Contribution of alpha 1GABAA and alpha 5GABAA receptor subtypes to the discriminative stimulus effects of ethanol in squirrel monkeys

Ethanol's ability to enhance 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 alpha(1)GABA(A) and alpha(5)GABA(A) receptors to the DS effects of ethanol. Squirrel were monkeys 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 alpha(1)GABA(A) agonists zolpidem, zaleplon, and CL 218,872 (3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine), the alpha(5)GABA(A) agonists QH-ii-066 (1-methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one) and panadiplon [3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)imidazo(1,5-a)quinoxalin-4(5H)-one], and representative nonselective agonists partially to fully reproduced the ethanol DS. In antagonism studies, the alpha(1)GABA(A) antagonist beta-carboline-t-butyl ester did not attenuate the DS effects of ethanol or the ethanol-like effects of zolpidem and zaleplon. In contrast, pretreatment with the alpha(5)GABA(A) inverse agonist L-655,708 (ethyl[S]-11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxlate) dose-dependently attenuated the DS effects of ethanol and the ethanol-like effects of QH-ii-066. RY-23 (tert-butyl 8-[(trimethylsilyl)ethynyl]-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4]benzodiazepine-3-carboxylate), another alpha(5)GABA(A) inverse agonist, similarly attenuated the ethanol-like DS effects of QH-ii-066. Antagonism of both QH-ii-066 and ethanol by the alpha(5)GABA(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 alpha(5)GABA(A), but not alpha(1)GABA(A), receptor mechanisms in the DS effects of ethanol and the ethanol-like DS effects of benzodiazepine agonists.