Glucocorticoid interactions with ethanol effects on depolarization-induced calcium influx in brain synaptosomes.
Depolarization-induced Ca2+ influx in brain synaptosomes is known to be inhibited by ethanol and stimulated by glucocorticoids. The present study was undertaken to characterize the interactions of corticosterone (CORT) with ethanol effects on 45Ca2+ uptake in synaptosomes depolarized by high K+ (70 mM). CORT was shown to antagonize the inhibitory effects of ethanol on the fast-phase component of the K(+)-induced 45Ca2+ uptake (the initial 3 s following depolarization). Glucocorticoid antagonism of ethanol inhibition of the 45Ca2+ uptake exhibited a high degree of steroid specificity; steroids with glucocorticoid activity including cortisol, dexamethasone and triamcinolone were effective, whereas gonadal steroids and excitatory neuroactive steroid metabolites were ineffective. From the shift of concentration-response relationships when CORT and ethanol were present in combination, the interaction between steroid stimulation and ethanol inhibition of 45Ca2+ uptake occurred in an additive manner over the range of their effective concentrations. Parallel to 45Ca2+ uptake, the binding sites for [3H]PN 200-110 were reduced by ethanol and increased by CORT. These opposite effects on [3H]dihydropyridine labeled sites were found also to antagonize each other, and the antagonism again occurred in an additive relationship. These results demonstrate that glucocorticoids antagonized ethanol inhibition of voltage-dependent Ca2+ channel activity in brain synaptosomes, and support the notion that these steroids may be among the endogenous factors that modulate neuronal sensitivity to ethanol.
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Department of Pharmacology and Molecular Biology, Chicago Medical School, IL 60064-3095, USA.
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects*; D013997:Time Factors
D005938:Glucocorticoids; D000431:Ethanol; D002118:Calcium