Ethanol modulation of GABA receptor-activated Cl- currents in neurons of the chick, rat and mouse central nervous system.
Modulation of gamma-aminobutyric acidA (GABAA) receptor function by drugs such as ethanol may depend on the genetic heterogeneity of GABAA receptor subunits, which vary across species and cell types. For this reason, the effects of ethanol on gamma-aminobutyric acid receptor-activated chloride currents (IGABA) were examined using whole-cell voltage-clamp recordings in primary cultures of neurons obtained from different species (chick, mouse and rat) and from different brain regions (cerebral cortex, hippocampus, cerebellum and spinal cord), and in acutely dissociated neurons from rat neocortical slices. Low concentrations (1-50 mM) of ethanol produced an enhancement of IGABA in some cells from each brain region examined. In cells obtained from the rat and chick cerebral cortex, 40-58% of cells exhibited an ethanol-sensitive IGABA. Moreover, a statistically significant variation in the response to ethanol was found in rat cortical neurons obtained from different litters. In mouse hippocampal neurons, potentiation of IGABA was obtained with ethanol concentrations (1-10 mM) well below those needed to inhibit neuronal responses to N-methyl-D-aspartic acid (30-50 mM), suggesting a differential sensitivity of these two receptor mechanisms to ethanol. Potentiation of IGABA by ethanol was reversed by the benzodiazepine receptor partial inverse agonist RO15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine - 3-carboxylate), but was not affected by chelation of intracellular calcium. Furthermore, high concentrations of GABA attenuated the ability of ethanol to enhance IGABA. These results are consistent with the hypothesis that ethanol facilitates coupling between receptor binding and chloride channel activation.
D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D001386:Azides; D018118:Chloride Channels; D002712:Chlorides; D007473:Ion Channels; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; C042957:Ro 15-4513