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 within the mesolimbic dopamine system. Repeated exposure to cocaine induces an augmented motor activity response which is termed behavioral sensitization, 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 sensitization remain to be elucidated. Studies on other forms of sensitization in the nervous system suggest a critical role for increased protein kinase C (PKC) activity in the development of the sensitized response. As a first step in examining the role of PKC in cocaine-induced behavioral sensitization, the effect of intra-A10 administration of a PKC inhibitor, H7, on the acute motor-stimulant response to cocaine was studied. Intra-A10 injections of H7 dose-dependently (1.0-30.0 nmol/side) inhibited cocaine (15.0 mg/kg)-induced motor activity. Pretreatment with H7 (30.0 nmol/side) also blocked the cocaine-induced rise of extracellular dopamine in a terminal region of the mesolimbic dopamine system, the nucleus accumbens, as measured by in vivo microdialysis. These data suggest that activation of protein kinases may be important in cocaine-induced motor activity.