The rat model of repeated, intermittent cocaine exposure, which is most representative of typical human drug abuse, results in a long-lasting increase in stereotypic behavior upon subsequent cocaine exposures. Sensitization of stereotypic behaviors associated with this regimen is thought to be mediated by the mesolimbic and nigrostriatal dopamine projection pathways, which also contain numerous GABAergic neurons. We have previously demonstrated that repeated cocaine decreases GABA's inhibitory role both pre- and post-synaptically in the neostriatum of sensitized rats. In order to determine if these changes in GABAergic function are causal in sensitization, the direct actions of cocaine need characterization. Therefore, I propose 1) to measure the effects of direct, in vitro cocaine on GABA-stimulate chloride uptake in naive and measure the effects of direct, in vitro cocaine on GABA-stimulated chloride uptake in naive and cocaine-sensitized rats, and 2) to determine the mechanisms of this effect. I hypothesize that in vitro cocaine will decrease GABA/A receptor channel function, and after cocaine sensitization, GABA/A receptor subunit composition will be modified so that receptor so that receptor function is decreased in a long lasting manner. I also hypothesize that the decrease in GABA/A receptor function results indirectly from the phosphorylation of the receptor either by dopamine receptor activation or activation of other protein kinases. Thus, with repeated intermittent cocaine there is development of sensitization because of decreases in the inhibitory GABA signal in the striatum. These experiments will serve as the basis for the elucidation of the mechanism of GABAergic down-regulation in cocaine sensitization.
