In the United States, approximately 14.4 million adults are diagnosed with alcohol use disorder (AUD). There is
an incomplete understanding of factors influencing the development of AUD, and of the specific long-term effects
of alcohol on the brain and behavior that perpetuate problematic use. Moreover, with only 7.9% of AUD patients
receiving medication-assisted treatment, there remains a substantial need for novel pharmacotherapies.
Evidence suggests that social stress can confer vulnerability to AUD. Evidence also suggests that cognitive
deficits caused by long-term alcohol consumption causes structural and functional deficits to the prefrontal cortex
(PFC), resulting in deficits in PFC-mediated behavior which may be remediated during abstinence or through
modulation of brain acetylcholine receptors. This multi-disciplinary study using well-established, highly
translational nonhuman primate (NHP) models, will investigate (1) the relationship between social
stress/enrichment, long-term alcohol consumption and executive function, (2) the capability of drugs that target
brain acetylcholine receptors to reverse alcohol-induced cognitive deficits and (3) the remediation of alcohol-
induced cognitive deficits during abstinence. Group-housed NHPs form social hierarchies that create a
continuum of social experiences from environmental enrichment (in high-ranked, “dominant” monkeys) to chronic
social stress (in low-ranked, “subordinate” monkeys). In the proposed experiments, group-housed NHPs will
drink ethanol over several hours per day. This study uses a longitudinal design that allows for both within- and
between-subject assessment of clinically relevant endpoints in ethanol-naïve, -consuming and –free states. The
cognitive task to be employed, a stimulus-discrimination-and-reversal task, will characterize behavioral flexibility.
The ability of cholinergic drugs that have already been assessed clinically or FDA-approved for other indications
to remediate chronic ethanol-induced deficits will be determined, which is expected to provide guidance to
medication development efforts. When finished, this study will provide significant insight into AUD vulnerabilities
impacting individual drinking trajectories, the effects long-term alcohol consumption on behavior and how
cholinergic drugs may be utilized as novel pharmacotherapeutic medications for AUD patients.