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Reinforcing effects of compounds lacking intrinsic efficacy at a1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced rhesus monkeys

journal contribution
posted on 2023-06-08, 14:49 authored by Nina M Shinday, Eileen K Sawyer, Bradford D Fischer, Donna M Platt, Stephanie C Licata, John R Atack, Gerard R Dawson, David S Reynolds, James K Rowlett
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 a1 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 a2, a3, and a5 subunit-containing GABAA receptors but lack efficacy at a1 subunit-containing GABAA receptors ('a1-sparing compounds'): MRK-623 (functional selectivity for a2/a3 subunit-containing receptors), TPA023B (functional selectivity for a2/a3/a5 subunit-containing receptors), and TP003 (functional selectivity for a3 subunit-containing receptors). The reinforcing effects of the a1-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 a1-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 a1 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 a3 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.

History

Publication status

  • Published

Journal

Neuropsychopharmacology

ISSN

0893-133X

Publisher

Nature Publishing Group

Issue

6

Volume

38

Page range

1006-1014

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2013-04-29

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    University of Sussex (Publications)

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