Project 2: Individual Variation in Dopamine Transmission and Attribution of Incen

项目总结（见说明）： 治疗药物成瘾的主要挑战之一是，大多数吸毒者即使非常希望戒毒，也无法克制自己吸毒，即使在长期戒毒后也经常复发。复发的一个强有力的触发因素是环境刺激的呈现， 先前与吸毒有关（即，药物相关的线索）。最重要的是，对于这个建议，有显着的个体差异的程度，其中呈现药物相关的线索增加了服用药物的激励动机。此外，这些线索增加吸毒欲望的程度是 在人类的PET研究和大鼠的临床前研究中，这与提示增加多巴胺（DA）传输的程度有关。因此，啮齿动物研究可以用来研究药物线索的激励价值与DA信号之间的关系。在目前的应用中，我们建议测量自由活动大鼠DA浓度的亚秒级变化，并检查相位DA之间的关系。 传递和个人差异的倾向属性奖励价值的奖励预测线索，特别是药物线索。这种技术，快速扫描循环伏安法（FSCV），可以区分DA传输的特定方面（如释放和摄取），并已被用来揭示可卡因摄入的新的神经后果和与线索可卡因条件反射相关的区域特异性。在这里，我们将使用FSCV来确定DA信号通路是否存在固有差异，这些差异可以预测将激励价值归因于奖励线索的倾向的个体差异。然后，我们将确定激励动机如何通过奖励预测线索（包括药物相关线索）影响增加的DA传输 以及这与个体在寻求毒品和复吸方面的差异有何关系。鉴于成瘾易感性的巨大差异，了解这种易感性的神经生物学基础对于治疗这种疾病至关重要。

PROJECT SUMMARY (See instructions): One of the primary challenges with the treatment of dmg addiction is that most drug addicts are not able to refrain from taking drugs even though they desperately wish to quit, frequently relapsing even after long periods of abstinence. One powerful trigger for relapse is the presentation of environmental stimuli that were previously associated with drug taking (i.e., a drug-associated cues). Most importantly for this proposal, there is significant individual variation in the degree to which presentation of a drug-associated cue increases the incentive motivation to take drugs. Moreover, the degree that such cues increase the desire to take drug is correlated with how much the cue increases dopamine (DA) transmission, both in PET studies in humans and in preclinical studies in rats. Therefore, rodent studies can be used to study the relationship between the incentive value of drug-cues and DA signaling. In the current application, we propose to measure subsecond changes in DA concentration in freely moving rats and examine the relationship between phasic DA transmission and individual variation in the propensity to attribute incentive value to reward-predictive cues, especially drug-cues. This technology, fast-scan cyclic voltammetry (FSCV), can distinguish between specific aspects of DA transmission (such as release and uptake) and has been used to reveal novel neural consequences of cocaine intake and regional specificity associated with cue-cocaine conditioning. Here, we will use FSCV to determine if there are inherent differences in DA signaling pathways that predict individual variation in the propensity to attribute incentive value to reward-cues. We will then determine how incentive motivation impacts increased DA transmission by reward-predictive cues (including drug-associated cues) and how this is related to individual differences in drug-seeking and relapse. Given the enormous variation in the susceptibility to develop addiction, understanding the neurobiological basis of this susceptibility is critical for treatment of the disease.