Received for publication November 8, 2004.
Revised January 6, 2005.
Accepted for publication January 12, 2005.

Contribution of ₁GABA_A and ₅GABA_A Receptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Abstract

Ethanol's ability to enhance -aminobutyric acid (GABA) neurotransmission via GABA_A receptors has been implicated as an important mechanism underlying its discriminative stimulus (DS) effects in animals and subjective effects in humans. The present study assessed the contribution of ₁GABA_A and ₅GABA_A receptors to the DS effects of ethanol. Squirrel monkeys were trained to discriminate i.v. ethanol from saline under a fixed-ratio schedule of food delivery. Under test conditions, ethanol engendered a dose-dependent increase in drug-lever responding, reaching an average maximum of >80%. In substitution experiments, the ₁GABA_A agonists zolpidem, zaleplon and CL 218,872, the ₅GABA_A agonists QH-ii-066 and panadiplon, and representative nonselective agonists partially-to-fully reproduced the ethanol DS. In antagonism studies, the ₁GABA_A antagonist -CCt did not attenuate the DS effects of ethanol or the ethanol-like effects of zolpidem and zaleplon. In contrast, pretreatment with the ₅GABA_A inverse agonist L-655,708 dose-dependently attenuated the DS effects of ethanol and the ethanol-like effects of QH-ii-066. RY-23, another ₅GABA_A inverse agonist, similarly attenuated the ethanol-like DS effects of QH-ii-066. Antagonism of both QH-ii-066 and ethanol by the ₅GABA_A inverse agonists occurred at doses that did not alter the rate of responding suggesting that this blockade was pharmacologically specific and not the result of a nonspecific disruption of operant behavior. These findings suggest a key role for ₅GABA_A, but not ₁GABA_A, receptor mechanisms in the DS effects of ethanol and the ethanol-like DS effects of benzodiazepine agonists.

Key words: GABA-A receptor mechanisms, alcohol, benzodiazepines, drug discrimination, ethanol, squirrel monkey