Ethanol selectively interferes with the trophic action of NMDA and carbachol on cultured cerebellar granule neurons undergoing apoptosis

Exposure of mature rat cerebellar granule neurons to non-depolarizing condi tions (5 mM K+) for 24 h resulted in the onset of apoptosis. NMDA, forskoli n, carbachol and GABA attenuated low Kf-induced toxicity, although to a dif ferent extent, with NMDA and GABA being the most effective agents. When cel ls were co-exposed for 24 h ro ethanol, the survival promoting action of NM DA and carbachol, but not that of forskolin and GABA, was attenuated. By co ntrast, a 24 h cell pre-treatment with ethanol, followed by its removal pri or to K+ deprivation, was ineffective towards the neurotrophic action of NM DA and carbachol. The concomitant presence of alcohol and neurotrophic fact ors was not required for the pro-apoptotic effect of ethanol to be manifest after a long-term alcohol exposure: inhibition of NMDA- and carbachol-medi ated neurotrophism was still observed when cells were pre-exposed for 72 h to alcohol in depolarizing conditions, prior to the challenge with 5 mM K+- containing medium and the test compounds in the absence of ethanol. The pre sent study shows that ethanol promotes apoptotic cell death of cultured cer ebellar neurons by selectively inhibiting the neurotrophic effect of NMDA a nd carbachol, and suggests that alcohol may cause permanent changes in the control mechanisms of apoptosis: this finding may have significant implicat ions for the in vivo toxicity of prenatal ethanol exposure on the developin g cerebellum. (C) 1998 Elsevier Science B.V. All rights reserved.