PRESYNAPTIC DOPAMINE MECHANISMS AFTER CHRONIC COCAINE

描述：(申请人摘要) 一些文献综述研究了耐受性和敏感度。 在延长的可卡因滥用戒断综合症中，及其与 累犯。然而，操纵潜在机制的可能性 出于治疗目的的耐受性和敏感度仍不清楚。我们的 这个项目的目标是研究慢性可卡因的机制。 戒断后一周的耐受性。我们的重点是审查 强健的突触前多巴胺自身受体机制，以及平行 评估多巴胺再摄取参数的变化。大鼠变得宽容 将可卡因连续给药与两个对照组进行比较 组：1)阳性药物对照组，使其对 每日间歇注射可卡因对行为的影响 每日剂量，2)生理盐水对照组。我们之前的研究已经确定 这一容忍度延伸到至少七天的撤资，并 伴随着多巴胺自身受体超敏反应的几个 不同的方法，从行为，到体外高效液相和 伏安法，用于反义ODN探针。我们现在提出一套 进一步、更广泛地表征多巴胺的实验 连续或间歇性戒断时的自身受体功能 吸食可卡因，使用相同的方法：1)检查行为 自身受体超敏的功能后果，2) 伏安法，凭借其超快的时间和空间分辨率，允许 评估DA释放和再摄取参数在特定的， 3)减少信使RNA的反义ODN 转录DA D2受体，以进一步评估ODN对 自身受体对多巴胺合成、神经元放电率的控制 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.