Benzodiazepine receptor mediated discriminative cues: effects of GABA-ergic drugs and inverse agonists.

Rats were exposed to a two-lever drug discrimination procedure using the benzodiazepine (BZ) receptor inverse agonists N'-methyl-beta-carboline-3-carboxamide (FG 7142) or methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). FG 7142 (30 mg/kg) failed to acquire discriminative stimulus control, although it did suppress responding. The same group of animals was trained successfully to discriminate diazepam (DZP, 2.5 mg/kg) from vehicle. The DZP cue was potentiated by the GABA agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol (THIP, 1,3 mg/kg); THIP alone produced vehicle-appropriate responding. In addition, clonazepam (0.2 mg/kg) and chlordiazepoxide (5 mg/kg) substituted for DZP (with potencies of 7.5 and 0.25 times that of DZP, respectively). In antagonism tests, FG 7142 (5-17.5 mg/kg), methyl-beta-carboline-3-carboxylate (beta-CCM, 2.5 mg/kg) did not effect, bicuculline (2 mg/kg) and DMCM (1 mg/kg) partially blocked, and the BZ receptor antagonist Ro 15-1788 (40 mg/kg) completely blocked the discriminative stimulus effects of DZP. In animals trained to discriminate DMCM (0.2 mg/kg) from vehicle, 95.2% substitution occurred with bicuculline (2 mg/kg); DZP (1-5 mg/kg) completely antagonized DMCM. These results indicate that the DZP cue is mediated by GABA-coupled BZ receptors and that GABA may modulate the efficacy of a BZ at its receptor site. However, since inverse BZ receptor agonists (FG 7142, DMCM and beta-CCM) were, at best, only marginally effective in antagonizing DZP, the DZP cue may be mediated by a distinct subclass of BZ receptors.