Reversal of a Scopolamine-Induced Cognitive Deficit in Group-Housed Monkeys Who Drink Ethanol

Abstract

<b>Abstract ID 17554</b> <b>Poster Board 18</b> Individuals who experience chronic social stress are vulnerable to developing problematic drinking behaviors that can impair important executive function behaviors, ultimately contributing to the development of alcohol use disorder (AUD). Interestingly, the basal forebrain cholinergic pathway to the prefrontal cortex (PFC), the brain region mediating cognitive flexibility, is sensitive to both stress and alcohol. The purpose of the present study was to examine the efficacy of M1/4 muscarinic and a4B2 nicotinic cholinergic receptor [partial] agonists in reversing a scopolamine-induced deficit of a PFC-mediated task in group-housed monkeys with ethanol self-administration histories. Twelve male cynomolgus macaques formed three established social groups and became dominant, experiencing chronic social enrichment, or subordinate, experiencing chronic social stress. Monkeys self-administered ethanol for one year and were trained to perform a serial stimulus discrimination reversal learning task. Subsequently, sensitivity to scopolamine’s cognitive impairing effects was determined followed by the pro-cognitive and scopolamine-reversal potential of xanomeline and varenicline alone and when co-administered with scopolamine. We hypothesized that subordinate monkeys, whom had greater mean daily ethanol intakes across one year of ethanol self-administration, would be more sensitive to the cognitive impairing effects of scopolamine and require greater doses of xanomeline and varenicline to reverse a scopolamine-induced cognitive deficit. Across one year of ethanol self-administration, subordinate monkeys had greater mean daily ethanol intakes than dominant monkeys in 2 of 3 groups. Scopolamine dose-response curves indicate that heavy drinkers, but not subordinate monkeys, were more sensitive to scopolamine’s cognitive impairing effects (p&lt;0.005). Xanomeline and varenicline dose-response curves when administered alone or with scopolamine are presently being collected. These findings will characterize the role of cholinergic receptor subtypes involved in mediating reversal learning, ultimately contributing to identification of putative pharmacotherapeutic targets for remediating AUD-induced cognitive deficits. This research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (R01 AA027556, P50 AA026117, F31 AA029588, T32 AA07565).