Date Approved

9-16-2020

Embargo Period

9-17-2020

Document Type

Thesis

Degree Name

M.S. Pharmaceutical Sciences

Department

Chemistry and Biochemistry

College

College of Science & Mathematics

First Advisor

Keck, Thomas M.

Second Advisor

Grinias, James

Third Advisor

Caputo, Gregory

Keywords

Alcohol Use Disorder, CB1 negative allosteric modulator, Dopamine D4 receptor antagonist, L-745, 870, PSNCBAM-1, rodent

Subject(s)

Alcoholism--Treatment; Drug development

Disciplines

Medicinal and Pharmaceutical Chemistry | Pharmacy and Pharmaceutical Sciences

Abstract

Alcohol use disorder (AUD) affects more than 15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. In this study, the effects of the D4 receptor antagonist, L-745,870, and the CB1 negative allosteric modulator, PSNCBAM-1, were both tested for effects in ethanol conditioned place preference (CPP) and oral ethanol self-administration. Food-restricted adult male mice were trained in operant chambers to nose poke for delivery of rewards, trained on ascending concentrations of alcohol with descending concentrations of Ensure and water, until the mixture self-administered was 8% w/v ethanol in water. L-745,870 did not significantly attenuate ethanol self-administration or ethanol CPP. These results suggest that D4R antagonism does not alter the rewarding value of ethanol. PSNCBAM-1 dose-dependently attenuated oral ethanol self-administration, significantly reducing ethanol rewards at a dose of 30 mg/kg but not at 10 or 18 mg/kg. However, 18 and 30 mg/kg PSNCBAM-1 also significantly reduced self-administration of a palatable food reward. These results suggest PSNCBAM-1 produces a non-specific anhedonic effect that may preclude its use in AUD or other neuropsychiatric conditions.

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