Developmental neurotoxicity of ethanol: further evidence for an involvement of muscarinic receptor-stimulated phosphoinositide hydrolysis

Various lines of evidence suggest that muscarinic receptor-stimulated phosphoinositide hydrolysis during postnatal development in the rat brain may play a relevant role in glial cell proliferation and neuronal differentiation. We have previously shown that administration of ethanol to developing rats during the brain growth spurt causes microencephaly and selectively decreases muscarinic receptor-stimulated phosphoinositide hydrolysis. In the present study we have investigated the sensitivity of the phosphoinositide system coupled to muscarinic receptors to ethanol inhibition during distinct stages of the brain growth spurt. Different groups of rats were treated for 3 days with ethanol (4 g/kg per day) on postnatal days 2-4 (initial), 6-8 or 10-12 (peak), 13-15 (final stage of the brain growth spurt). The results show that the period of maximal sensitivity to ethanol of muscarinic receptor-stimulated phosphoinositide hydrolysis coincides with the peak of the brain growth spurt and with the period of maximal efficacy of muscarinic receptor agonists to induce inositol phosphates accumulation. Interestingly, only when muscarinic receptor-stimulated phosphoinositide hydrolysis was inhibited, a significant reduction of brain weight was observed. The close parallel between inhibition of this second messenger response and reduction of brain weight suggests that the phosphoinositide system coupled to muscarinic receptors may represent a target for the neurotoxic effects of ethanol during this stage of brain development.