INJECTION OF THE PROTEIN-KINASE INHIBITOR H7 INTO THE A10 DOPAMINE REGION BLOCKS THE ACUTE RESPONSES TO COCAINE - BEHAVIORAL AND IN-VIVO MICRODIALYSIS STUDIES

Cocaine produces a motor-stimulant response in part by its actions wit hin the mesolimbic dopamine system. Repeated exposure to cocaine induc es an augmented motor activity response which is termed behavioral sen sitization, or reverse tolerance. Previous studies have suggested that sensitization may result from increased dopamine neuronal activity in the A10 region; the origin of the mesolimbic dopamine system. However , the exact mechanisms involved in the development of behavioral sensi tization remain to be elucidated. Studies on other forms of sensitizat ion in the nervous system suggest a critical role for increased protei n kinase C (PKC) activity in the development of the sensitized respons e. As a first step in examining the role of PKC in cocaine-induced beh avioral sensitization, the effect of intra-A10 administration of a PKC inhibitor, H7, on the acute motor-stimulant response to cocaine was s tudied. Intra-A10 injections of H7 dose-dependently (1.0-30.0 nmol/sid e) inhibited cocaine (15.0 mg/kg)-induced motor activity. Pretreatment with H7 (30.0 nmol/side) also blocked the cocaine-induced rise of ext racellular dopamine in a terminal region of the mesolimbic dopamine sy stem, the nucleus accumbens, as measured by in vivo microdialysis. The se data suggest that activation of protein kinases may be important in cocaine-induced motel activity.