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NEUROCHEMISTRY OF MODAFINIL-MA INTERACTION IN RAT BRAIN

大鼠脑中莫达非尼-MA 相互作用的神经化学

基本信息

批准号：
7689052
负责人：
RONALD KUCZENSKI
金额：
$ 75.35万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7689052
关键词：
Acute Affect Animal Model Animals Appendix Attenuated Behavior Behavioral Brain Brain imaging Brain region Catecholamines Clinical Cognitive Condition Cues Dependence Development Dopamine Dose Drug Addiction Drug Exposure Drug abuse Drug usage Foundations Funding Future Goals Human Infusion procedures Intravenous Laboratories Literature Longitudinal Studies Methamphetamine Methodology Microdialysis Modafinil Modeling Neurobiology Neurocognitive Neurocognitive Deficit Neurotransmitters Norepinephrine Nucleus Accumbens Participant Pattern Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Plasma Positive Reinforcer Prefrontal Cortex Procedures Process Property Rattus Recording of previous events Relapse Research Design Sampling Self Administration Simulate Site Techniques Testing Work base craving drug of abuse experience extracellular human data human study human subject improved in vivo insight neural circuit neurochemistry neuroimaging nonhuman primate pharmacokinetic model research study response

项目摘要

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.

尽管相对复杂技术的发展使得研究甲基苯丙胺引起的人脑变化，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。本文提出的研究项目将包含两种动物模型，提供直接测试特定假设的范式关于甲基苯丙胺（MA）和莫达非尼之间的药效学和行为相互作用。莫达非尼已被选为研究的探针，用于调节人类项目中的反应抑制拟议的中心，基于其已被证实的改善健康人类抑制控制的能力科目。首先，药代动力学模型，使用静脉注射甲基苯丙胺输送方法，独特地使我们能够近似人类中发生的血浆 MA 分布，将用于评估莫达非尼对未经历过 MA 的大鼠和经历过 MA 的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拟建中心人类研究参与者的历史。将使用微透析程序评估莫达非尼和 MA 对细胞核内多巴胺和去甲肾上腺素动力学的相互作用伏隔核和前额皮质。我们将检验以下假设：莫达非尼预处理会减弱伏隔核多巴胺对 MA 的反应（对应于减弱的强化效应），并且会增强前额皮质去甲肾上腺素对甲基苯丙胺的反应（对应于认知效果）。其次，将使用自我管理模型以及提示和 MA 诱导的恢复程序检查莫达非尼治疗对 MA 增强特性和 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。我们还将通过使用局部药物研究莫达非尼对 MA 自我给药影响的神经回路将莫达非尼输注到特定的大脑目标部位。我们将检验莫达非尼预处理的假设将减少强化效应并减少 MA 和线索诱导的甲基苯丙胺寻求恢复行为。这些研究结果将为人类数据提供机制基础起源于该中心，可能会为潜在的新药物疗法提供重要的新见解治疗MA依赖性。