Role of GABAA receptors in the GABA attenuation of ethanol neurotoxicity.
We have previously reported that GABA reverses the neuronotoxic effects of ethanol in neuroblast-enriched cultures derived from 3-day-old whole chick embryo (E3WE). In the present study, we examined the effects of GABA agonists and antagonists on morphological growth patterns and on cholinergic neuronal phenotypic expression, using choline acetyltransferase (ChAT) activity as a marker. E3WE neuroblast-enriched cultures showed positive immunoreactivity for neurofilament and as previously reported, control cultures exhibited the characteristic pattern of outgrowth of neurites of varying thickness radiating from the aggregates. In contrast, cultures grown in ethanol consisted of neuronal aggregates lacking fasciculation but having a complex network of individual thin neurites. Both GABA and GABAA agonist muscimol enhanced neuritic fasciculation and arborization in control and ethanol-treated cultures, and this growth enhancement was inhibited by GABAA antagonist bicuculline. No effects were noted with GABAB agonist baclofen. GABA increased ChAT activity in E3WE control cultures, as previously reported. A similar effect was seen with GABAA agonist muscimol, but not with GABAB agonist baclofen. However, the GABA effect was not apparent in the presence of GABAB antagonist phaclofen. Thus, it appears that the cholinotrophic effects of GABA are mediated by both GABAA and GABAB receptors. In ethanol-treated cultures the already-reported ChAT decline was reversed by GABA and muscimol, but not by baclofen. Moreover, the GABA effect in ethanol-treated cultures was not antagonized by GABAB antagonist phaclofen, suggesting that the GABA effect was mediated by a GABAA receptor. We conclude from these findings that the cholinotrophic effects of GABA are mediated by GABAA and GABAB receptors, while the rescuing effects of GABA in the ethanol-treated cultures are mediated via GABAA receptors.
Spoerri
P E
PE
Department of Psychiatry, University of Colorado, Health Sciences Center, Denver 80262, USA.
Srivastava
N
N
Vernadakis
A
A
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D002642:Chick Embryo; D002795:Choline O-Acetyltransferase / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity*; D011963:Receptors, GABA-A / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D002795:Choline O-Acetyltransferase