Relationship of brain cyclic nucleotide levels and the interaction of ethanol with chlordiazepoxide.
The effects of combined administration of ethanol (4 g/kg) and chlordiazepoxide (CDP, 12.5 mg/kg) on mouse brain c-AMP and c-GMP levels were investigated in order to test the hypothesis that the supra-additive effect of CDP on ethanol sleep time may be related to a supra-additive alteration in brain cyclic nucleotide levels induced by the combined drugs. Ethanol alone or CDP by itself did not cause any change in brain c-AMP levels, except for a transient decrease in the cerebral cortex and midbrain at 0.5 hr after ethanol injection, as well as a transient increase in the cerebellum at 0.5 hr after CDP injection. The combined drug treatment did not result in a supra-additive effect on c-AMP levels. On the other hand, c-GMP levels were depressed significantly for 4 hr after ethanol injection especially in the cerebellum. The mice regained the righting reflex when the c-GMP levels were still about 30 per cent of control values. Ethanol and CDP together induced a supra-additive decrease of c-GMP concentrations in the cerebellum at 2 and 4 hr. This resulted in a lengthened period (about 2.5 hr) during which the cerebellar c-GMP levels were below 30 per cent of control values, and this interval coincided with the increase in sleep time, suggesting a possible relationship between these two factors. Injection of ethanol and N-demethyl-chlordiazepoxide (NDCDP) simultaneously (the latter being a metabolite of CDP) also elicited a more than additive depression of cerebellar c-GMP levels at 4 hr. These data suggest that NDCDP or its metabolite could be responsible for the supra-additive effect of CDP on the ethanol-induced decrease in cerebellar c-GMP levels.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002707:Chlordiazepoxide / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000378:metabolism*
D009712:Nucleotides, Cyclic; D000431:Ethanol; D002707:Chlordiazepoxide; D000242:Cyclic AMP; D006152:Cyclic GMP