Interaction of short chain aliphatic alcohols with muscarinic receptor-stimulated phosphoinositide metabolism in cerebral cortex from neonatal and adult rats.
Muscarinic receptor-stimulated phosphoinositide metabolism has been recently suggested as a possible target for the neurotoxic effects of ethanol during brain development. Since two other alcohols, tertiary butanol and n-propanol, have been shown to cause microencephaly in the rat when administered during the brain growth spurt, in the present study we investigated the in vitro effects of five short chain aliphatic alcohols on muscarinic receptor-stimulated phosphoinositide metabolism in cerebral cortical slices from 7 day-old rats. In neonatal animals all alcohols tested inhibited carbachol (1 mM)-stimulated [3H]inositol phosphates accumulation in a dose- and time-dependent manner. The order of potency was t-butanol greater than n-propanol greater than or equal to iso-propanol greater than ethanol greater than methanol. After 90 min of incubation, ethanol, n-propanol and t-butanol caused a significant inhibition of muscarinic receptor-stimulated inositol metabolism at doses as low as 15 - 50 mM, comparable to the blood concentrations reached after in vivo administration of doses able to induce developmental neurotoxicity. The inhibitory effect of ethanol was additive to that of iso-propanol or t-butanol. Differently from these effects in 7 day-old rats, in cortical slices from adult animals methanol and ethanol had no effect on carbachol-stimulated phosphoinositide metabolism, while the two propanol isomers and t-butanol were less effective than in neonatal animals. These results suggest that muscarinic receptor-coupled phosphoinositide metabolism might be a common neurochemical target for the developmental neurotoxicity of short chain aliphatic alcohols.
Candura
S M
SM
Department of Environmental Health, University of Washington, Seattle 98195.
Balduini
W
W
Costa
L G
LG
D000438:Alcohols / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002217:Carbachol / Q000037:antagonists & inhibitors; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*
D000438:Alcohols; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D002217:Carbachol