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 γ-aminobutyric acid type A (GABAA) receptors containing α1 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 GABAA receptor modulator with intrinsic efficacy in vitro at α2, α3, and α5 subunit-containing GABAA receptors, and little demonstrable intrinsic efficacy in vitro at α1 subunit-containing GABAA receptors. The present study evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the α2, α3, and α5 subunit-containing GABAA 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 α1 subunit-containing GABAA receptors compared to α2, α3, and α5 subunit-containing GABAA receptors, barbiturates and ethanol (which modulate the GABAA 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). βCCT, an antagonist that binds with 20-fold greater affinity for α1 subunit-containing GABAA receptors relative to α2, α3, and α5-containing GABAA 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 α2, α3, and/or α5 subunit-containing GABAA receptors likely are sufficient for engendering BZ-like discriminative stimulus effects.