Steketee J D
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Brain Res Bull. 1997;43(6):565-71. doi: 10.1016/s0361-9230(97)00089-0.
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.
先前的研究表明，腹侧被盖区（VTA）中蛋白激酶C活性的增加可能在对可卡因敏感行为反应的急性发作和发展中起作用。本研究旨在进一步明确蛋白激酶在敏化发展中的作用。在动物每天四次全身性注射生理盐水或可卡因之前，先向其VTA注射生理盐水或非特异性蛋白激酶抑制剂H7。在24小时或1周的戒断期后，用全身性可卡因激发注射对动物进行敏化测试。敏化测试包括监测可卡因诱导的运动活动和/或通过体内微透析测量的伏隔核中的多巴胺浓度。在VTA中用H7预处理可减弱对可卡因的急性运动刺激反应以及可卡因诱导的伏隔核细胞外多巴胺增加。此外，在每天注射可卡因之前用H7预处理的动物，在24小时戒断后进行测试时，可防止可卡因致敏动物伏隔核中多巴胺的增强增加。然而，在1周戒断后进行测试时，无论动物在每天注射可卡因之前接受的是VTA内生理盐水还是H7，它们对可卡因诱导的运动活动增加和伏隔核中多巴胺增加均表现出敏化。这些数据表明，向VTA注射蛋白激酶抑制剂会延迟但不会阻止可卡因诱导的行为敏化的发展。
