Rapid dopamine dynamics after repeated cocaine exposure

描述（由申请方提供）：美国的可卡因滥用仍然令人关切，估计每年有100万新的可卡因使用者（USHHS，2006年）。皮质醇的作用是抑制大脑中的多巴胺转运蛋白，这反过来又增加了多巴胺的可用性，从而产生欣快的感觉。此外，这些多巴胺效应导致几种行为变化，包括运动过度活跃、可卡因寻求行为和可卡因自我给药。虽然微透析文献已经说明了一个渐进的，或致敏的，多巴胺水平和运动过度活跃与重复可卡因暴露的增加，这些研究还没有扩展到包括快速多巴胺动力学。快速扫描循环伏安法（FSCV）可以在亚秒的时间尺度上检测多巴胺的波动，为此类分析提供了理想的手段。此外，这些快速多巴胺动力学的理解是重要的，因为它们已被观察到在响应于急性可卡因给药，并可能发挥作用的行为反应可卡因。本文提出的工作将使用体内FSCV 1）表征急性和重复可卡因暴露后中脑核核和壳中的真实的多巴胺释放，2）确定中脑核中多巴胺快速释放在可卡因介导的运动敏化中的作用。具体而言，将在可卡因给药和戒断的不同时期后在大鼠中进行体内FSCV记录，以充分表征这些多巴胺能反应。这项研究的总体目标是确定长期接触可卡因如何改变大脑中多巴胺的作用，从而影响行为。这项工作将提供宝贵的见解，这些过程如何可能有助于人类滥用可卡因。

DESCRIPTION (provided by applicant): Cocaine abuse in the United States continues to be of concern with an estimated 1 million new cocaine users each year (USHHS, 2006). Cocaine acts to inhibit dopamine transporters in the brain, which in turn increases dopamine availability to produce feelings of euphoria. In addition, these dopamine effects lead to several behavioral changes including locomotor hyperactivity, cocaine seeking behavior and cocaine self- administration. While the microdialysis literature has illustrated a progressive, or sensitized, increase in dopamine levels and locomotor hyperactivity with repeated cocaine exposure, these studies have not been extended to include rapid dopamine dynamics. Fast scan cyclic voltammetry (FSCV), which can detect dopamine fluctuations on a sub-second time scale, provides an ideal means for such analyses. Further, an understanding of these rapid dopamine dynamics is important as they have been observed in response to acute cocaine administration and may play a role in behavioral responses to cocaine. The work proposed here will use in vivo FSCV to 1) characterize real time dopamine release in the nucleus accumbens core and shell after acute and repeated cocaine exposure and 2) determine the role of rapid dopamine release in the nucleus accumbens in cocaine-mediated locomotor sensitization. Specifically, in vivo FSCV recordings will be performed in rats after different periods of cocaine administration and withdrawal in order to fully characterize these dopaminergic responses. ' r The overall goal of this research is to determine how long term cocaine exposure alters dopamine effects in the brain to infleunce behavior. Such work will provide valuable insight as to how such processes may contribute to cocaine abuse in humans.