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Little Evidence of a Role for the α 1 GABA A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking
Author(s) -
Sawyer Eileen K.,
Moran Casey,
Sirbu Madelynn H.,
Szafir Melissa,
Linn Michael,
Namjoshi Ojas,
Phani Babu Tiruveedhula VVN,
Cook James M.,
Platt Donna M.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12320
Subject(s) - flumazenil , zolpidem , gabaa receptor , pharmacology , agonist , chemistry , benzodiazepine , alcohol , triazolam , endocrinology , partial agonist , medicine , receptor , biochemistry , insomnia
Background Alcohol potentiates GABA ergic neurotransmission via action at the GABA A receptor. α 1 subunit‐containing GABA A receptors have been implicated as mediators, in part, of the behavioral and abuse‐related effects of alcohol in rodents. Methods We systematically investigated the effects of 1 α 1‐preferring benzodiazepine agonist, zolpidem, and 2 antagonists, β ‐carboline‐3‐carboxylate‐tert‐butyl ester ( β CCT ) and 3‐propoxy‐ β ‐carboline hydrochloride (3‐ PBC ), on oral self‐administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist β ‐carboline carboxylate ( β CCE ). Results Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α 1‐preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels ( BAL s) at any of the doses tested. Zolpidem, β CCT , and 3‐ PBC increased latency to first sipper extension in animals self‐administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol‐drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol‐drinking animals, triazolam increased sucrose intake and latency. Flumazenil nonsystematically increased number of extensions for alcohol but decreased BAL , with no effects on sucrose drinking. β CCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose–effect relationships could not be determined due to seizures at higher doses. Conclusions Alcohol‐drinking animals appeared more sensitive to the effects of GABA ergic compounds on drinking behavior. However, these results do not support a strong contribution of α 1 GABA A receptors to the reinforcing effects of alcohol in primates.