Neuroactive Steroids,Dopamine and Cocaine Sensitization

描述(申请人提供)：中脑多巴胺系统 与精神分裂症和帕金森病的病因有关 就像精神刺激剂的增强特性一样，包括可卡因和 安非他命。我们实验室最近的证据表明，一些 神经活性类固醇通过以下途径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。少校 该项目的目标是通过评估 这些神经活性类固醇在伏隔、边缘核的活动 纹状体复合体的一部分，是增强效应的部位 很多滥用药物的人。为此，我们将评估 神经活性类固醇对致离子作用的行为和神经化学影响 伏隔核核心和外壳中的谷氨酸受体激动剂。 使用微透析(结合高效液相-EC和高效液相-质谱仪)和行为 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 离子型谷氨酸对神经活性类固醇调节的影响 伏核外壳中的受体--III)神经活动的影响 类固醇对可卡因行为敏感化的启动和iv) 神经活性类固醇对可卡因诱导的脑电活动恢复的影响 寻找可卡因的行为。总的来说，这些实验将提供 关于中枢神经系统中神经活性类固醇活性的信息，这将是 对于开发类固醇作为潜在的药理作用是非常宝贵的 涉及离子型谷氨酸受体障碍的一般治疗 尤其是与可卡因成瘾有关的渴望。

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.