Self-administration of benzodiazepine and cocaine combinations by male and female rhesus monkeys in a choice procedure: role of α1 subunit–containing GABA_A receptors

Abstract

Rationale

Compounds lacking efficacy at the α1 subunit–containing GABA_A (α1GABA_A) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience.

Objectives

We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABA_A receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABA_A receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure.

Methods

One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003–0.1 mg/kg/injection), zolpidem (0.003–0.3 mg/kg/injection), or L-838-417 (0.01–0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own.

Results

Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in three of four subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject.

Conclusion

Compounds that lack efficacy at α1GABA_A receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.