Ethanol and the GABA receptor complex: studies with the partial inverse benzodiazepine receptor agonist Ro 15-4513.
Ethanol potentiates GABA-receptor-mediated Cl- ion flux in vitro and, at similar concentrations, has anxiolytic and intoxicating properties in vivo. The imidazobenzodiazepine, Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-meth-6-oxo-4H- imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylate), is a potent partial inverse agonist of the benzodiazepine/GABA receptor which can antagonize the in vitro actions of ethanol in potentiating GABA receptor-mediated Cl- ion flux. Moreover, several of the behavioral effects of ethanol are also antagonized by Ro 15-4513, and these effects can be demonstrated in several paradigms at doses of Ro 15-4513 that do not produce opposite behavioral effects. In contrast, in our studies, other benzodiazepine receptor antagonist and inverse agonists, including Ro 15-1788, FG-7142, and beta-CCE were not able to antagonize these biochemical or behavioral effects of ethanol at doses that were without intrinsic effects. However, both Ro 15-1788 and beta-CCE blocked the antagonism of ethanol's effects by Ro 15-4513, suggesting a role for the GABA receptor complex in the actions of ethanol. These studies provide further evidence that GABAergic neurones may mediate at least some of the behavioral and biochemical actions of low-to-moderate doses of ethanol.
Glowa
J R
JR
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892.
Crawley
J
J
Suzdak
P D
PD
Paul
S M
SM
D000435:Alcoholic Intoxication / Q000503:physiopathology; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D002713:Chlorine / Q000378:metabolism; D003220:Conflict, Psychological; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D015201:Meta-Analysis as Topic; D051379:Mice; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D001386:Azides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D002713:Chlorine; C042957:Ro 15-4513; D010424:Pentobarbital