Neurochemistry of Cocaine Reinforcement

描述(由申请人提供)：据报道，可卡因 刺激性、增强性和成瘾性等。一种共识 存在中皮质边缘多巴胺参与可卡因的情况 大鼠的自我给药，有研究表明 皮质酮可能参与了可卡因的强化。几项研究已经 证明了提供可卡因的环境可以改变行为和 对药物的神经化学反应，强调使用 在评估神经机制时适当的行为模型 增援。在此应用程序中要检验的假设是 与可卡因自我给药相关的寻药行为引发 脑内多巴胺能系统相互作用的一系列事件 大脑具有下丘脑-垂体-肾上腺(HPA)轴，这取决于 药物介绍的背景，即药物是否被积极使用 或者被动地注入。为了检验这一假设，有必要 成功地将复杂的行为实验(自我管理和 通过复杂的神经化学程序在体内进行) 来自不同脑区的微透析被认为参与了 寻求可卡因行为的调解。首先，体内微透析耦合 用高效液相色谱(HPLC法)测定 微透析液中多巴胺和皮质酮的浓度 从大鼠内侧前额叶皮质采集对几种 剂量的可卡因。在第二个实验中，有限的剂量反应将是 采用体内微透析结合高效液相色谱分析多巴胺和 微透析样品中皮质酮的放射免疫测定 杏仁核杏仁核的中央核这项研究的结果将决定 中脑边缘和中皮质多巴胺能投射在药物中的作用 成瘾，表明神经化学反应是否对 自服可卡因与被动用药后观察到的可卡因不同 注射可卡因。微透析法与微透析法的结合 三联体模型将使我们能够区分可卡因的激活作用 从与药物寻找相关的HPA轴的激活看HPA轴 行为(即，自我给药与被动注射可卡因)。因此， 这些实验的结果将证明如何控制药物输送 会影响荷尔蒙的输入对功能特征的影响 神经系统的特定解剖投影。这些结果将 也提供了类固醇激素在塑形过程中所起作用的证据 大脑的功能活动。

DESCRIPTION (provided by applicant): Cocaine has been reported to have stimulant, reinforcing and addictive properties, among others. A consensus exists that mesocorticolimbic dopamine is involved in cocaine self-administration in rats and there are studies suggesting that corticosterone may be involved in cocaine reinforcement. Several studies have demonstrated that the context of cocaine delivery can alter the behavioral and neurochemical responses to the drug, emphasizing the importance of using appropriate behavioral models when assessing neural mechanisms of reinforcement. The hypothesis to be tested in this application is that drug-seeking behavior associated with cocaine self-administration triggers a sequence of events involving the interaction of dopaminergic systems in the brain with the hypothalamo-pituitary-adrenal (HPA) axis, which depends on the context of drug presentation, i.e., whether the drug is actively administered or infused passively. To test this hypothesis, it will be necessary to successfully combine the complex behavioral experiment (self-administration and yoked infusions) with the complex neurochemical procedure, in vivo microdialysis from different brain areas thought to be involved in the mediation of cocaine-seeking behavior. First, in vivo microdialysis coupled with high performance liquid chromatography (HPLC) will be used to determine the concentrations of dopamine and corticosterone in the microdialysates collected from the medial prefrontal cortex of rats in response to several doses of cocaine. In the second experiment, a limited dose response will be performed using in vivo microdialysis with the HPLC analysis of dopamine and radioimmunoassay of corticosterone in the microdialysis samples collected from the central nucleus of the amygdala. The results of this study will determine the role of mesolimbic and mesocortical dopaminergic projections in drug addiction, demonstrating whether or not the neurochemical response to self-administered cocaine is different from that observed after the passive infusions of cocaine. Using the combination of microdialysis with the yoked-triad model will allow us to distinguish the activating effect of cocaine on the HPA axis from the activation of the HPA axis related to drug-seeking behavior (i.e., self-administration vs. passively infused cocaine). Thus, the results of these experiments will demonstrate how control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the neural system. These results will also provide evidence of the role that is played by steroid hormones in shaping the functional activity of the brain.