PERSISTENT COCAINE-INDUCED CHANGES IN DOPAMINE RELEASE

这是对ADAMHA RSDA（二级）的请求。 拟议的实验 将研究是否增强多巴胺（DA）溢出和D-1 DA 受体功能有助于观察到的行为敏化 因为反复服用可卡因 具体来说，我们假设 在从重复的可卡因给药中戒断后， 从神经末梢的溢出只有当可卡因 挑战是给定的，但终端释放的功能- 调节自身受体和突触后D-1 DA受体的作用将更大， 是否给予可卡因挑战。 体内伏安法 将使用麻醉大鼠和体外切片制备物来 研究多巴胺转运蛋白和诱发的多巴胺溢出 因为反复服用可卡因 结果显示， (NAc)和纹状体进行比较。 DA或可卡因局部激发 并使用可卡因进行全身激发。 结果将 表明（1）是否需要可卡因激发来增加诱发的DA 溢出，（2）是否观察到溢出的变化时，刺激 是局限于终端还是依赖于细胞体 和/或脉冲流以及（3）囊泡释放的变化和/或 DA运输机也参与了。 体外结合和第二信使测定 将用于研究激动剂与D-1和D- 2 DA受体亚型在这些相同的大脑区域。 为了进一步测试 观察到的神经化学变化与行为的关系 致敏，神经化学物质的时间过程和剂量依赖性， 将比较行为变化。 SCH-23390（一种D-1 DA）预处理 受体拮抗剂，或MK-801，一种N-甲基-D-天冬氨酸受体 拮抗剂，这两种药物都被报道可以阻断刺激诱导的 行为敏化，也将被用来测试关系 神经化学和行为观察之间的联系。 的结果 这些研究将增强我们对DA持续变化的理解， 中脑边缘和黑质纹状体DA的神经化学和调节 由于反复服用可卡因而产生的系统。 是 我们希望，了解这些变化将提高我们的能力， 预测低水平、间歇性使用的长期后果 中央DA系统的可卡因 这个RSDA对我的 专业成长将是（1）有机会专注于这种可卡因 研究项目，（2）学习其他新技术的机会 科学家的实验室，将扩大拟议的研究范围， (3)有机会与这一领域的专家互动， 将我自己的研究扩展到新的领域。 四大领域 我的可卡因研究项目会直接把它作为 RSDA结果包括体内电化学记录， 行为大鼠，血清素系统，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.