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

• Published in: Drug and alcohol dependence 2020-08, Vol.213, p.108076-108076, Article 108076
• Main Authors: Berro, Lais F., Rowlett, James K.
• Format: Article
• Language: English
• Subjects: Abuse; Allosteric properties; benzodiazepine; Benzodiazepines; Drug abuse; Drug addiction; drug history; Efficacy; GABAA receptor; Intravenous administration; Intravenous drugs; Lorazepam; Management; Modulators; Monkeys; Narcotics; Neurotransmitters; Opioid receptors; Opioids; Primates; Receptors; Remifentanil; rhesus monkey; SAT assessment; Schedules; Self-administration; Stimulants; Substance use disorder; Subtypes; Triazolam; γ-Aminobutyric acid A receptors
• ISSN: 0376-8716; 1879-0046
• DOI: 10.1016/j.drugalcdep.2020.108076

•Full GABAA modulators have reinforcing effects in monkeys trained with remifentanil•A partial GABAA modulator was not self-administered by remifentanil-trained monkeys•An α1-sparing partial modulator was not self-administered by these monkeys•High efficacy GABAA modulators have reinforcing effects in opioid-trained monkeys 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. 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. 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. 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.