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BEHAVIORAL PHARMACOLOGY

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

Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts (D.M.P., A.D., R.D.S., J.K.R.); and Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin (J.M.C., X.L., W.Y.)

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 ₁GABA_A and ₅GABA_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 ₁GABA_A agonists zolpidem, zaleplon, and CL 218,872 (3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine), the ₅GABA_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 ₁GABA_A antagonist -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 ₅GABA_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 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.

Address correspondence to: Dr. Donna M. Platt, Harvard Medical School/New England Primate Research Center, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102. E-mail: donna_platt{at}hms.harvard.edu