Functional tolerance and physical dependence are thought to involve adaptive changes in the central nervous system (CNS) as compensation for prolonged ethanol-induced depression. An understanding of these mechanisms has been considered to have important implications for the development of a rational therapy of alcoholism. Experimental evidence supports the hypothesis that increased neurotransmission mediated by the inhibitor transmitter, gamma-aminobutyric acid (GABA), is responsible in part for ethanol-induced CNS depression. Conversely, it is also likely that continuous treatment with ethanol causes a compensatory GABAergic hypoactivity to develop. The consequences of this action are believed to be two-fold. Functional tolerance would result from a diminished ability of ethanol to activate GABAergic transmission. Physical dependence and ethanol withdrawal-related, CNS, hyperexcitability would occur due to an imbalance in CNS excitatory-inhibitory activity caused by GABAergic hypodactivity in the absence of ethanol. The present proposal will attempt to evaluate the functional validity oif this hypothesis in three ways. First, the effect of pharacologically activating GABAergic neurotransmission during long-term ethanol treatment will be studied. If the hypothesis is correct then functional tolerance to ethanol and physical dependence should be accelerated. Second, long-term pharmacological activation of GABAergic transmission should result in functional tolerance to ethanol and cause signs similar to ethanol withdrawal if the hypothesis is correct. Finally, rotational behavior caused by unilateral activation of substantia nigra GABA receptors by GABA agonists will be used to evaluate the effects of a single or multiple doses of ethanol on the functional capacity of postsynaptic GABA receptors. These results will determine wehther functionally significant changes in GABA receptors occur, and if these are consistent with both the acute and chronic effecs of ethanol on CNS excitability.
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