The central nervous system (CNS) mechanisms that determine alcohol's addictive properties are only partly understood. Numerous studies, however, have reported that ethanol modulates the function of ligand- gated ion channels in the brain, leading to alterations in behavior. For example, gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors have been associated with the intoxicating and rewarding properties of ethanol. Interfering with these neuro- transmitter systems shows promise as a potential therapeutic strategy for treating alcohol abuse and alcoholism. All drugs of abuse share the common attribute that they produce subjective stimulus effects in humans. These stimulus properties of drugs are important determinants of abuse liability because drugs that do not produce stimulus effects are not abused. Drug discrimination procedures model these stimulus effects in animals and provide a method of understanding the neurochemical systems that mediate the subjective effects of alcohol. The studies in this project combine site-specific brain microinjection techniques with drug discrimination behavioral techniques to elucidate the transmitter systems, and brain regions, that mediate the subjective effects of alcohol.
Four specific aims are proposed to test the general hypothesis that alcohol's subjective stimulus effects are mediated by GABAA and glutamate receptors in limbic brain regions, which are known to be involved in addiction. The studies of Aims 1 and 2 will determine which binding sites on GABA,, and glutamate (i.e., including NMDA) receptors, located in limbic brain regions, mediate the discriminative stimulus effects of low and high doses of ethanol.
Aim 3 will examine interactions among these receptor systems. The experiments of Aim 4 will examine the influence of limbic GABAA and NMDA circuits involving the important brain region of the nucleus accumbens. The long range goal of these studies is to determine the specific brain mechanisms that mediate the subjective stimulus effects of alcohol with the hope of identifying novel targets for drug therapy in alcohol abuse and alcoholism.
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