Parada A, Soares-da-Silva P
Department of Research and Development, BIAL, 4785, S. Mamede do Coronado, Portugal.
Neuropharmacology. 2000 Jul 10;39(9):1645-52. doi: 10.1016/s0028-3908(99)00238-5.
The present work examined the effects of pre-treatment with Sch 23390, a selective D(1) receptor antagonist, on the dizocilpine-induced blockade of sensitization to the locomotor-stimulating effect of cocaine. Rats were given either cocaine [15mgkg(-1)day(-1), intraperitoneally (i.p.)] from day 1 to day 5 (cocaine-experienced rats) or vehicle (cocaine-naïve rats). From day 6 to day 15, animals remained drug-free in their home cages. On day 16 rats received a challenge injection of cocaine (15mgkg(-1)) or vehicle, and were tested for sensitization to the locomotor-stimulating effect of cocaine. In cocaine-naïve rats the acute effect of cocaine was a 1.5 times increase in locomotor activity. In cocaine-experienced rats, the acute effects of cocaine were considerably more pronounced than in cocaine-naïve rats; the stimulating effect of cocaine in these animals was a doubling in locomotor activity. In cocaine-naïve rats, pre-treatment with dizocilpine (100microgkg(-1)), Sch 23390 (100microgkg(-1)) or a combination of the two drugs from day 1 to day 5 changed neither spontaneous locomotor activity nor cocaine stimulant activity. By contrast, cocaine-experienced animals that had been given 100microgkg(-1) dizocilpine from day 1 to day 5 failed to show the increase in locomotor activity when challenged with cocaine on day 16. Pre-treatment with Sch 23390 (100microgkg(-1)day(-1), i.p.) from day 1 to day 5 was found to prevent completely the cocaine anti-sensitization properties of 100microgkg(-1) dizocilpine, but failed to prevent cocaine sensitization. On the other hand, horizontal activity in cocaine-experienced rats that had been given dizocilpine (100microgkg(-1)) 15min before cocaine challenge on day 16 was higher than in corresponding controls. It is concluded that prevention of cocaine sensitization by dizocilpine may be related to the events set into motion by the NMDA antagonist at the level of dopaminergic transmission involving D(1) receptors.
本研究考察了选择性D(1)受体拮抗剂Sch 23390预处理对二氮嗪诱导的可卡因运动刺激效应致敏性阻断的影响。从第1天至第5天，给大鼠腹腔注射可卡因15mg/kg(-1)/天或注射赋形剂(未接触过可卡因的大鼠)。从第6天至第15天，动物在其饲养笼中不接触药物。在第16天，给大鼠注射一次可卡因(15mg/kg(-1))或赋形剂，并检测对可卡因运动刺激效应的致敏性。在未接触过可卡因的大鼠中，可卡因的急性效应是运动活性增加1.5倍。在可卡因经历组大鼠中，可卡因的急性效应比未接触过可卡因的大鼠明显得多；可卡因对这些动物的刺激效应是运动活性加倍。在未接触过可卡因的大鼠中，从第1天至第5天用二氮嗪(100μg/kg(-1))、Sch 23390(100μg/kg(-1))或两种药物联合预处理，既不改变自发运动活性，也不改变可卡因刺激活性。相比之下，从第1天至第5天给予100μg/kg(-1)二氮嗪的可卡因经历组动物，在第16天用可卡因激发时未表现出运动活性增加。从第1天至第5天用Sch 23390(100μg/kg(-1)/天，腹腔注射)预处理可完全阻止100μg/kg(-1)二氮嗪的可卡因抗致敏特性，但不能阻止可卡因致敏。另一方面，在第16天可卡因激发前15分钟给予二氮嗪(100μg/kg(-1))的可卡因经历组大鼠的水平活性高于相应对照组。得出结论：二氮嗪对可卡因致敏的预防作用可能与NMDA拮抗剂在涉及D(1)受体的多巴胺能传递水平引发的事件有关。
