR agonist which reduces nicotine, alcohol and sucrose consumption, can reduce stress, a driving factor in substance use disorders. We also examined the effect of stress on nucleus accumbens (NAc) α4*nAChR expression. Methods: Transgenic mice with fluorescent tags attached to α4*nAChRs were administered varenicline and/or yohimbine (a pharmacological stressor) and plasma corticosterone and NAc α4*nAChR expression were measured. A separated group of mice were exposed to maternal separation (MS) during post-natal day (P) 2⁻14, then restraint stressed (30 min) at six weeks of age. Body weight, anxiety-like behaviours (elevated plus maze), plasma corticosterone and NAc α4*nAChR levels were measured. Results: Varenicline attenuated yohimbine-induced plasma corticosterone increases with no effect on NAc α4*nAChR expression. MS reduced unrestrained plasma corticosterone levels in both sexes. In females, MS increased body weight and NAc α4*nAChR expression, whereas, in males, MS and restraint caused a greater change in anxiety-like behaviours and plasma corticosterone levels. Restraint altered NAc α4*nAChR expression in both male and female MS mice. Conclusions: The effects of stress on NAc α4*nAChR are sex-dependent. While varenicline attenuated acute stress-induced rises in corticosterone levels, future studies are required to determine whether varenicline is effective for relieving the effects of stress. Keywords: maternal separation; nicotinic receptors; nucleus accumbens; stress; varenicline.