Self-administration of benzodiazepine and cocaine combinations by male and female rhesus monkeys in a choice procedure: role of α1 subunit–containing GABAA receptors
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Compounds lacking efficacy at the α1 subunit–containing GABAA (α1GABAA) 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.
We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABAA receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABAA receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure.
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.
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.
Compounds that lack efficacy at α1GABAA receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.
KeywordsChoice Cocaine Benzodiazepine Rhesus monkey Self-administration
The authors would like to thank Georganna Nutt, Hunter Bruce, Josh Woods, Yvonne Zuchowski, Morgan Brasfield, Jessica Howard, and Kandace Farmer for their technical assistance.
This research and manuscript preparation were supported by the National Institute on Drug Abuse (NIDA) grants R01 DA043204 and R01 DA011792 to J.K.R, R01 DA045011 to S.L.H, and R01 DA039167 to K.B.F.
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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