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Neuroactive Steroids,Dopamine and Cocaine Sensitization

神经活性类固醇、多巴胺和可卡因致敏

基本信息

批准号：
6751694
负责人：
David H Farb
金额：
$ 24.23万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2006-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The mesotelencephalic dopamine system is implicated in the etiologies of schizophrenia and Parkinson's disease as well as in the reinforcing properties of psychostimulants, including cocaine and amphetamine. Recent evidence from our laboratory indicates that a number of neuroactive steroids influence dopamine transmission in the striatum by potentiating or inhibiting ionotropic glutamate receptor function. The major objective of this project is to follow up on these findings by assessing the activity of these neuroactive steroids in the nucleus accumbens, the limbic portion of the striatal complex that is the locus for the reinforcing effects of many drugs of abuse. To that end, we will assess the modulatory influence of neuroactive steroids on the behavioral and neurochemical effects of ionotropic glutamate receptor agonists in the core and shell of the nucleus accumbens. Using microdialysis (coupled with HPLC-EC and HPLC-MS) and behavioral techniques we will determine, i) the accumulation of systemically administered neuroactive steroids in the brain, ii) the behavioral and neurochemical consequences of neuroactive steroid modulation of ionotropic glutamate receptors in the nucleus accumbens shell, iii) the influence of neuroactive steroids on the initiation of behavioral sensitization to cocaine and iv) the influence of neuroactive steroids on cocaine priming-induced reinstatement of cocaine-seeking behavior. Collectively, these experiments will provide information on the activity of neuroactive steroids in the CNS, which will be invaluable for the development of steroids as potential pharmacological treatments for disorders involving ionotropic glutamate receptors in general and the craving associated with cocaine addiction in particular.

描述（由申请人提供）：中端脑多巴胺系统是也与精神分裂症和帕金森病的病因有关例如可卡因等精神兴奋剂的强化特性安非他明。我们实验室的最新证据表明，许多神经活性类固醇通过以下方式影响纹状体中的多巴胺传递增强或抑制离子型谷氨酸受体功能。主要该项目的目标是通过评估来跟进这些发现这些神经活性类固醇在伏隔核、边缘系统中的活性纹状体复合体的一部分，是增强效应的场所许多滥用药物。为此，我们将评估调节影响神经活性类固醇对离子型药物行为和神经化学作用的影响伏隔核核心和外壳中的谷氨酸受体激动剂。使用微透析（结合 HPLC-EC 和 HPLC-MS）和行为分析我们将确定的技术，i）系统管理的积累大脑中的神经活性类固醇，ii) 行为和神经化学物质离子型谷氨酸神经活性类固醇调节的后果伏隔核壳中的受体，iii) 神经活性的影响类固醇对可卡因行为敏感的启动和 iv) 神经活性类固醇对可卡因启动诱导恢复的影响寻求可卡因的行为。总的来说，这些实验将提供有关中枢神经系统中神经活性类固醇活性的信息，这将是对于作为潜在药理作用的类固醇的开发具有不可估量的价值涉及离子型谷氨酸受体疾病的一般治疗尤其是与可卡因成瘾相关的渴望。