Effect of ethanol dependence on GABAA antagonist-induced seizures and agonist-stimulated chloride uptake.
The functional state of GABAA receptors during physical dependence on ethanol was evaluated in two ways. First, the ability of ethanol dependence to change the convulsant potency of GABAA antagonists microinjected into the inferior colliculus was examined. A second approach evaluated the effects of ethanol dependence on the ability of muscimol or pentobarbital to stimulate chloride uptake in rat brain vesicles. In the studies examining changes in convulsant potency, bilateral microinfusions of GABAA antagonists, bicuculline methiodide and picrotoxinin, as well as the excitatory amino acid agonist, kainic acid (used as a positive control) induced similar dose-related increases in the frequency of wild-running seizures. Ethanol dependence did not significantly change susceptibility to wild-running seizure induction by an of the convulsants, although susceptibility to the more severe, clonic seizures was significantly increased for each convulsant. This suggested that the receptor-blocking effects of GABAA antagonists responsible for inducing wild-running seizures were not selectively increased by ethanol dependence, but that spread of seizure activity responsible for clonic seizures following the initiation of wild running was generally increased. Finally, in studies examining changes in GABAA receptor-mediated chloride uptake, both muscimol and pentobarbital were found to induce concentration-dependent increases in chloride uptake in rat brain vesicles. However, responses to these drugs were not reduced by ethanol dependence suggesting that a generalized adaptive decrease in GABAA receptor function was unlikely. Together these results do not provide support for the hypothesis that the GABAA receptor-chloride channel complex is down-regulated during the development of physical dependence on ethanol.
Frye
G D
GD
Department of Medical Pharmacology and Toxicology, Texas A&M University College of Medicine College Station 77843.
Mathew
J
J
Trzeciakowski
J P
JP
D000818:Animals; D002712:Chlorides / Q000493:pharmacokinetics* / Q000502:physiology; D003292:Convulsants; D000431:Ethanol; D018756:GABA Antagonists; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced*; D019966:Substance-Related Disorders / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors
D002712:Chlorides; D003292:Convulsants; D018756:GABA Antagonists; D009118:Muscimol; D000431:Ethanol; D010424:Pentobarbital