NEUROCHEMISTRY OF MODAFINIL-MA INTERACTION IN RAT BRAIN

尽管相对复杂的技术的发展使得对 甲基苯丙胺诱导的人脑变化，更精确和彻底的检查 潜在的过程和机制仍然需要使用动物模型。在这篇文章中提出的研究 该项目将包括两个动物模型，它们提供了直接测试特定假设的范例 关于甲基甲基苯丙胺(MA)和莫达非尼之间的药效学和行为相互作用。 莫达非尼已被选为一种探针，用于调节人类项目中的反应抑制 建议的中心，基于其被证明有能力改善健康人的抑制控制 研究对象。 首先，一个药代动力学模型，使用静脉注射甲基苯丙胺的方法 独一无二地允许我们近似人体内发生的血浆MA分布，将被用来评估 莫达非尼对MA-NATVE和MA-经历大鼠体内神经递质反应的影响。 MA暴露将模拟与人类MA暴露的数量特征平行的条件 拟建中心的人体研究参与者的历史。将使用微透析程序 莫达非尼和MA对多巴胺和去甲肾上腺素在核内的相互作用 伏隔核和前额叶皮质。我们将检验莫达非尼预处理会减弱 伏隔核对MA的多巴胺反应(对应于减弱的增强效应)，并将 增强前额叶皮质去甲肾上腺素对甲基苯丙胺的反应(对应于认知 效果)。 其次，将使用自我管理模式以及提示和MA诱导的恢复程序 观察莫达非尼治疗对MA强化特性和MA复发的影响 寻求与拟议中心的人类项目中描述的研究并行的研究。我们还将 用局灶法研究莫达非尼对MA自我给药影响的神经回路 将莫达非尼注入特定的大脑靶点。我们将检验莫达非尼预处理的假设 会减少增强效应，减少MA和线索诱导的甲基苯丙胺搜索的恢复 行为。这些研究的结果将为人类数据提供一个机械基础 并可能为潜在的新药物疗法提供重要的新见解 MA依赖的治疗。

Although the development of relatively sophisticated techniques has enabled the study of methamphetamine-induced changes in the human brain, a more precise and thorough examination of underlying processes and mechanisms still requires the use of animal models. The studies proposed in this project will incorporate two animal models that provide paradigms to directly test specific hypotheses regarding pharmacodynamic and behavioral interactions between metharriphetamine (MA) and modafinil. Modafinil has been selected for study as a probe to modulate response inhibition in the human projects of the proposed Center, on the basis of its proven ability to improve inhibitory control in healthy human subjects. First, a pharmacokinetic model, using an intravenous methamphetamine delivery methodology that uniquely allows us to approximate the plasma MA profile that occurs in humans, will be used to assess the effects of modafinil on the in vivo neurotransmitter response to MA in MA-naTve and MA-experienced rats. The MA exposure will simulate conditions that parallel the quantitative features of the human MA exposure histories of participants in the human studies of the proposed Center. Microdialysis procedures will be used to assess the interactions between modafinil and MA on dopamine and norepinephrine dynamics in nucleus accumbens and prefrontal cortex. We will test the hypothesis that modafinil pretreatment will attenuate the nucleus accumbens dopamine response to MA (corresponding to an attenuated reinforcing effect), and will enhance the prefrontal cortex norepinephrine response to methamphetamine (corresponding to the cognitive effects). Second, a self-administration model and cue- and MA-induced reinstatement procedures will be used to examine the consequences of modafinil treatment on the reinforcing properties of MA and relapse to MA seeking in parallel to studies described in the human projects of the proposed Center. We will also investigate the neural circuitry responsible for modafinil's effects on MA self-administration by using local infusion of modafinil into specific brain target sites. We will test the hypothesis that modafinil pretreatment will reduce the reinforcing effects and decrease MA- and cue-induced reinstatement of methamphetamineseeking behavior. The results of these studies will provide a mechanistic foundation for the human data originating in the Center and may provide important new insight into potential new pharmacotherapies in the treatment of MA dependence.