Rapid dopamine dynamics after repeated cocaine exposure

描述(由申请人提供)：美国的可卡因滥用仍然令人担忧，估计每年有100万新的可卡因使用者(USHHS，2006)。可卡因会抑制大脑中的多巴胺转运体，进而增加多巴胺的供应，从而产生欣快感。此外，这些多巴胺效应还会导致一些行为变化，包括运动多动、寻找可卡因的行为和可卡因的自我给药。虽然微透析文献显示，反复接触可卡因后，多巴胺水平逐渐增加，或敏化，运动亢进，但这些研究并未扩展到包括快速的多巴胺动态。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，了解这些快速的多巴胺动态是很重要的，因为它们已经被观察到对急性可卡因注射的反应，并可能在对可卡因的行为反应中发挥作用。本文提出的工作将利用体内的FSCV来1)表征急性和重复暴露可卡因后伏隔核核心和外壳中的实时多巴胺释放，以及2)确定伏隔核多巴胺的快速释放在可卡因介导的运动敏化中的作用。具体地说，体内FSCV记录将在大鼠服用和戒断可卡因的不同时期进行，以充分表征这些多巴胺能反应。‘R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的多巴胺效应，从而影响行为。这项工作将提供宝贵的洞察力，以了解这种过程可能如何导致人类滥用可卡因。

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.