Glucocorticoid regulation of dopamine clearance, cocaine seeking, and reward

描述（由申请人提供）：成瘾的一个阴险的方面是，即使在长期戒断之后，受折磨的人也有复发的风险。生活压力事件 是导致可卡因成瘾者复吸的重要因素，但人们对它们影响动机系统的机制知之甚少。研究表明，压力可能会增加大脑奖赏回路对药物相关刺激的敏感性，从而为旧病复发“埋下伏笔”。该提案旨在阐明压力通过糖皮质激素增加而影响复发易感性的机制。我们之前已经表明，用糖皮质激素应激水平治疗啮齿动物不会导致寻药行为的恢复，但会增强对可卡因剂量的恢复，而可卡因本身不足以引发复发。与其行为效应并行，皮质酮预处理还增强了低剂量可卡因对伏隔核细胞外多巴胺浓度的影响，这表明糖皮质激素可能通过增强这一关键奖励处理大脑区域的多巴胺能神经传递来增强药物寻求。我们正在研究有机阳离子转运蛋白 3（一种高容量多巴胺转运蛋白，可被糖皮质激素急性直接抑制）在介导糖皮质激素对多巴胺能神经传递、可卡因复吸和啮齿动物动机行为的影响中的作用。由于缺乏 OCT3 的药理学特异性抑制剂，我们正在使用两种不同的遗传学方法来检验以下假设：皮质酮通过抑制伏隔核中 OCT3 介导的多巴胺清除来增强可卡因诱导的多巴胺能神经传递和药物寻求行为。第一个目标是，通过使用体内微透析和快速扫描循环伏安法测量可卡因动物体内的多巴胺浓度和清除率，确定皮质酮诱导的伏隔核多巴胺清除率抑制对多巴胺信号传导和药物复发的影响。在第二个目标中，我们将通过检查皮质酮对药物寻求行为和伏隔核多巴胺信号传导的影响，确定 OCT3 在皮质酮的行为和神经化学效应中的作用，这些动物经过基因改造，在整体或伏隔核中缺乏 OCT3 表达。在第三个目标中，我们将检验以下假设：皮质酮引起的多巴胺清除率降低会调节奖励敏感性和自然奖励处理。这些发现将彻底描述一种新的机制，通过这种机制，应激激素可以快速调节多巴胺信号传导，并有助于压力对药物摄入和总体动机行为的影响。

DESCRIPTION (provided by applicant): An insidious aspect of addiction is that afflicted individuals are at risk of relapse even after extended periods of abstinence. Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may "set the stage" for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. This proposal seeks to elucidate the mechanisms by which stress, through increases in glucocorticoid hormones, influences relapse vulnerability. We have previously shown that treatment of rodents with stress levels of glucocorticoids does not lead to reinstatement of drug-seeking behavior, but potentiates reinstatement in response to a dose of cocaine that, by itself, is not sufficient to trigger relapse. In parallel to its behavioral effect, corticosterone pretreatment also potentiates the effects of low-dose cocaine on extracellular dopamine concentration in the nucleus accumbens, suggesting that glucocorticoids may potentiate drug seeking by enhancing dopaminergic neurotransmission in this critical reward-processing brain region. We are examining the role of organic cation transporter 3, a high-capacity dopamine transporter that is acutely and directly inhibited by glucocorticoids, in mediating the effects of glucocorticoids on dopaminergic neurotransmission, cocaine relapse, and motivated behavior in rodents. Because of a lack of pharmacologically specific inhibitors for OCT3, we are using two different genetic approaches to test the hypothesis that corticosterone potentiates cocaine-induced dopaminergic neurotransmission and drug-seeking behavior by inhibiting OCT3-mediated clearance of dopamine in the nucleus accumbens. In the first aim, we will determine the impact of corticosterone-induced inhibition of dopamine clearance in the nucleus accumbens on dopamine signaling and drug relapse by using in vivo microdialysis and fast-scan cyclic voltammetry to measure dopamine concentration and clearance in cocaine-seeking animals. In the second aim, we will determine the role of OCT3 in the behavioral and neurochemical effects of corticosterone by examining corticosterone effects on drug-seeking behavior and nucleus accumbens dopamine signaling in animals genetically modified to lack OCT3 expression either globally or specifically in the nucleus accumbens. In the third aim, we will test the hypothesis that corticosterone-induced decreases in dopamine clearance modulate reward sensitivity and natural reward processing. These findings will thoroughly characterize a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake and motivated behavior in general.