RT Journal Article
SR Electronic
T1 Contribution of α<sub>1</sub>GABA<sub>A</sub> and α<sub>5</sub>GABA<sub>A</sub> Receptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 658
OP 667
DO 10.1124/jpet.104.080275
VO 313
IS 2
A1 Donna M. Platt
A1 Annemarie Duggan
A1 Roger D. Spealman
A1 James M. Cook
A1 Xiaoyan Li
A1 Wenyuan Yin
A1 James K. Rowlett
YR 2005
UL http://jpet.aspetjournals.org/content/313/2/658.abstract
AB Ethanol's ability to enhance GABA neurotransmission via GABAA 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 α1GABAA and α5GABAA 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 &gt;80%. In substitution experiments, the α1GABAA agonists zolpidem, zaleplon, and CL 218,872 (3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine), the α5GABAA 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 α1GABAA antagonist β-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 α5GABAA 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 α5GABAA inverse agonist, similarly attenuated the ethanol-like DS effects of QH-ii-066. Antagonism of both QH-ii-066 and ethanol by the α5GABAA 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 α5GABAA, but not α1GABAA, receptor mechanisms in the DS effects of ethanol and the ethanol-like DS effects of benzodiazepine agonists. The American Society for Pharmacology and Experimental Therapeutics