Effects of the benzodiazepine GABA_A α1-preferring antagonist 3-isopropoxy-β-carboline hydrochloride (3-ISOPBC) on alcohol seeking and self-administration in baboons.

Abstract

The major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), modulates many of the behavioral effects of alcohol, including sedation, tolerance, and withdrawal. The α1 subunit of the benzodiazepine GABA_A receptor is the most widely expressed alpha subunit in the brain, and has been implicated in the reinforcing- and abuse-related effects of alcohol. The aim of the present study was to examine whether treatment with a benzodiazepine GABA_A α1-preferring ligand, 3-isopropoxy-β-carboline hydrochloride (3-ISOPBC), selectively decreases alcohol seeking and consumption. Eight baboons self-administered alcohol (4% w/v; n=5; alcohol group) or a non-alcoholic beverage (n=3; control group) in Component 3 of a chained schedule of reinforcement. Responses in Component 2 provided indices of motivation to drink (seeking). Doses of 3-ISOPBC (5.0-30.0mg/kg) and vehicle were administered before drinking sessions under both acute and chronic (5day) conditions. Chronic, and not acute, administration of 3-ISOPBC significantly decreased self-administration responses, g/kg alcohol consumed, and the number of drinks in and duration of the first drinking bout in the alcohol group. In the control group, chronic administration of 3-ISOPBC did not significantly decrease any of these measures at any of the doses. The GABA_A α1-preferring ligand 3-ISOPBC may have therapeutic potential in the treatment of alcohol use disorder due to its ability to selectively reduce alcohol use.