ELECTROPHYSIOLOGY OF COCAINE, ETHANOL, AND COCAETHYLENE

描述：（申请人摘要） 可卡因和乙醇混合使用的发生率一直在增加 数年 在全国各地的急诊室， 时间和数百万美元花费在急性中毒的治疗上， 判断力受损造成的创伤，以及慢性医疗 这些物质的使用带来的问题。 的发展 神经药理学药物，将减少渴望和导致禁欲， 才是终极目标 这是一份给M. R. S. D.A.的提案(KO1)这将发展 申请人在研究滥用药物对 大脑，特别是腹侧被盖区的多巴胺能神经元 (VTA)这对药物诱发的奖赏效应有重要作用。 说教式教学 （研究生水平课程），监督文献综述，并指导 研究经验将为长期目标奠定基础， 研究药物滥用在大脑中的相互作用 研究中 申请人将掌握各种电生理技术 评估乙醇与可卡因结合的作用， 对腹侧被盖区神经元的作用。 申请人是一名急诊医生，有治疗 药物滥用的后遗症 作为一名独立的科学家，他将 联合收割机的临床经验与研究， 药物滥用背后的神经电生理机制 这些 研究将建立在他导师实验室的观察基础上， 5-羟色胺增强多巴胺和乙醇对多巴胺能VTA的作用 神经元，介导药物诱导的奖励。 因为可卡因会阻碍再摄取 可卡因和乙醇的混合物可能 在VTA中以超加性方式起作用以增强奖励。 变化 VTA神经元的放电率将用细胞外记录测量， 脑切片，响应a）乙醇和可卡因的组合，或 乙醇和可卡因，B）可卡因和乙醇的组合，或 乙醇和可可烯，在多巴胺D2拮抗剂存在的情况下 舒必利、5-羟色胺5-HT 2拮抗剂酮色林、GABAB拮抗剂 沙氯芬和5-羟色胺5-HT 1B拮抗剂氰基吲哚洛尔。 变化 将用细胞内记录测量尖峰后超极化 响应于a）乙醇和可卡因，或乙醇和可卡因乙烯和B） 这些组合在存在下， 5-羟色胺5-HT 2拮抗剂酮色林。 这个KO 1奖将释放 申请人从临床责任，并允许足够的时间，他 作为基础研究科学家/临床医生的发展。

DESCRIPTION: (Applicant's Abstract) The incidence of the combined use of cocaine and ethanol has been increasing for several years. In emergency departments around the country, increasing time and millions of dollars is spent on the treatment of acute intoxication traumatic injuries caused by impaired judgement, and chronic medical problems caused by use of these substances. The development of neuropharmacological agents that will reduce craving and lead to abstinence, is the ultimate goal. This is a proposal for the M.R.S.D.A.(KO1) which would develop the applicant's skill in studying the effects of substances of abuse on the brain, specifically dopaminergic neurons of the ventral tegmental area (VTA), which are important for drug-induced reward. Didactic instruction (graduate level courses), supervised literature review, and mentored research experience will provide the groundwork for the long-term goal of studying the interaction of substance abuse in the brain. In the research project, the applicant will master various electrophysiological techniques to evaluate the actions of ethanol in combination with cocaine or cocaethylene, on VTA neurons. The applicant, an emergency physician, has experience in treating the sequelae of substance abuse. To develop as a independent scientist, he will combine this clinical experience with studies of the neuroelectrophysiological mechanisms underlying substance abuse. These studies will build upon observations made in his mentor's laboratory, that serotonin enhances the action of dopamine and ethanol on dopaminergic VTA neurons, which mediate drug-induced reward. Since cocaine blocks reuptake of serotonin as well as dopamine, the combination of cocaine and ethanol may act in a superadditive manner in the VTA to enhance reward. Changes in the firing rate of VTA neurons will be measured with extracellular recording in brain slices, in response to a) the combination of ethanol and cocaine, or ethanol and cocaethylene, b) the combination of cocaine and ethanol, or ethanol and cocaethylene, in the presence of the dopamine D2 antagonist sulpiride, the serotonin 5-HT2 antagonist ketanserin, the GABAB antagonist saclofen and the serotonin 5-HT1B antagonist cyanopindolol. Changes in the spike afterhyperpolarization will be measured with intracellular recording in response to a) ethanol and cocaine, or ethanol and cocaethylene and b) these combinations in the presence of the serotonin 5-HT2 antagonist ketanserin. This KO1 award would free the applicant from clinical responsibility and permit sufficient time for his development as a basic research scientist/clinician.