PERSISTENT COCAINE-INDUCED CHANGES IN DOPAMINE RELEASE

这是对ADAMHA RSDA(II级)的申请。拟议中的实验 将调查增强的多巴胺(DA)是否溢出和D-1 DA 受体功能对观察到的行为敏感化有贡献 在反复服用可卡因之后。具体来说，我们假设 在反复停用可卡因后，诱发了DA 只有在注射可卡因时，神经末梢的溢出才会增加。 提出了挑战，但终端版本的功能- 调节自身受体和突触后D-1DA受体的作用将会更大 不管有没有可卡因挑战。在体伏安法 麻醉大鼠和体外切片制剂将用于 研究戒断后DA转运体和诱发的DA溢出 因为反复服用可卡因。伏隔核内的结果 (NAC)和纹状体进行比较。DA或可卡因对当地的挑战 和可卡因的系统性挑战将被利用。结果将会是 指出(1)是否需要可卡因刺激以增加诱发的DA 溢出，(2)当刺激时是否观察到溢出的变化 是否仅限于终末或它是否依赖于细胞体 和/或脉冲流以及(3)囊泡释放和/或脉冲流的变化 DA传送器也参与其中。体外结合试验和第二信使试验 将用于研究激动剂与D-1和D-1相互作用的变化 2相同脑区的DA受体亚型。为了进一步测试 观察到的神经化学变化与行为的关系 敏化，时间进程和剂量依赖的神经化学和 行为变化将会被比较。D-1 DA-SCH-23390的前处理 受体拮抗剂，或与N-甲基-D-天冬氨酸受体MK-801联合使用 拮抗剂，据报道这两种药物都能阻断兴奋剂诱导的 行为敏感化，也将被用来测试这种关系 在神经化学和行为观察之间。结果是 这些研究将加强我们对DA持续变化的理解 中脑边缘区和黑质纹状体多巴胺的神经化学和调节 由于反复服用可卡因而产生的系统。它是 我们希望了解这些变化将增强我们的能力 预测低水平间歇性使用的长期后果 中枢DA系统上的可卡因。这个RSDA对我的重要性 职业成长将是(1)专注于这种可卡因的机会 研究项目，(2)在其他地方学习新技术的机会 科学家实验室，将扩大拟议研究的范围，并 (3)有机会与该领域的专家互动，以便 将我自己研究的广度扩展到新的领域。四大领域 这将被我的可卡因研究项目吸收为直接 RSDA的结果包括体内电化学记录 行为大鼠，5-羟色胺系统，分子生物学方法和 药物遗传学。

This is a request for an ADAMHA RSDA (Level II). The proposed experiments will investigate whether enhanced dopamine (DA) overflow and D-1 DA receptor function contribute to the behavioral sensitization observed following repeated cocaine administration. Specifically, we hypothesize that following withdrawal from repeated cocaine administration, evoked DA overflow from nerve terminals will be increased only when a cocaine challenge is given but that the functionality of terminal release- modulating autoreceptors and postsynaptic D-1 DA receptors will be greater whether or not a cocaine challenge is given. In vivo voltammetry in anesthetized rats and in vitro slice preparations will be used to investigate the DA transporter and evoked DA overflow following withdrawal from repeated cocaine administration. Results in the nucleus accumbens (NAc) and striatum will be compared. Local challenge with DA or cocaine and systemic challenge with cocaine will be utilized. The results will indicate (1) whether cocaine challenge is required to increase evoked DA overflow, (2) whether the change in overflow is observed when the stimulus is restricted to the terminal or whether it is dependent on the cell body and/or impulse flow and (3) whether changes in vesicular release and/or the DA transporter are involved. In vitro binding and second messenger assays will be used to investigate changes in agonist interactions with D-1 and D- 2 DA receptor subtypes in these same brain regions. To test further the relationship of the observed neurochemical changes with behavioral sensitization, the time course and dose-dependency of the neurochemical and behavioral changes will be compared. Pretreatment with SCH-23390, a D-1 DA receptor antagonist, or with MK-801, an N-methyl-D-aspartate receptor antagonist, both of which have been reported to block stimulant-induced behavioral sensitization, will also be used to test the relationship between the neurochemical and behavioral observations. The results of these studies will enhance our understanding of persistent changes in DA neurochemistry and regulation of the mesolimbic and nigrostriatal DA systems that occur as a result of repeated cocaine administration. It is our hope that understanding these changes will enhance our ability to predict the long-term consequences of low-level, intermittent use of cocaine on central DA systems. The importance of this RSDA to my professional growth will be (1) the opportunity to focus on this cocaine research project, (2) the opportunity to learn new techniques in other scientists' labs that will enhance the scope of the proposed research and (3) the opportunity to interact with experts in this field in order to extend the breadth of my own research into new areas. The four major areas that would be assimilated into my cocaine research program as a direct consequence of an RSDA include in vivo electrochemical recording in behaving rats, serotonin systems, molecular biological approaches and pharmacogenetics.