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

摘要: Previous reports suggest that gamma-aminobutyric acid type A (GABA(A)) receptors containing alpha1 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 GABA(A) receptor modulator with intrinsic efficacy vitro at alpha2, alpha3, and alpha5 subunit-containing receptors, little demonstrable receptors. The present study evaluated order to determine extent which contribute interoceptive BZ-type drugs. Squirrel monkeys (Saimiri sciureus) were trained discriminate (0.3 mg/kg, i.v.) from vehicle under 5-response fixed-ratio schedule food reinforcement. Under test conditions, administration resulted dose-dependent increases drug-lever responding antagonized by BZ-site antagonist, flumazenil. Administration non-selective BZs, compounds 10-fold greater affinity for compared barbiturates ethanol (which modulate via non-BZ site), all majority responses on L-838,417-paired lever (65-100% responding). betaCCT, an antagonist binds 20-fold relative alpha5-containing had no significant effect or L-838,417-like diazepam zolpidem. These data and/or likely are sufficient engendering BZ-like effects.