Sabeti Jilla, Gerhardt Greg A, Zahniser Nancy R
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado, USA.
J Pharmacol Exp Ther. 2003 Apr;305(1):180-90. doi: 10.1124/jpet.102.047258.
Behavioral sensitization to cocaine reflects neuroadaptive changes that intensify drug effects. However, repeated cocaine administration does not induce behavioral sensitization in all male Sprague-Dawley rats. Because cocaine inhibits the dopamine (DA) transporter (DAT), we investigated whether altered DAT function contributes to these individual differences. Freely moving rats had electrochemical microelectrode/microcannulae assemblies chronically implanted in the nucleus accumbens so that exogenous DA clearance signals were recorded simultaneous with behavior. The peak DA signal amplitude (A(max)) and efficiency of clearance (k) were used as indices of in vivo DAT function. Low and high cocaine responders (LCRs and HCRs, respectively) were identified based on their locomotor responsiveness to an initial injection of cocaine (10 mg/kg i.p.). Consistent with DAT inhibition, cocaine elevated A(max) and reduced k in HCRs, but not in LCRs. The same dose of cocaine was administered for six additional days and after a 7-day withdrawal. Baseline behavioral and dopamine clearance indices were unaltered by repeated cocaine or after withdrawal. Only LCRs expressed cocaine-induced sensitized locomotor activation, and this was accompanied by cocaine-induced elevations in A(max) and reductions in k. These sensitized responses to cocaine persisted in LCRs after withdrawal. In contrast, neither locomotor nor electrochemical responses were altered by repeated saline administration or a saline challenge after repeated cocaine administration, suggesting that conditioning did not significantly contribute. Our results suggest that increased DAT inhibition by cocaine is associated with locomotor sensitization and that DAT serves as a common substrate for mediating both the initial and sensitized locomotor responsiveness to cocaine.
对可卡因的行为敏化反映了增强药物作用的神经适应性变化。然而，反复给予可卡因并不会在所有雄性Sprague-Dawley大鼠中诱导行为敏化。由于可卡因抑制多巴胺（DA）转运体（DAT），我们研究了DAT功能改变是否导致了这些个体差异。自由活动的大鼠在伏隔核中长期植入电化学微电极/微套管组件，以便在记录行为的同时记录外源性DA清除信号。DA信号峰值幅度（A(max)）和清除效率（k）被用作体内DAT功能的指标。根据对初次注射可卡因（10 mg/kg腹腔注射）的运动反应性，确定了低和高可卡因反应者（分别为LCRs和HCRs）。与DAT抑制一致，可卡因使HCRs中的A(max)升高并使k降低，但在LCRs中则不然。相同剂量的可卡因再给药6天，并在停药7天后进行观察。反复给予可卡因或停药后，基线行为和多巴胺清除指标未发生改变。只有LCRs表现出可卡因诱导的敏化运动激活，并且这伴随着可卡因诱导的A(max)升高和k降低。这些对可卡因的敏化反应在LCRs停药后持续存在。相比之下，反复给予生理盐水或在反复给予可卡因后给予生理盐水激发，均未改变运动或电化学反应，这表明条件作用没有显著影响。我们的结果表明，可卡因对DAT抑制的增加与运动敏化相关，并且DAT是介导对可卡因的初始和敏化运动反应性的共同底物。
