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.
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Acknowledgements
This project was funded by an unrestricted research grant from Merck & Co., USPHS grants DA011792, DA033795 (JKR), AA016179 (DMP); and RR000168 (currently Office of Research Infrastructure Programs grant OD011103). The authors would like to thank Donna Reed, Annemarie Duggan, and Laura Teixeira for technical assistance.
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During the course of these studies, the research was supported, in part, by a research agreement from Merck Research Laboratories with Dr Rowlett as the Principal Investigator. During the studies, Drs Atack, Reynolds, and Dawson were employees of Merck Research Laboratories (Merck, Sharp and Dohme, Ltd.). Ms. Shinday, Drs Sawyer, Fischer, Platt, and Licata had no financial relationship with Merck Research Laboratories. The agreement between Harvard Medical School and Merck Research Laboratories was a scientific collaboration, and did not involve studies that by the publication thereof would engender financial gain or loss from public disclosure. Therefore, the authors declare no conflict of interest.
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Shinday, N., Sawyer, E., Fischer, B. et al. Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys. Neuropsychopharmacol 38, 1006–1014 (2013). https://doi.org/10.1038/npp.2012.265
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DOI: https://doi.org/10.1038/npp.2012.265
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