Little Evidence of a Role for the [alpha]1GABAA Subunit-Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Background Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. [alpha]1 subunit-containing GABAA 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 [alpha]1-preferring benzodiazepine agonist, zolpidem, and 2 antagonists, [beta]-carboline-3-carboxylate-tert-butyl ester ([beta]CCT) and 3-propoxy-[beta]-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 [beta]-carboline carboxylate ([beta]CCE). Results Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The [alpha]1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels (BALs) at any of the doses tested. Zolpidem, [beta]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. [beta]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 GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of [alpha]1GABAA receptors to the reinforcing effects of alcohol in primates.