Dopamine Transporter Changes Following Cocaine Self-Administration

描述（由申请人提供）：可卡因自我给药的神经生物学后果根据所使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“暴饮暴食”可卡因自我服用和剥夺会导致可卡因改变多巴胺（DA）神经传递的效力急剧下降。通过微透析获得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）不再显著提高伏隔核（NAc）的细胞外DA水平。为了检验可卡因对DA转运体的影响，我们使用脑切片伏安法直接测量DA的摄取。与未给药的动物相比，自我给药的大鼠的可卡因抑制DA摄取的能力受到严重限制。此外，DA的最大摄取率或增加或减少，取决于方案，但可卡因的效力持续下降。这表明在DA摄取和可卡因抑制摄取之间存在分离，尽管结合研究表明可卡因仍然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引起的。这些发现的含义是，可卡因效应可以独立于DA摄取而被操纵，这可能最终与可卡因成瘾药物治疗的设计相关，这些药物治疗可以阻断可卡因抑制作用，但保持DA摄取完整。然而，关于DA摄取和可卡因效应之间的分离的文献还处于早期阶段。这项建议的目标是对自我给药后可卡因效力的降低进行彻底调查。相关性：这项提议的总体目的是了解多巴胺转运体（大脑中可卡因的主要目标）如何在几天的高剂量可卡因治疗后变得对可卡因不敏感。这一结果将为设计治疗可卡因成瘾的药物提供一个新的方向。这些新药可能会改变多巴胺转运体，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.