Heidbreder C A, Thompson A C, Shippenberg T S
Behavioral Pharmacology and Genetics Section, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1996 Aug;278(2):490-502.
Repeated intermittent administration of cocaine has been shown to sensitize animals to the locomotor-activating effects of this agent. The neurobiochemical basis of this phenomenon, however, remains only partially understood. The present study sought to characterize basal dialysate dopamine (DA) concentrations within the nucleus accumbens (NAc), 2, 12 or 22 days after the cessation of either repeated cocaine (20 mg/kg/day x 5 days) or saline (1.0 ml/kg/day x 5 days) treatment. Locomotor activity and dialysate DA levels in response to a subsequent cocaine administration (20 mg/kg i.p.) were assessed at the same time intervals. Cocaine-pretreated animals exhibited an enhanced motor response to a cocaine injection 2 days after cessation of cocaine treatment. The magnitude of this effect increased progressively over time. Basal DA overflow was elevated 2 days after termination of cocaine treatment; at this time, however, a blunted response of DA neurons to the cocaine administration was observed. As the duration of withdrawal increased, basal dialysate DA concentrations gradually declined, whereas the response of DA neurons to cocaine progressively increased. By day 22 of withdrawal, a significant enhancement of cocaine-induced DA overflow was seen. These findings demonstrate that increased DA overflow in response to cocaine cannot account for the short-term expression of behavioral sensitization to cocaine. Rather, an enhanced DA response develops during later stages of the sensitization process and, therefore, may be one of the mechanisms responsible for the long-term expression of cocaine sensitization.
反复间歇性给予可卡因已被证明会使动物对该药物的运动激活作用产生敏感。然而，这一现象的神经生化基础仍仅得到部分理解。本研究旨在描述在停止重复给予可卡因（20毫克/千克/天×5天）或生理盐水（1.0毫升/千克/天×5天）治疗后2天、12天或22天，伏隔核（NAc）内的基础透析液多巴胺（DA）浓度。同时评估在相同时间间隔内，后续给予可卡因（20毫克/千克腹腔注射）后动物的运动活性和透析液DA水平。可卡因预处理的动物在停止可卡因治疗后2天，对可卡因注射表现出增强的运动反应。这种效应的程度随时间逐渐增加。可卡因治疗终止后2天，基础DA溢出升高；然而，此时观察到DA神经元对可卡因给药的反应减弱。随着戒断时间的延长，基础透析液DA浓度逐渐下降，而DA神经元对可卡因的反应逐渐增强。到戒断第22天时，可卡因诱导的DA溢出显著增强。这些发现表明，对可卡因反应性增加的DA溢出不能解释对可卡因行为敏感化的短期表现。相反，在敏感化过程的后期阶段会出现增强的DA反应，因此，这可能是导致可卡因敏感化长期表现的机制之一。
