BASAL GANGLIA OUTPUT AND PSYCHOSTIMULANT ABUSE

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DESCRIPTION (provided by applicant): Interactions between the basal ganglia and the cerebral cortex are critical for the organization of motivated behavior and are implicated in psychostimulant addiction. Dopamine in the striatum regulates these interactions. Exposure to psychostimulants such as cocaine produces changes in gene expression in striatal neurons that are part of the anatomical circuits that interconnect the basal ganglia and the cortex. Such molecular changes likely alter activity in these circuits and seem to play a role in drug-induced behavioral changes such as addiction and dependence. The long-term objective of this research project is to determine functional consequences of psychostimulant-induced molecular changes in striatal output neurons, with focus on their effects on cortical function. The proposed research will investigate how changes in striatal output produced by cocaine affect cortical function, by using immediate-early genes (lEGs) as functional markers. For one, "basal" expression of lEGs in defined cortical regions will be assessed. In addition, sensory-evoked responses in the sensorimotor cortex (i.e., lEG expression evoked by whisker stimulation) will be examined as a model of cortical function. The proposed studies will (1) determine and compare the effects of acute and repeated cocaine treatment on "basal" and sensory-evoked cortical lEG expression. (2) The relative contributions of D1- and D2 dopamine receptor-regulated striatal outputs to these cortical effects will be assessed by intrastriatal administration of selective dopamine receptor antagonists. (3) Other studies will investigate the anatomical pathways that mediate this basal ganglia-cortical regulation. These studies will further our understanding of the mechanisms that govern basal ganglia-cortical interactions and will show how these interactions are changed by the psychostimulant cocaine. This work will help establish an improved cellular framework necessary to understand and successfully treat cocaine addiction.