Role of GABAA/benzodiazepine receptors containing alpha 1 and alpha 5 subunits in the discriminative stimulus effects of triazolam in squirrel monkeys.

Abstract

Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABA(A) receptors containing alpha(1), alpha(2), alpha(3), or alpha(5) subunits. The role of these different GABA(A) receptor subtypes in mediating the subjective effects of BZs remains largely unknown. The purpose of the present study was to evaluate the role of GABA(A) receptors containing the alpha(1) or alpha(5) subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist triazolam. Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 schedule of food reinforcement. The GABA(A)/alpha(1)-preferring agonists zolpidem and zaleplon engendered responses predominantly on the triazolam lever (73-80% drug-lever responding), and the GABA(A)/alpha(1) partial agonist CL 218,872 engendered an average maximum of less than 50% triazolam-lever responding. The GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (betaCCT) and 3-(propyloxy)-beta-carboline (3-PBC) blocked the DS effects of triazolam and zolpidem in a surmountable manner. Schild analyses for betaCCT and 3-PBC in combination with triazolam and zolpidem suggest that the interactions between these compounds were competitive in nature and mediated by a common population of receptors, presumably GABA(A)/alpha(1) receptors. In contrast, the GABA(A)/alpha(5)-preferring agonist QH-ii-66 did not engender triazolam-lever responding regardless of dose and did not alter the DS effects of triazolam when administered in combination. The results are consistent with GABA(A)/alpha(1) receptor involvement in mediating the DS effects of triazolam. In contrast, binding to GABA(A)/alpha(5) receptors may not play a critical role in mediating triazolam's DS effects.