Analysis of the nucleus accumbens in ethanol's discriminative stimulus effects

Oregon Health & Science University, Portland OR

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Abstract

? DESCRIPTION (provided by applicant): Alcoholism is a chronic, progressive disorder often characterized by patterns of binge drinking that lead to detrimental health consequences and a great economic burden on society. Alcohol is known to produce subjective effects (i.e. feelings of intoxication) that have been associated with the perpetuation of binge drinking, suggesting that these subjective effects contribute to alcohol's abuse potential. Drug discrimination is a reliable in vivo pharmacological assay that can be used to characterize the receptor basis of alcohol's subjective effects, as measured through a behavioral output. Previous work using this technique has established that alcohol (or ethanol) is a stimulus complex made up of concurrent activity at multiple receptor systems in rodents and primates. Specifically, alcohol acts as a positive modulator at the GABAA receptor and an antagonist at the NMDA receptor, leading to an overall dampening of neuronal activity. While a great deal of research has been dedicated to alcohol's receptor basis in the brain, very little is known about the circuitry that underlies ethanol's subjective effects. Importantly, there are no published studies to date that have directly examined brain circuitry that mediates ethanol subjective effects in monkeys. Mapping circuitry that mediates the subjective effects of ethanol in the primate brain will help bridge our understanding of brain mechanisms mediating alcohol intoxication from rodents to primates and improve targeting strategies for potential pharmacotherapies. There is converging evidence from both rodents and humans suggesting that the nucleus accumbens (NAc) is involved in subjective alcohol intoxication, and that these effects are composed of both GABAergic and NMDA glutamatergic mechanisms. Thus, as a first step in mapping the circuitry related to the stimulus effects of ethanol intoxication, the current proposal utilizes a chemogenetic strategy to directly manipulate neural activity within the NAc core. Further, this study proposes to use drug discrimination to characterize the pharmacological basis of NAc core involvement in ethanol's subjective effects, providing a novel investigation of the intersection between circuitry and pharmacology. Overall, the goal of these studies is to better understand the basis of alcohol intoxication in the primate brain, which will improve targeted treatment strategies for alcohol use disorders.