The objectives of this study are to determine if a kindling- like phenomenon, mediated via the GABA receptor complex, contributes significantly to the development of physical dependence on ethanol. The numerous episodes of ethanol induced depression of the CNS and the following rebound hyperexcitability are postulated to exert a kindling like effect during the periods of hyperexcitability. Studies are proposed in which ethanol will be administered to rats under a regimen designed to promote kindling effects. The development of ethanol dependence will be assessed during the course of treatment by measurements of seizure threshold with electroshock and two agents with convulsant properties, pentylenetetrazole (PTZ) and a beta-carboline, DMCM, which are known to interact with the GABA receptor complex. Concurrent studies will be directed towards determining whether ethanol dependence and changes of seizure threshold can be correlated with alterations in the neurochemical properties of the GABA receptor complex. The neurochemical studies will include assay of receptor density and allosteric modulation of radioligand binding, quantitative receptor autoradiography and chloride flux assays to assess changes in GABA receptor function. A major goal of this research is to determine if a long-lasting decrease of seizure threshold, similar to that seen with PTZ kindling, can be induced with the proposed method of chronic ethanol administration. Results from this study may be of value for establishing pharmacological and biochemical correlates of ethanol dependence in humans, which develops after years of excessive drinking and results in a long- lasting susceptibility to readdiction.
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