NEUROCHEMISTRY OF MODAFINIL-MA INTERACTION IN RAT BRAIN

尽管相对复杂的技术的发展使得研究成为可能 甲基苯丙胺引起的人脑变化，一个更精确和彻底的检查， 基本的过程和机制仍然需要使用动物模型。本报告中提出的研究 一个项目将包括两个动物模型，提供范例，直接测试特定的假设 关于甲基苯丙胺（MA）和莫达非尼之间的药效学和行为相互作用。 莫达非尼已被选择用于研究作为探针，以调节人类项目中的反应抑制， 拟议的中心，其基础上证明有能力提高抑制控制在健康的人 科目 首先，使用静脉内甲基苯丙胺递送方法的药代动力学模型， 唯一允许我们近似发生在人体中的血浆MA曲线，将用于评估 莫达非尼对MA-naTve和MA-experienced大鼠体内神经递质对MA反应的影响。 MA暴露将模拟与人类MA暴露的定量特征平行的条件 参与拟议中心人类研究的参与者的历史。将使用微透析程序 评估莫达非尼和MA对核内多巴胺和去甲肾上腺素动力学的相互作用 大脑皮层和前额叶皮层。我们将检验莫达非尼预处理将减弱 延髓核多巴胺对MA的反应（对应于减弱的强化作用），并将 增强前额皮质去甲肾上腺素对甲基苯丙胺的反应（对应于认知功能） 效果）。 第二，自我管理模式和线索和MA诱导的恢复程序将被使用 研究莫达非尼治疗对MA的强化特性和MA复发的影响 寻求与拟议中心的人类项目中描述的研究平行的研究。我们还将 研究神经回路负责莫达非尼的影响MA自我管理，通过使用局部 将莫达非尼输注到特定的脑靶部位。我们将检验莫达非尼预处理 将降低增强效应，减少MA和线索诱导的甲基苯丙胺寻找恢复 行为这些研究结果将为人体数据提供一个机制基础 起源于该中心，并可能为潜在的新药物治疗提供重要的新见解， 治疗MA依赖。

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.