Neuroactive Steroids,Dopamine and Cocaine Sensitization

描述（由申请人提供）：中脑多巴胺系统是 与精神分裂症和帕金森病的病因有关 如精神兴奋剂的增强特性，包括可卡因和 安非他明我们实验室的最新证据表明， 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 这些神经活性类固醇在丘脑核、边缘核、 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 神经活性类固醇对促离子化剂的行为和神经化学作用 谷氨酸受体激动剂的核心和壳的核。 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）全身给药的累积 大脑中的神经活性类固醇，ii）行为和神经化学 离子型谷氨酸的神经活性类固醇调节的结果 伏隔核壳中的受体，iii）神经活性物质的影响 类固醇对可卡因行为敏化的起始作用，以及iv） 神经活性类固醇对可卡因诱发脑功能恢复影响 寻求可卡因的行为总的来说，这些实验将提供 关于CNS中神经活性类固醇活性的信息， 对于类固醇作为潜在药理学的发展是非常宝贵的 涉及离子型谷氨酸受体的疾病的一般治疗方法 尤其是与可卡因成瘾相关的渴望。

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.