PARAMETERS AND MECHANISMS OF COCAINE TOLERANCE

描述：（申请人摘要） 关于可卡因的文献清楚地表明， 对可卡因的后续行为影响深远。 例如，通过渗透微泵连续给予可卡因 导致对可卡因行为影响的耐受性。 但 这些结果的剂量和时间依赖性，以及机制基础 这些影响，并没有完全被理解。 本申请 建议系统地评估诱导耐受性的因素 连续给予可卡因后，以及DA 自身受体功能和多巴胺转运蛋白（DAT）结合， 不同的可卡因持续给药方案 具体而言是 本申请将评价耐受性的剂量依赖性， 以及连续服用可卡因后的耐受时间过程 给药，以及DA自身受体的相应变化 功能 本建议将扩大数据库， 宽容 大鼠将暴露于预处理方案，包括 通过渗透微型泵持续输注盐水或可卡因。 然后将大鼠从该预处理方案中退出3、7、14 或28天，并评估行为、DA自身受体和DAT， 5-羟色胺转运体（SET）结合变化。 具体来说，目前 应用程序将检查，在三个不同的分析水平：（1） 诱导耐受、DA自身受体超敏性和DAT变化 和SET结合，通过连续给药40 mg/kg可卡因， 渗透微型泵持续5、10或15天。 (2)耐受诱导 自身受体超敏性，以及DAT和SET结合的变化，由 连续给予0、5、10、20或40 mg/kg可卡因，通过渗透压 迷你泵14天。 (3)多巴胺自身受体时程 超敏性（通过行为和伏安法评估）和变化 在DAT和SET结合中，在连续给予40 mg/kg 可卡因，通过渗透微泵14天。 在过去的几年里，我们 已经记录了连续给予高剂量的 可卡因 目前的实验是这一研究的逻辑延伸。 因此，本实验将进一步阐明 可卡因耐受性，以及DA自身受体在可卡因滥用中的作用， 戒断，并可能有助于开发有效的药物疗法 用于治疗可卡因滥用

DESCRIPTION: (Applicant's Abstract) The literature on cocaine clearly suggests that several experimental factors have a profound influence on the subsequent behavioral effects of cocaine. For example, the continuous cocaine administration via osmotic minipump results in tolerance to the behavioral effects of cocaine. However, the dose and time dependency of these results, as well as the mechanistic bases of these effects, are not entirely understood. The present application proposes to systematically evaluate the factors that induce tolerance following continuous cocaine administration, as well as changes in DA autoreceptor function, and dopamine transporter (DAT) binding following different continuous cocaine administration regimens. Specifically, the present application will evaluate the dose-dependent nature of tolerance, as well as the time course of tolerance following continuous cocaine administration, as well as the corresponding changes in DA autoreceptor function. The present proposal will extend the data base regarding tolerance. The rats will be exposed to pretreatment regimen involving either the continuous infusion of saline or cocaine via osmotic minipump. The rats will then be withdrawn from this pretreatment regiment for 3, 7, 14 or 28 days, and assessed for behavioral, DA autoreceptor, and DAT and serotonin transporter (SET) binding changes. Specifically, the present application will examine, at three different levels of analysis: (1) the induction of tolerance, DA autoreceptor supersensitivity, and changes in DAT and SET binding, by the continuous administration 40 mg/kg cocaine via osmotic minipump for 5, 10, or 15 days. (2) the induction of tolerance, DA autoreceptor supersensitivity, and changes in DAT and SET binding, by the continuous administration of 0, 5, 10, 20 or 40 mg/kg cocaine, via osmotic minipump for 14 days. (3) the time course of DA autoreceptor supersensitivity (assessed behaviorally and voltammetrically), and changes in DAT and SET binding, following the continuous administration of 40 mg/kg cocaine, via osmotic minipump for 14 days. Over the last several years we have documented the residual effects of continuously administered, high dose cocaine. The present experiments are a logical extension of this research. Hence, the present experiments will further elucidate the parameters of cocaine tolerance, and the role of the DA autoreceptor in cocaine abuse and withdrawal, and may aid in the development of effective pharmacotherapies for the treatment of cocaine abuse.