Time-, concentration-, and age-dependent inhibition of muscarinic receptor-stimulated phosphoinositide metabolism by ethanol in the developing rat brain |
| |
| Authors: | Walter Balduini Stefano M Candura Luigi Manzo Flaminio Cattabeni Dr Lucio G Costa |
| |
| Institution: | (1) Department of Environmental Health, University of Washington, 98195 Seattle, WA;(2) Department of Internal Medicine and Therapeutics, Pharmacology and Toxicology Division, University of Pavia, Pavia, Italy;(3) Institute of Pharmacological Sciences, University of Milano, Milano, Italy;(4) Present address: Institute of Pharmacology and Pharmacognosy, University of Urbino, Urbino, Italy |
| |
| Abstract: | We have previously reported that administration of ethanol (EtOH; 4 g/Kg/day) to rats from postnatal day 4 to day 10 causes microencephaly and decreases muscarinic receptor-stimulated inositol metabolism on days 7 and 10 (1). An identical exposure to EtOH of adult rats, which resulted in similar blood EtOH concentrations, did not have any effect on the same system. Initial in vitro studies have shown the presence of a differential sensitivity to EtOH of the phosphoinositide system coupled to muscarinic receptors during development (2). In the present study we have expanded these findings by investigating the concentration-, time-, and age-dependent effects of EtOH on accumulation of 3H]inositol phosphates (3H]InsPs) in brain slices. EtOH caused a dose-dependent inhibition of carbachol-stimulated phosphoinositide metabolism in cerebral cortex slices from 7 day-old rats. When the time of incubation with EtOH was increased to 90 minutes, concentrations as low as 50 mM, which are reached following in vivo administration of EtOH, significantly inhibited the muscarinic response. The effect of EtOH was rather specific for the muscarinic receptors, since, even with longer incubation times, the accumulation of 3H]InsPs induced by norepinephrine or serotonin was inhibited only at concentrations of 150–500 mM. The effect of EtOH was more pronounced in cerebral cortex, hippocampus and cerebellum, and less in the brainstem. The potency of EtOH in inhibiting carbachol-stimulated phosphoinositide metabolism was also dependent on the age of the animals. Its effect was maximal in the 7 day-old rat and less pronounced in younger and older animals. These results confirm that the phosphoinositide system coupled to muscarinic receptors might represent a relevant target for the developmental neurotoxicity of EtOH.Presented in part at the 29th Annual Meeting of the Society of Toxicology (Toxicologist 1990; 10: 273). |
| |
| Keywords: | Ethanol developmental neurotoxicity phosphoinositide metabolism muscarinic receptor |
| 本文献已被 SpringerLink 等数据库收录！ |
|
