Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes

Previous reports suggest that gamma-aminobutyric acid type A (GABA(A)) receptors containing alpha 1 subunits may play a pivotal role in mediating the discriminative stimulus effects of benzodiazepines (BZs). L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[ 1,2,4]triazolo[4,3-b]pyridazine) is a GABA(A) receptor modulator with intrinsic efficacy in vitro at alpha 2, alpha 3, and alpha 5 subunit-containing GABA(A) receptors, and little demonstrable intrinsic efficacy in vitro at alpha 1 subunit-containing GABA(A) receptors. The present study evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the alpha 2, alpha 3, and alpha 5 subunit-containing GABA(A) receptors contribute to the interoceptive effects of BZ-type drugs. Squirrel monkeys (Saimiri sciureus) were trained to discriminate L-838,417 (0.3 mg/kg. i.v.) from vehicle under a 5-response fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 administration resulted in dose-dependent increases in drug-lever responding that were antagonized by the BZ-site antagonist, flumazenil. Administration of non-selective BZs, compounds with 10-fold greater affinity for alpha 1 subunit-containing GABA(A) receptors compared to alpha 2, alpha 3, and alpha 5 subunit-containing GABA(A) receptors, barbiturates and ethanol (which modulate the GABA(A) receptor via a non-BZ site), all resulted in a majority of responses on the L-838,417-paired lever (65-100% drug-lever responding). beta CCT, an antagonist that binds with 20-fold greater affinity for alpha 1 subunit-containing GABA(A) receptors relative to alpha 2, alpha 3, and alpha 5-containing GABA(A) receptors, had no significant effect on the discriminative stimulus effects of L-838,417 or the L-838,417-like effects of diazepam or zolpidem. These data suggest that efficacy at alpha 2, alpha 3, and/or alpha 5 subunit-containing GABA(A) receptors likely are sufficient for engendering BZ-Iike discriminative stimulus effects. (C) 2009 Elsevier Ltd. All rights reserved.