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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005234-07
Application #
3108953
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1982-09-29
Project End
1991-12-31
Budget Start
1990-03-01
Budget End
1991-12-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Pharmacy
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Morland, J; Jones, B L; Palomares, M L et al. (1994) Morphine-6-glucuronide: a potent stimulator of locomotor activity in mice. Life Sci 55:PL163-8
Finn, D A; Syapin, P J; Bejanian, M et al. (1994) Temperature dependence of ethanol depression in mice: dose response. Alcohol Clin Exp Res 18:382-6
Alkana, R L; Finn, D A; Jones, B L et al. (1992) Genetically determined differences in the antagonistic effect of pressure on ethanol-induced loss of righting reflex in mice. Alcohol Clin Exp Res 16:17-22
Finn, D A; Bejanian, M; Jones, B L et al. (1991) The relationship between brain temperature during intoxication and ethanol sensitivity in LS and SS mice. Alcohol Clin Exp Res 15:717-24
Finn, D A; Syapin, P J; Bejanian, M et al. (1991) Body temperature influences ethanol and ethanol/pentobarbital lethality in mice. Alcohol 8:39-41
Bejanian, M; Jones, B L; Syapin, P J et al. (1991) Brain temperature and ethanol sensitivity in C57 mice: a radiotelemetric study. Pharmacol Biochem Behav 39:457-63
Bejanian, M; Alkana, R L; von Hungen, K et al. (1991) Temperature alters ethanol-induced fluidization of C57 mouse brain membranes. Alcohol 8:117-21
Finn, D A; Bejanian, M; Jones, B L et al. (1990) Body temperature differentially affects ethanol sensitivity in both inbred strains and selected lines of mice. J Pharmacol Exp Ther 253:1229-35
Bejanian, M; Finn, D A; Syapin, P J et al. (1990) Body temperature and ethanol pharmacokinetics in temperature-challenged mice. Alcohol 7:331-7
Finn, D A; Bejanian, M; Jones, B L et al. (1989) Temperature affects ethanol lethality in C57BL/6, 129, LS and SS mice. Pharmacol Biochem Behav 34:375-80

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