GABAA Receptor Subtypes and the Reinforcing Effects of Benzodiazepines in Remifentanil-Experienced Rhesus Monkeys.

BACKGROUND: Opioid-use disorder is associated with a high degree of co-abuse with benzodiazepines. While the mechanisms underlying the co-abuse of opioids and benzodiazepines remain unknown, α1 subunit-containing GABAA receptors may play a critical role in the reinforcing effects of benzodiazepine-type compounds, depending on whether the monkeys have a history of benzodiazepine or stimulant self-administration. The present study extended our prior research by comparing the reinforcing effects of a compound lacking activity at α1 subunit-containing GABAA receptors with the reinforcing effects of non-selective GABAA receptor positive allosteric modulators in monkeys with a history of opioid self-administration.

METHODS: The reinforcing effects of L-838,417 (partial intrinsic efficacy at α2, α3, and α5 subunit-containing GABAA receptors, but no efficacy at α1 subunit-containing GABAA receptors, i.e., "α1-sparing compound") were compared with those of the non-selective GABAA receptor partial modulator MRK-696, and non-selective GABAA receptor full modulators, triazolam and lorazepam, in rhesus monkeys (n = 3) experienced in remifentanil self-administration under a progressive-ratio schedule of intravenous drug injection.

RESULTS: Neither the partial modulator nor the α1-sparing compound were self-administered above vehicle levels. The full modulators triazolam and lorazepam were self-administered significantly above vehicle levels, albeit at lower levels than remifentanil.

CONCLUSIONS: Our findings suggest that relatively high efficacy at one or more GABAA receptor subtypes is required for a compound to have reinforcing effects in monkeys with a history of remifentanil self-administration, in contrast to monkeys with benzodiazepine or stimulant self-administration histories.