Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α 1 Subunit-Containing GABA A Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

Benzodiazepines are prescribed widely but their utility is limited by unwanted side effects, including abuse potential. The mechanisms underlying the abuse-related effects of benzodiazepines are not well understood, although α 1 subunit-containing GABA A receptors have been proposed to have a critical role. Here, we examine the reinforcing effects of several compounds that vary with respect to intrinsic efficacy at α 2, α 3, and α 5 subunit-containing GABA A receptors but lack efficacy at α 1 subunit-containing GABA A receptors (‘ α 1-sparing compounds’): MRK-623 (functional selectivity for α 2/ α 3 subunit-containing receptors), TPA023B (functional selectivity for α 2/ α 3/ α 5 subunit-containing receptors), and TP003 (functional selectivity for α 3 subunit-containing receptors). The reinforcing effects of the α 1-sparing compounds were compared with those of the non-selective benzodiazepine receptor partial agonist MRK-696, and non-selective benzodiazepine receptor full agonists, midazolam and lorazepam, in rhesus monkeys trained to self-administer midazolam or cocaine, under a progressive-ratio schedule of intravenous (i.v.) drug injection. The α 1-sparing compounds were self-administered significantly above vehicle levels in monkeys maintained under a midazolam baseline, but not under a cocaine baseline over the dose ranges tested. Importantly, TP003 had significant reinforcing effects, albeit at lower levels of self-administration than non-selective benzodiazepine receptor agonists. Together, these results suggest that α 1 subunit-containing GABA A receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of stimulant self-administration, whereas α 3 subunit-containing GABA A receptors may be important mediators of the reinforcing effects of benzodiazepine-type compounds in animals with a history of sedative-anxiolytic/benzodiazepine self-administration.