Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY 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.
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