Staurosporine, a protein kinase inhibitor, increases the intoxicating potencies of ethanol and other n-alkanols in Rana pipiens tadpoles.
Central nervous system protein kinases are the intracellular effectors for many of the signal transduction pathways essential to neurotransmission. Although the in vitro activity of at least one of these important enzymes, protein kinase C, is diminished by therapeutic concentrations of ethanol and other central depressants, the relationship of this effect to intoxication in vivo is not known. If intoxication by ethanol involves central protein kinase inhibition, then other inhibitors of these enzymes should enhance ethanol's intoxicating potency. To test this hypothesis, we compared the median effective concentrations of ethanol and two other n-alkanols for loss-of-righting reflex in Rana pipiens tadpoles pretreated with staurosporine and in untreated controls. Alkanol concentrations were confirmed by gas chromatography and staurosporine concentrations by ultraviolet absorbance spectrophotometry. Results obtained with 650 animals demonstrate that pretreatment with staurosporine concentrations in the nanomolar range significantly decrease the median effective concentration for ethanol (56% of control; p < 0.001), butanol (38% of control; p < 0.001), and octanol (59% of control; p < 0.001). This finding supports that central protein kinase inhibition may be involved in the acute intoxicating effects of ethanol and other n-alkanols.
Firestone
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Department of Anesthesiology, University of Pittsburgh, PA 15261, USA.
Firestone
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D020001:1-Butanol; D020003:1-Octanol; D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D000440:Butanols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D007814:Larva; D000442:Octanols / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D011894:Rana pipiens; D019311:Staurosporine
D000470:Alkaloids; D000440:Butanols; D000442:Octanols; D000431:Ethanol; D020001:1-Butanol; D011493:Protein Kinase C; D019311:Staurosporine; D020003:1-Octanol