Cass W A, Gerhardt G A, Gillespie K, Curella P, Mayfield R D, Zahniser N R
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
J Neurochem. 1993 Jul;61(1):273-83. doi: 10.1111/j.1471-4159.1993.tb03565.x.
We investigated whether changes in the dopamine transporter in the nucleus accumbens or striatum are involved in cocaine-induced behavioral sensitization by using in vivo electrochemistry to monitor the clearance of locally applied dopamine in anesthetized rats. Rats were injected with cocaine-HCl (10 mg/kg i.p.) or saline daily for 7 consecutive days and then withdrawn for 7 days. Pressure ejection of a finite amount of dopamine at 5-min intervals from a micropipette adjacent to the electrochemical recording electrode produced transient and reproducible dopamine signals. After a challenge injection of cocaine (10 mg/kg i.p.), the signals in the nucleus accumbens of cocaine-treated animals became prolonged and the clearance rate of the dopamine decreased, indicating significant inhibition of the dopamine transporter. In contrast, simultaneous measurements in the dorsal striatum indicated a transient increase in both the amplitude of the signals and the clearance rate of the dopamine. The signals in both brain regions in the saline-treated animals given the cocaine challenge were similar to those in untreated animals given an acute injection of cocaine (10 mg/kg i.p.) or saline. Behaviorally, not all of the cocaine-treated animals were sensitized; however, both sensitized and nonsensitized animals displayed similar changes in dopamine clearance rate. Quantitative autoradiography with [3H]mazindol revealed that the affinity of the dopamine transporter for cocaine and the density of binding sites were similar in cocaine- and saline-treated rats. The decrease in dopamine clearance rate observed in the nucleus accumbens of the cocaine-treated rats after a challenge injection of cocaine is consistent with increased dopaminergic transmission, but does not appear to be sufficient in itself for producing behavioral sensitization.
我们通过在麻醉大鼠中使用体内电化学方法监测局部应用多巴胺的清除情况，来研究伏隔核或纹状体中多巴胺转运体的变化是否与可卡因诱导的行为敏化有关。大鼠连续7天每天腹腔注射盐酸可卡因（10 mg/kg）或生理盐水，然后停药7天。每隔5分钟从与电化学记录电极相邻的微量移液器中压力注射一定量的多巴胺，产生短暂且可重复的多巴胺信号。在一次激发注射可卡因（10 mg/kg腹腔注射）后，可卡因处理组动物伏隔核中的信号延长，多巴胺清除率降低，表明多巴胺转运体受到显著抑制。相比之下，在背侧纹状体中的同步测量表明，信号幅度和多巴胺清除率均出现短暂增加。给予可卡因激发的生理盐水处理组动物的两个脑区中的信号，与给予急性注射可卡因（10 mg/kg腹腔注射）或生理盐水的未处理动物中的信号相似。在行为上，并非所有可卡因处理组动物都出现了敏化；然而，敏化和未敏化动物在多巴胺清除率上都表现出相似的变化。用[3H]马吲哚进行的定量放射自显影显示，可卡因处理组和生理盐水处理组大鼠中多巴胺转运体对可卡因的亲和力和结合位点密度相似。在激发注射可卡因后，可卡因处理组大鼠伏隔核中观察到的多巴胺清除率降低与多巴胺能传递增加一致，但这本身似乎不足以产生行为敏化。
