Henry D J, Greene M A, White F J
Wayne State University School of Medicine, Department of Psychiatry, Lafayette Clinic, Detroit, Michigan.
J Pharmacol Exp Ther. 1989 Dec;251(3):833-9.
Behavioral evidence indicates that the potent rewarding effects of cocaine are mediated, in part, by the mesoaccumbens dopamine (DA) system projecting from A10 DA cells in the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous electrophysiological studies from our laboratory have indicated that cocaine (i.v.) exerts inhibitory effects on A10 DA neurons, due to enhanced stimulation by DA at DA autoreceptors are well as by activation of NAc-VTA feedback pathways. In the present experiments, extracellular single-unit recording and microiontophoretic techniques were used to determine the possible alterations in the mesoaccumbens DA system after repeated cocaine administration. Twice daily injections of cocaine (10 mg/kg i.p., 14 days) caused significant subsensitivity to the inhibitory effects of low i.v. doses of the DA agonist apomorphine in comparison to rats receiving similar treatments with saline or procaine. Iontophoretic application of DA to A10 DA neurons in rats treated repeatedly with cocaine (2X10 mg/kg, 14 days) also produced significantly less inhibition as compared to control rats. Cell population analysis of the VTA revealed that autoreceptor subsensitivity in cocaine-treated rats resulted in a significantly greater number of spontaneously active A10 DA neurons, and a significantly higher firing rate as compared to A10 DA neurons in control rats. In striking contrast to A10 DA cells, recordings from NAc neurons in cocaine-treated rats (2X10 mg/kg, 14 days) indicated that these cells were supersensitive to the inhibitory effects of iontophoretic DA. Although the mechanism underlying such supersensitivity remains unclear, the increased sensitivity of postsynaptic NAc DA receptors combined with the subsensitivity of A10 DA autoreceptors could lead to greatly enhanced DA transmission and may help to explain some aspects of cocaine-induced behavioral sensitization.
行为学证据表明，可卡因的强效奖赏作用部分是由中脑伏隔核多巴胺（DA）系统介导的，该系统从腹侧被盖区（VTA）的A10 DA细胞投射到伏隔核（NAc）。我们实验室之前的电生理学研究表明，静脉注射可卡因对A10 DA神经元具有抑制作用，这是由于DA对DA自身受体的刺激增强以及NAc-VTA反馈通路的激活。在本实验中，采用细胞外单单位记录和微量离子电泳技术来确定反复给予可卡因后中脑伏隔核DA系统可能发生的变化。与接受生理盐水或普鲁卡因类似处理的大鼠相比，每天两次注射可卡因（10 mg/kg腹腔注射，共14天）会导致对低剂量静脉注射DA激动剂阿扑吗啡的抑制作用产生显著的敏感性降低。对反复给予可卡因（2×10 mg/kg，共14天）的大鼠，向其A10 DA神经元进行离子电泳施加DA，与对照大鼠相比，产生的抑制作用也显著更小。对VTA的细胞群体分析显示，可卡因处理的大鼠中自身受体敏感性降低导致自发活动的A10 DA神经元数量显著增加，且与对照大鼠的A10 DA神经元相比，放电频率显著更高。与A10 DA细胞形成鲜明对比的是，对可卡因处理的大鼠（2×10 mg/kg，共14天）的NAc神经元记录表明，这些细胞对离子电泳施加DA的抑制作用超敏感。尽管这种超敏感性的潜在机制尚不清楚，但突触后NAc DA受体敏感性增加与A10 DA自身受体敏感性降低相结合可能导致DA传递大大增强，并可能有助于解释可卡因诱导的行为敏化的某些方面。
