The long term objectives of the proposed work are to understand the role body temperature plays in mediating and modulating ethanol's effects, to increase knowledge regarding the mechanism(s) and resultant cascade(s) by which ethanol induces intoxication, tolerance and physical dependence and to apply this knowledge to reduce human problems associated with ethanol use and misuse. Past results indicate that body temperature change induced by ethanol during intoxication represents an important factor in determining ethanol sensitivity and can interfere with attempts to investigate and understand ethanol's actions and effects. The proposed Specific Aims will advance our knowledge regarding the importance of temperature as a determinant of ethanol sensitivity by addressing four important questions: 1). Does body temperature during intoxication play a major role in determining genetically based differences in acute sensitivity to ethanol? 2). What are the mechanisms by which temperature alters ethanol sensitivity? Specifically, are temperature-induced changes in membrane fluidity, within-session functional tolerance and ethanol pharmacokinetics involved? 3). Does body temperature influence the development of chronic functional ethanol tolerance and does this effect play a role in mediating genetically determined differences in tolerance development? 4). Can body temperature manipulation reduce lethality from ethanol overdose alone or in combination with other drugs? To achieve the proposed aims, ethanol sensitivity in C57BL/6, DBA/2, 129, A/He, LS and SS mice will be measured using locomotor activity, loss of righting reflex and lethality, in conjunction with blood and brain ethanol concentrations. Exposure to ambient temperatures from 12-34 degrees C will be used to adjust body temperature in intoxicated mice. Brain, peritoneal and rectal temperatures will be monitored by standard and radiotelemetric techniques. Electron paramagnetic resonance spectroscopy will be used to determine the interaction between temperature and ethanol on brain synaptosomal membranes. These experiments will lead to a better understanding of the factors influencing genetically determined differences in ethanol sensitivity, will begin a systematic investigation of the mechanisms by which temperature influences ethanol sensitivity and will test feedback body temperature control as a new means of treatment that may lead to reduced deaths from ethanol overdose.
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