Differential sensitivity of ethanol withdrawal signs in the rat to gamma-aminobutyric acid (GABA)mimetics: blockade of audiogenic seizures but not forelimb tremors.
Intraperitoneal injection of ethanol (1-2 g/kg) and chlordiazepoxide (2-16 mg/kg) suppressed susceptibility to audiogenically induced, clonic-tonic seizures and antagonized forelimb tremor in rats undergoing ethanol withdrawal, 30 min after treatment. However, a smaller dose of ethanol (0.5 g/kg) actually increased clonic seizure frequency, suggesting that ethanol exerts a biphasic proconvulsant/anticonvulsant action. Direct activation of gamma-aminobutyric acid (GABA) receptors by intracisternal administration of GABA (100-1000 micrograms), muscimol (0.3-1.0 micrograms) or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) (0.3-3.0 micrograms) 5 to 10 min before testing also reduced susceptibility to audiogenic clonic-tonic seizures. In sharp contrast to these anticonvulsant actions, GABA, muscimol and THIP had no effect on withdrawal-induced forelimb tremors. Blockade of GABA uptake with 1-2,4-diaminobutyric acid (300 and 600 mg/kg i.p.) and inhibition of GABA transaminase with aminooxyacetic acid (12.5 and 25.0 mg/kg i.p.) both reduced susceptibility to seizures. However, anticonvulsant doses of these two drugs, unlike GABA, muscimol and THIP, also reduced forelimb tremor. Three other GABA transaminase inhibitors, gamma-vinyl GABA (450 and 900 mg/kg i.p.), gamma-acetylenic GABA (50-150 mg/kg i.p.) and ethanolamine-O-sulfate (250-750 mg/kg i.p.), were inactive against ethanol withdrawal audiogenic seizures and forelimb tremors. These results indicate that direct GABA receptor activation can selectively suppress one type of ethanol withdrawal response (i.e., audiogenic seizure susceptibility) while failing to influence another (forelimb tremors).
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000161:Acoustic Stimulation; D000613:Aminobutyrates / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002707:Chlordiazepoxide / Q000008:administration & dosage; D004198:Disease Susceptibility; D000431:Ethanol / Q000633:toxicity*; D005552:Forelimb; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage; D008297:Male; D009118:Muscimol / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011963:Receptors, GABA-A; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage
D000613:Aminobutyrates; D007555:Isoxazoles; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D009118:Muscimol; C005959:2,4-diaminobutyric acid; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D002707:Chlordiazepoxide; D000612:4-Aminobutyrate Transaminase; C015542:gaboxadol