Sex Specific Alterations in a4*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 (α4nAChRs) are both impacted by stress and capable of modulating the stress response. In this study, we investigated whether varenicline, a partial α4β2nAChR 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) α4nAChR expression. Methods: Transgenic mice with fluorescent tags attached to α4nAChRs were administered varenicline and/or yohimbine (a pharmacological stressor) and plasma corticosterone and NAc α4nAChR 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 α4nAChR levels were measured. Results: Varenicline attenuated yohimbine-induced plasma corticosterone increases with no effect on NAc α4nAChR expression. MS reduced unrestrained plasma corticosterone levels in both sexes. In females, MS increased body weight and NAc α4nAChR expression, whereas, in males, MS and restraint caused a greater change in anxiety-like behaviours and plasma corticosterone levels. Restraint altered NAc α4nAChR expression in both male and female MS mice. Conclusions: The effects of stress on NAc α4nAChR 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.