Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels.
The interaction of ethanol with gamma-aminobutyric acid (GABA)-mediated 36-Cl-influx and its modulation by various drugs was investigated in C57 mice spinal cord cultured neurons. Ethanol (5-100 mM) potentiated the effect of GABA on 36Cl-influx; whereas at concentrations greater than or equal to 50 mM ethanol activated Cl- channels directly. The effect of ethanol was specific for GABAA receptor-gated Cl- channels, as ethanol did not potentiate glycine-induced 36Cl-influx in the same neurons. Both the enhancing and direct effects of ethanol on 36Cl-influx were blocked by GABA antagonists like bicuculline, picrotoxinin and inverse agonists of the benzodiazepine site like the imidazodiazepine R015-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5 alpha], [1,4]benzodiazepine-3-carboxylate) and N-methyl-beta-carboline-3-carboxamide (FG-7142). Ethanol potentiating effect of GABA-induced 36Cl-influx was also reversed by methyl-6,7-dimethyl-4-ethyl-beta-carboline-3-carboxylate. The effects of the inverse agonists were blocked by the benzodiazepine receptor antagonist R015-1788. Both R015-4513 and FG-7142 reversed direct and GABA potentiating effects of ethanol effect at concentrations lower than those that exhibit inverse agonistic activity in the 36Cl-influx assay in cultured neurons. These results suggest that ethanol facilitation of GABAAergic transmission involves GABA receptor-gated Cl- channels and that this interaction may be responsible for some of the pharmacological effects of ethanol.
Mehta
A K
AK
Department of Pharmacology, University of Texas Health Science Center, San Antonio.
Ticku
M K
MK
D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002478:Cells, Cultured; D002713:Chlorine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018756:GABA Antagonists; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011868:Radioisotopes; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D001386:Azides; D002243:Carbolines; D018756:GABA Antagonists; D007473:Ion Channels; D011868:Radioisotopes; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; D002713:Chlorine; D005680:gamma-Aminobutyric Acid; C035874:FG 7142; C042957:Ro 15-4513