Date Approved

1-20-2021

Embargo Period

1-22-2021

Document Type

Thesis

Degree Name

M.S. Pharmaceutical Sciences

Department

Chemistry & Biochemistry

College

College of Science & Mathematics

First Advisor

Keck, Thomas M.

Second Advisor

Grinias, James

Third Advisor

Fischer, Bradford D.

Keywords

Addiction, Alcohol use disorder, CB1 negative allosteric modulator, condition place preference, Dopamine D4 antagonist, Two bottle choice

Subject(s)

Alcoholism--Treatment; Drug development

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

The USA faces $220 billion economic loss and eighty thousand deaths per year due to alcohol abuse while affecting more than 15 million people, making it the third largest life-style related cause of death. The U.S. FDA has approved four medications namely, disulfiram, acamprosate, oral naltrexone, and injectable long-acting naltrexone. These existing drugs are trashed with side effects, have a low success rate, indicating a demand for new potential drugs. We studied the effects of the CB1 negative allosteric modulator, PSNCBAM-1, and the dopamine D4 receptor antagonist, L-745,870 in mouse models of alcohol addiction. PSNCBAM-1 did not significantly reduce CPP for 2.0 g/kg ethanol or alter locomotor activity, but its dose-dependently attenuated oral ethanol self-administration at the dose of 30 mg/kg. 18 and 30 mg/kg PSNCBAM-1 significantly reduced self-administration of palatable food reward. These results suggest, PSNCBAM-1 produces a non-specific anhedonic effect that may preclude its use in AUD. L-745,870 did not significantly affect conditioned place preference for 2.0 g/kg ethanol, ethanol self-administration, locomotor activity in an open field, or co-ordination in the rotarod test. These results suggest that D4R antagonism does not alter the rewarding value of ethanol.

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