PRESYNAPTIC DOPAMINE MECHANISMS AFTER CHRONIC COCAINE

描述：（申请人摘要） 一些文献综述已经检查了耐受性和致敏性 在长期可卡因滥用戒断综合征中的作用， 累犯。 然而，操纵潜在机制的可能性 用于治疗目的的耐受性和致敏性仍不清楚。 我们 本项目的目标是研究慢性可卡因的潜在机制 停药后一周的耐受性。 我们的重点是检查 强大的突触前多巴胺自身受体机制，沿着平行 评估多巴胺再摄取参数的变化。 大鼠耐受性 将通过连续可卡因施用与两个对照组进行比较 组：1）阳性药物对照组， 通过每天间歇注射可卡因对行为的影响 每日剂量，和2）盐水对照。 我们之前的研究已经证实 这种容忍度延伸到至少七天的停药期， 伴随着多巴胺自身受体超敏性， 不同的方法，从行为，到体外HPLC， 伏安法，反义ODN探针。 我们现在提出一套 更深入、更广泛地描述多巴胺 连续或间歇戒断期间的自身感受器功能 可卡因管理，使用这些相同的方法：1）行为检查 自身受体超敏性的功能后果，2） 伏安法具有超快的时间和空间分辨率， DA释放和再摄取参数的评估， 局部脑区，和3）反义ODN的，以减少信使RNA 转录的DA D2受体，以进一步评估ODN对 多巴胺合成的自身受体控制，神经元放电率，和 多巴胺介导的行为。

DESCRIPTION: (Applicant's Abstract) Several literature reviews have examined tolerance and sensitization in the extended cocaine abuse withdrawal syndrome, and its relevance for recidivism. However, the potential for manipulating mechanisms underlying tolerance and sensitization for therapeutic purposes remains unclear. Our goal in this project is to examine the mechanisms underlying chronic cocaine tolerance at one week after withdrawal. Our focus is on an examination of the robust presynaptic dopamine autoreceptor mechanisms, along with parallel assessment of changes in dopamine reuptake parameters. Rats made tolerant by continuous cocaine administration will be compared with two control groups: 1) a positive drug control group made supersensitive to the behavioral effects of cocaine by daily intermittent injections of the same daily dose, and 2) saline controls. Our previous studies have established that tolerance extends out to at least seven days of withdrawal and is accompanied by dopamine autoreceptor supersensitivity as measured by several different methods ranging from behavioral, to in vitro HPLC and voltammetric, to antisense ODN probes. We are now proposing a set of experiments that further, and more extensively, characterize dopamine autoreceptor function during withdrawal from continuous or intermittent cocaine administration, using these same methods: 1) Behavior to examine the functional consequences of autoreceptor supersensitivity, 2) Voltammetry, with its ultra-fast temporal and spatial resolution allows for the assessment of both DA release and reuptake parameters in specific, localized brain areas, and 3) Antisense ODN's to reduce messenger RNA transcription of DA D2 receptors, to further assess the ODN effects on autoreceptor control of dopamine synthesis, neuronal firing rates, and dopamine mediated behaviors.