Dopamine Transporter Changes Following Cocaine Self-Administration

描述（由申请方提供）：可卡因自我给药的神经生物学后果根据所用的实验方案而变化，并且高度依赖于给药的剂量和频率。我们最近发现，大剂量的“狂欢”可卡因自我管理和剥夺大鼠产生显着降低可卡因的效力，改变多巴胺（DA）的神经传递。使用微透析来获得DA水平的整体视图，我们发现，静脉注射剂量的可卡因（1.5 mg/kg）不再显着升高细胞外DA水平在延髓核（NAc）。为了研究可卡因对DA转运蛋白的影响，我们在脑切片中使用伏安法直接测量DA摄取。可卡因抑制DA摄取的能力是严重有限的大鼠，有自我管理的可卡因相比，药物幼稚的动物。此外，根据方案的不同，DA的最大吸收率要么增加要么减少，但可卡因的效力始终下降。这表明DA摄取和可卡因抑制摄取之间存在解离，尽管结合研究表明可卡因仍以不变的亲和力与转运蛋白结合。这是一种独特的情况，是由自我服用高剂量可卡因造成的。这些研究结果的含义是，可卡因的影响可以独立于DA的摄取，这可能最终有相关的可卡因成瘾的药物治疗的设计，这将阻止可卡因抑制，但留下DA的摄取完整。然而，在DA摄取和可卡因效应之间的分离的文献中，这些都是早期的。本提案的目的是对自我给药后可卡因效力的降低进行彻底调查。相关性：这项提案的总体目标是了解多巴胺转运蛋白，可卡因在大脑中的主要靶点，如何在高剂量可卡因治疗数天后变得对可卡因不敏感。这些结果将为设计治疗可卡因成瘾的药物提供新的方向。这些新药可能会改变多巴胺转运蛋白，使可卡因不会上瘾，也不会被滥用。

DESCRIPTION (provided by applicant): The neurobiological consequences of cocaine self-administration vary according to the experimental protocol used and are highly dependent upon the dose and frequency of administration. We have recently found that high-dose "binge" cocaine self-administration and deprivation in rats produces dramatic decreases in the potency of cocaine to alter dopamine (DA) neurotransmission. Using microdialysis to get an overall view of DA levels, we found that an i.v. administered dose of cocaine (1.5 mg/kg) no longer significantly elevated extracellular DA levels in the nucleus accumbens (NAc). To examine cocaine effects on the DA transporter, we used voltammetry in brain slices to measure DA uptake directly. The ability of cocaine to inhibit DA uptake was severely limited in rats that had self-administered cocaine compared to drug naive animals. In addition, the maximal rate of DA uptake was either increased or decreased, depending on the protocol, but the potency of cocaine was consistently decreased. This suggested a dissociation between DA uptake and inhibition of uptake by cocaine, although binding studies show that cocaine still binds to the transporter with unaltered affinity. This is a unique situation, caused by self-administration of high doses of cocaine. The implication of these findings is that cocaine effects can be manipulated independently of DA uptake, which may ultimately have relevance for the design of pharmacotherapies for cocaine addiction which would block cocaine inhibition but leave DA uptake intact. These are early days, however, in the documentaion of the dissociation between DA uptake and cocaine effects. The goal of this proposal is to provide a thorough investigation of the reduction in the potency of cocaine following self-administration. Relevance: The overall aim of this proposal is to understand how the dopamine transporter, the main target of cocaine in the brain, becomes insensitive to cocaine after several days of high-dose treatment with cocaine. The results will provide a new direction in the design of drugs to treat cocaine addiction. Potentially, the new drugs could change the dopamine transporter so that cocaine has no addictive effects and would not be abused.