Although alcohol is the most widely used and abused drug in our society today, the mechanisms which underlie its central pharmacological (intoxication, anesthesia) and toxicological (brain damage, memory deficits) effects are largely unknown. An area of emerging importance in understanding the neurochemical mechanisms which mediate or are consequent to ethanol use and abuse is that of excitatory amino acid (EAA) function. In particular, a subtype of EAA receptor, the N-methyl-D asparate (NMDA) receptor, is implicated in learning, memory, and neurodegenerative processes. Our preliminary data show that ethanol, at concentrations which are consistent with its pharmacological range achieved in vivo (10-60 mM), inhibits NMDA receptor function. The broad, long term objectives of this project are to investigate and gain further information about the interaction between EAA neurotransmission and ethanol in an in vivo system.
The specific aims of this proposal are to determine (l) whether endogenous glycine agonists interact with the ability of acute ethanol to inhibit NMDA receptor function in vivo, (2) if acute ethanol administration alters extracellular excitatory amino acid concentrations in vivo, (3) if the mechanism of chronic ethanol-induced alteration of extracellular dopamine concentration in rat nucleus accumbens involves excitatory amino acid neurotransmission, and (4) whether ethanol interference with excitatory amino acid neurotransmission in the hippocampus contributes to the development of rapid tolerance to ethanol. The research design involves both in vivo and in vitro experiments. In vivo experiments will use intracerebral microdialysis to measure the effects of systemic ethanol on NMDA receptor function by monitoring the extracellular levels of dopamine and norepinephrine after perfusion of NMDA through the microdialysis probe. Both hippocampus and striatum will be investigated because in vitro data suggest that these areas are sensitive to ethanol. In addition, glycine agonist (glycine and D-serine) levels will be monitored in dialysates because these endogenous compounds may interfere with ethanol's effects on NMDA receptors. In vitro experiments will also investigate the regulation of release of these compounds by depolarization and ethanol. Further experiments will investigate the role that glutamate and aspartate may play in ethanol's mechanism of action by measuring extracellular levels of these BAA's after acute and chronic ethanol administration. Finally, behavioral measurements of rapid tolerance to ethanol's ataxic effects will be made while monitoring EAA levels in striatum and hippocampus during the behavioral test. The knowledge gained from these studies will contribute to our understanding of the role that BAA's play in the mechanisms of acute and chronic ethanol administration in vivo. This information may lead to new therapeutic approaches for the treatment of alcohol related problems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008484-05
Application #
2044569
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1991-02-01
Project End
1998-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
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Jaworski, J N; Gonzales, R A; Randall, P K (2001) Effect of dopamine D2/D3 receptor antagonist sulpiride on amphetamine-induced changes in striatal extracellular dopamine. Eur J Pharmacol 418:201-6
Ludvig, N; George, M A; Tang, H M et al. (2001) Evidence for the ability of hippocampal neurons to develop acute tolerance to ethanol in behaving rats. Brain Res 900:252-60
Yim, H J; Gonzales, R A (2000) Ethanol-induced increases in dopamine extracellular concentration in rat nucleus accumbens are accounted for by increased release and not uptake inhibition. Alcohol 22:107-15
Robinson, D L; Lara, J A; Brunner, L J et al. (2000) Quantification of ethanol concentrations in the extracellular fluid of the rat brain: in vivo calibration of microdialysis probes. J Neurochem 75:1685-93
Yim, H J; Robinson, D L; White, M L et al. (2000) Dissociation between the time course of ethanol and extracellular dopamine concentrations in the nucleus accumbens after a single intraperitoneal injection. Alcohol Clin Exp Res 24:781-8
Crippens, D; White, M L; George, M A et al. (1999) Gender differences in blood levels, but not brain levels, of ethanol in rats. Alcohol Clin Exp Res 23:414-20
Yim, H J; Schallert, T; Randall, P K et al. (1998) Comparison of local and systemic ethanol effects on extracellular dopamine concentration in rat nucleus accumbens by microdialysis. Alcohol Clin Exp Res 22:367-74
Gonzales, R A; McNabb, J; Yim, H J et al. (1998) Quantitative microdialysis of ethanol in rat striatum. Alcohol Clin Exp Res 22:858-67
Yim, H J; Schallert, T; Randall, P K et al. (1997) Effect of ethanol on extracellular dopamine in rat striatum by direct perfusion with microdialysis. J Neurochem 68:1527-33

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