Functional tolerance and physical dependence appear to involve adaptive changes in the central nervous system (CNS) which compensate for repeated ethanol intoxication. These changes may play an important role in maintaining the pathological consumption of alcoholic beverages. For this reason, an understanding of the cellular mechanisms responsible for functional tolerance and physical dependence could have important implications for the rational development of methods to prevent or treat alcohol abuse or alcoholism. In this regard, increasing experimental evidence suggests that GABAergic neurotransmission and more specifically, GABA receptors are a likely target for ethanol. This proposal will test the hypothesis that: Functional tolerance to and physical dependence on ethanol results in part from GABA receptor down-regulation in response to the initial enhancement of GABA receptor activity during ethanol intoxication. Experiments proposed in this application will characterize the extent of functional down-regulation of GABA-A and GABA-B receptors associated with the development of physical dependence on ethanol modeled in the rat. In addition, the driving forces responsible for adaptive changes in the function of these GABA receptors will be explored to determine whether receptors must exhibit acute ethanol sensitivity in order to undergo functional down-regulation. These questions will be addressed by comparing GABA receptor responses in six distinct populations of anatomically identified neurons using intracellular electrophysiological recording techniques. Measurements will be made in tissue slices prepared from the hippocampus, cerebral cortex, medial and lateral septum which are proposed to possess ethanol sensitive or resistant GABA receptors. The results should help clarify the role of GABA receptors in the neuropharmacology of ethanol.
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