Evidence That Sedative Effects of Benzodiazepines Involve Unexpected GABA A Receptor Subtypes: Quantitative Observation Studies in Rhesus Monkeys.

In nonhuman primates we tested a new set of behavioral categories for observable sedative effects using pediatric anesthesiology classifications as a basis. Using quantitative behavioral observation techniques in rhesus monkeys, we examined the effects of alprazolam and diazepam (nonselective benzodiazepines), zolpidem (preferential binding to α 1 subunit-containing GABAA receptors), HZ-166 (8-ethynyl-6-(2'-pyridine)-4 H -2,5,10b-triaza-benzo[ e ]azulene-3-carboxylic acid ethyl ester; functionally selective with relatively high intrinsic efficacy for α 2 and α 3 subunit-containing GABAA receptors), MRK-696 [7-cyclobutyl-6-(2-methyl-2 H -1,2,4-triazol-2-ylmethoxy)-3-(2-flurophenyl)-1,2,4-triazolo(4,3- b )pyridazine; no selectivity but partial intrinsic activity], and TPA023B 6,2'-diflouro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2- b ][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile; partial intrinsic efficacy and selectivity for α 2, α 3, α 5 subunit-containing GABAA receptors]. We further examined the role of α 1 subunit-containing GABAA receptors in benzodiazepine-induced sedative effects by pretreating animals with the α 1 subunit-preferring antagonist β -carboline-3-carboxylate- t -butyl ester ( β CCT). Increasing doses of alprazolam and diazepam resulted in the emergence of observable ataxia, rest/sleep posture, and moderate and deep sedation. In contrast, zolpidem engendered dose-dependent observable ataxia and deep sedation but not rest/sleep posture or moderate sedation, and HZ-166 and TPA023 induced primarily rest/sleep posture. MRK-696 induced rest/sleep posture and observable ataxia. Zolpidem, but no other compounds, significantly increased tactile/oral exploration. The sedative effects engendered by alprazolam, diazepam, and zolpidem generally were attenuated by β CCT pretreatments, whereas rest/sleep posture and suppression of tactile/oral exploration were insensitive to β CCT administration. These data suggest that α 2/3-containing GABAA receptor subtypes unexpectedly may mediate a mild form of sedation (rest/sleep posture), whereas α 1-containing GABAA receptors may play a role in moderate/deep sedation.