King G R, Ellinwood E H, Silvia C, Joyner C M, Xue Z, Caron M G, Lee T H
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina.
J Pharmacol Exp Ther. 1994 May;269(2):743-9.
Intermittent cocaine administration produces sensitization, whereas the continuous administration of cocaine produces tolerance to the effects of subsequent cocaine administration during withdrawal. The present study examined whether the effects of these two dosing regimens are related to alterations in the functional status of dopamine (DA) D2 receptors. In all experiments, rats were withdrawn for 7 days from a 14-day pretreatment regimen involving either continuous or intermittent cocaine administration. Experiments examined changes in the behavioral response to an autoreceptor-selective dose of apomorphine, the effects of sulpiride on electrically stimulated DA release in striatal brain slices and striatal D2 receptor binding, and mRNA levels. The results indicate that the continuous administration of cocaine produces findings consistent with D2 autoreceptor supersensitivity; there was enhanced inhibition of behavior after the autoreceptor-selective dose of apomorphine, decreased electrically stimulated DA release in the absence of sulpiride, and enhanced electrically stimulated DA release in the presence of sulpiride. However, there were no changes in postsynaptic D2 receptor binding or mRNA levels. Intermittent cocaine administration did not produce evidence of D2 autoreceptor subsensitivity: there was no decrease in inhibition of behavior after the autoreceptor-selective dose of apomorphine, no changes in electrically stimulated DA release in the absence or presence of D2 receptor blockade, and no change in the levels of D2 receptor binding; however, D2 mRNA levels were decreased by 22%. Overall, the present results are consistent with the hypothesis that the expression of tolerance induced by continuous cocaine administration is associated with D2 autoreceptor supersensitivity.
间歇性给予可卡因会产生致敏作用，而持续给予可卡因则会使机体在戒断期间对后续给予可卡因的效应产生耐受性。本研究考察了这两种给药方案的效应是否与多巴胺（DA）D2受体功能状态的改变有关。在所有实验中，大鼠均从为期14天的预处理方案（包括持续或间歇性给予可卡因）中撤药7天。实验考察了对阿扑吗啡自受体选择性剂量的行为反应变化、舒必利对纹状体脑片电刺激DA释放及纹状体D2受体结合的影响以及mRNA水平。结果表明，持续给予可卡因产生的结果与D2自受体超敏反应一致；在给予阿扑吗啡自受体选择性剂量后行为抑制增强，在无舒必利时电刺激DA释放减少而在有舒必利时电刺激DA释放增强。然而，突触后D2受体结合或mRNA水平没有变化。间歇性给予可卡因未产生D2自受体亚敏反应的证据：在给予阿扑吗啡自受体选择性剂量后行为抑制没有降低，在有无D2受体阻断的情况下电刺激DA释放均无变化，D2受体结合水平也无变化；然而，D2 mRNA水平下降了22%。总体而言，本研究结果与以下假设一致，即持续给予可卡因诱导的耐受性表达与D2自受体超敏反应有关。
