Are GABAB receptors involved in the pharmacological effects of ethanol?
The interaction of ethanol with GABAB-receptor system and the selectivity of phaclofen for GABA-receptor subtypes were investigated by employing an in vitro model of 36Cl-influx assay in mammalian cultured neurons and also in vivo models of picrotoxin- and NMDA-induced convulsions in rats. Ethanol (20 mM), without having any effect per se, potentiated the effect of GABA on 36Cl-influx, whereas at concentration 50 mM, ethanol activated Cl(-)-channels directly in mice spinal cord cultured neurons. In contrast, (-)baclofen (100 microM) did not modify the effects of GABA or ethanol on 36Cl-influx. Similarly, phaclofen (500 microM), as well as pertussis toxin (140 ng/ml, overnight incubation) did not modify these effects. Interestingly, phaclofen (200 micrograms i.c.v.) reversed the anticonvulsant effect of ethanol, but not that of pentobarbital or diazepam or progabide, against picrotoxin-induced convulsions in rats. However, phaclofen failed to modify the anticonvulsant effect of ethanol against NMDA-induced convulsions. These observations indicate that phaclofen is devoid of GABAA-receptor blockade property, and the anticonvulsant effect of ethanol against picrotoxin may be mediated through the activation of both GABA-receptor subtypes.
Mehta
A K
AK
Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
Ticku
M K
MK
D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D002713:Chlorine; D003975:Diazepam / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011868:Radioisotopes; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D001418:Baclofen; D002713:Chlorine; D003975:Diazepam; D000431:Ethanol; D016202:N-Methylaspartate; D010852:Picrotoxin; D011868:Radioisotopes; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C052329:phaclofen; C017985:progabide