Intra-Ventral Tegmental Area Administration of H7 Delays, But Does Not Prevent the Development of Cocaine-Induced Sensitization

Abstract

Previous studies have suggested that increased protein kinase C activity in the ventral tegmental area (VTA) may play a role in the acute and development of the sensitized behavioral responses to cocaine. The present study was conducted to further characterize the role of protein kinases in the development of sensitization. Animals received injections of saline or the nonspecific protein kinase inhibitor H7 into the VTA before each of their four daily systemic injections of saline or cocaine. Animals were tested for sensitization with a challenge injection of systemic cocaine after a withdrawal period of 24 h or 1 week. Tests for sensitization included monitoring cocaine-induced motor activity and/or dopamine concentrations in the nucleus accumbens, as measured by in vivo microdialysis. Pretreatment with H7 in the VTA attenuated the acute motor stimulant response to cocaine as well as the cocaine-induced increase in extracellular dopamine in the nucleus accumbens. In addition, the augmented increase in dopamine in the nucleus accumbens of cocaine-sensitized animals was prevented in animals pretreated with H7 before each of their daily cocaine injections, when tested after a 24 h withdrawal. However, when tested after a 1 week withdrawal, animals demonstrated sensitization to both the cocaine-induced increase in motor activity and the cocaine-induced increase in dopamine in the nucleus accumbens regardless of whether they received intra-VTA saline or H7 before each of their daily cocaine injections. These data suggest that injection of a protein kinase inhibitor into the VTA delays, but does not prevent the development of cocaine-induced behavioral sensitization.