title: Reinforcing effects of compounds lacking intrinsic efficacy at α1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced rhesus monkeys.
abstract: 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 α1 subunit-containing GABAA 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 α2, α3, and α5 subunit-containing GABAA receptors but lack efficacy at α1 subunit-containing GABAA receptors ('α1-sparing compounds'): MRK-623 (functional selectivity for α2/α3 subunit-containing receptors), TPA023B (functional selectivity for α2/α3/α5 subunit-containing receptors), and TP003 (functional selectivity for α3 subunit-containing receptors). The reinforcing effects of the α1-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 α1-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 α1 subunit-containing GABAA receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of stimulant self-administration, whereas α3 subunit-containing GABAA receptors may be important mediators of the reinforcing effects of benzodiazepine-type compounds in animals with a history of sedative-anxiolytic/benzodiazepine self-administration.
authors.affiliation: Department of Psychiatry, Division of Neuroscience, New England Primate Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, MA 01772, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Shinday
authors.forename: Eileen K
authors.initials: EK
authors.lastname: Sawyer
authors.forename: Bradford D
authors.initials: BD
authors.lastname: Fischer
authors.forename: Donna M
authors.initials: DM
authors.lastname: Platt
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Licata
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: David S
authors.initials: DS
authors.lastname: Reynolds
authors.forename: James K
authors.initials: JK
authors.lastname: Rowlett
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000008:administration & dosage*; D021122:Protein Subunits / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: C546240:GABRA1 protein, human; C546257:GABRA3 protein, human; D021122:Protein Subunits; D011963:Receptors, GABA-A; D003042:Cocaine; D008874:Midazolam