Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA₂ analysis

Abstract

Background: Conventional benzodiazepines bind non-selectively to GABA(A) receptors containing alpha 1, alpha 2, alpha 3, and alpha 5 subunits (alpha 1GABA(A), alpha 2GABA(A), alpha 3GABA(A), and alpha 5GABA(A) receptors, respectively), and the role of these different GABA(A) receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABA(A) receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. Methods: Rhesus monkeys (n = 4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), beta CCT and 3-PBC (alpha 1GABA(A)-preferring antagonists), and XLi-093 (alpha 5GABA(A)-selective antagonist). Results: Flumazenil, beta CCT and 3-PBC shifted the dose response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil = beta CCT > 3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABA(A) receptor subtypes suggested that the potencies for beta CCT and 3-PBC were most consistent with binding at alpha 2GABA(A) and alpha 3GABA(A) receptors, but not alpha 1GABA(A) or alpha 5GABA(A) receptor subtypes. Conclusions: Our findings were not entirely consistent with blockade of alpha 1GABA(A) receptors and are consistent with the possibility of alpha 2GABA(A) and/or alpha 3GABA(A) subtype involvement in antagonism of the reinforcing effects of triazolam. The alpha 5GABA(A) receptor subtype likely does not play a substantial role in self-administration under these conditions. (C) 2015 Elsevier Ireland Ltd. All rights reserved.