Pierce R C, Quick E A, Reeder D C, Morgan Z R, Kalivas P W
Department of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.
J Pharmacol Exp Ther. 1998 Sep;286(3):1171-6.
To assess the influence of calcium channel antagonists on the expression of behavioral sensitization to cocaine, the L-type calcium channel antagonist diltiazem or the N-type calcium channel antagonist omega-conotoxin GVIA was microinjected into the medial nucleus accumbens before a systemic cocaine challenge injection among rats that were previously treated with daily systemic saline or cocaine injections. The results indicated that both of these drugs attenuated the expression of behavioral sensitization to cocaine. Among saline-pretreated rats, diltiazem did not influence the behavioral response to an acute injection of cocaine, whereas omega-conotoxin significantly impaired acute cocaine-induced behavioral hyperactivity. A second series of experiments assessed the influence of protein kinases on the expression of behavioral sensitization to cocaine. Inhibitors of calcium/calmodulin-dependent protein kinase II (KN-93, N-[2-[[[3-(4'-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-( 2-hydroxyethyl)-4'-methoxy-benzenesulfonamide phosphate), protein kinase A (H-89, N-[2((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide) or calcium-dependent protein kinase C (bisindolymaleimide I, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimi de) were microinjected into the medial nucleus accumbens before a challenge injection of cocaine among rats repeatedly administered either saline or cocaine. None of the kinase inhibitors influenced the behavioral response induced by cocaine in saline-pretreated rats. Among cocaine-sensitized animals, the microinjection of KN-93 or bisindolymaleimide I blocked the expression of behavioral sensitization to cocaine, whereas H-89 had no effect. Taken together, these results indicate that neuronal calcium, acting via calcium-dependent kinases, promotes the expression of behavioral sensitization to cocaine.
为评估钙通道拮抗剂对可卡因行为敏化表达的影响，在先前每日接受全身生理盐水或可卡因注射的大鼠中，于全身可卡因激发注射前，将L型钙通道拮抗剂地尔硫䓬或N型钙通道拮抗剂ω-芋螺毒素GVIA微量注射到伏隔核内侧。结果表明，这两种药物均减弱了对可卡因的行为敏化表达。在生理盐水预处理的大鼠中，地尔硫䓬不影响对急性注射可卡因的行为反应，而ω-芋螺毒素显著损害急性可卡因诱导的行为多动。第二系列实验评估了蛋白激酶对可卡因行为敏化表达的影响。在反复给予生理盐水或可卡因的大鼠中，于可卡因激发注射前，将钙/钙调蛋白依赖性蛋白激酶II抑制剂（KN-93，N-[2-[[[3-(4'-氯苯基)-2-丙烯基]甲基氨基]甲基]苯基]-N-(2-羟乙基)-4'-甲氧基苯磺酰胺磷酸盐）、蛋白激酶A抑制剂（H-89，N-[2-((对溴肉桂基)氨基)乙基]-5-异喹啉磺酰胺）或钙依赖性蛋白激酶C抑制剂（双吲哚马来酰亚胺I，2-[1-(3-二甲基氨基丙基)-1H-吲哚-3-基]-3-(1H-吲哚-3-基)-马来酰亚胺）微量注射到伏隔核内侧。在生理盐水预处理的大鼠中，没有一种激酶抑制剂影响可卡因诱导的行为反应。在对可卡因敏感的动物中，微量注射KN-93或双吲哚马来酰亚胺I可阻断对可卡因的行为敏化表达，而H-89则无作用。综上所述，这些结果表明，通过钙依赖性激酶起作用的神经元钙促进了对可卡因的行为敏化表达。
