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GABA A Receptor Subtypes and the Abuse‐Related Effects of Ethanol in Rhesus Monkeys: Experiments with Selective Positive Allosteric Modulators
- Source :
- Alcoholism: Clinical and Experimental Research. 43:791-802
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Background Previous studies have investigated α1GABAA and α5GABAA receptor mechanisms in the behavioral effects of ethanol (EtOH) in monkeys. However, genetic studies in humans and preclinical studies with mutant mice suggest a role for α2GABAA and/or α3GABAA receptors in the effects of EtOH. The development of novel positive allosteric modulators (PAMs) with functional selectivity (i.e., selective efficacy) at α2GABAA and α3GABAA receptors allows for probing of these subtypes in preclinical models of the discriminative stimulus and reinforcing effects of EtOH in rhesus macaques. Methods In discrimination studies, subjects were trained to discriminate EtOH (2 g/kg, intragastrically) from water under a fixed-ratio (FR) schedule of food delivery. In oral self-administration studies, subjects were trained to self-administer EtOH (2% w/v) or sucrose (0.3 to 1% w/v) under an FR schedule of solution availability. Results In discrimination studies, functionally selective PAMs at α2GABAA and α3GABAA (HZ-166) or α3GABAA (YT-III-31) receptors substituted fully (maximum percentage of EtOH-lever responding ≥80%) for the discriminative stimulus effects of EtOH without altering response rates. Full substitution for EtOH also was engendered by a nonselective PAM (triazolam), an α5GABAA -preferring PAM (QH-ii-066) and a PAM at α2GABAA , α3GABAA , and α5GABAA receptors (L-838417). A partial (MRK-696) or an α1GABAA -preferring (zolpidem) PAM only engendered partial substitution (i.e., ~50 to 60% EtOH-lever responding). In self-administration studies, pretreatments with the functionally selective PAMs at α2GABAA and α3GABAA (XHe-II-053 and HZ-166) or α3GABAA (YT-III-31 and YT-III-271) receptors increased EtOH, but not sucrose, drinking at doses that had few, or no, observable sedative-motor effects. Conclusions Our results confirm prior findings regarding the respective roles of α1GABAA and α5GABAA receptors in the discriminative stimulus effects of EtOH and, further, suggest a key facilitatory role for α3GABAA and potentially α2GABAA receptors in several abuse-related effects of EtOH in monkeys. Moreover, they reveal a potential role for these latter subtypes in EtOH's sedative effects.
- Subjects :
- endocrine system
Zolpidem
Triazolam
Chemistry
GABAA receptor
Allosteric regulation
030508 substance abuse
Medicine (miscellaneous)
Alpha (ethology)
Pharmacology
Toxicology
03 medical and health sciences
Psychiatry and Mental health
0302 clinical medicine
mental disorders
medicine
Functional selectivity
0305 other medical science
Self-administration
Receptor
reproductive and urinary physiology
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15300277 and 01456008
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- Alcoholism: Clinical and Experimental Research
- Accession number :
- edsair.doi...........a593c0b6164bfa7fcf5526966342ba74