Transporter Mechanism of Amphetamine Sensitization

安非他明致敏的转运蛋白机制

• 批准号: 8064488
• 负责人: Rong Chen
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064488
• 关键词: Acute; Affect; Agonist; Amphetamine Dependence; Amphetamines; Animal Model; Animals; Behavioral; Binding; Bipolar Disorder; Corpus striatum structure; DRD2 gene; Development; Disease; Dopamine; Dopamine D2 Receptor; Drug Exposure; Drug Sensitization; Drug abuse; Excision; Funding; Grant; Human; Incentives; Intervention; Knockout Mice; Laboratory Animals; Light; Mediating; Mental Depression; Modeling; Mus; Nerve; Nucleus Accumbens; Pharmaceutical Preparations; Phase; Play; Prefrontal Cortex; Psychological reinforcement; Quinpirole; Recycling; Regulation; Rodent; Role; Saline; Schizophrenia; Serotonin; Signal Transduction; Stimulus; Substance abuse problem; Surface; Synapses; Time; Withdrawal; behavioral sensitization; clinically relevant; dopamine transporter; drug addict; drug craving; drug of abuse; neurochemistry; neuropsychiatry; presynaptic; public health relevance; research study; response; serotonin transporter; syntaxin; syntaxin 1A; trafficking; transmission process

DESCRIPTION (provided by applicant): This proposal will provide for the first time characterization and understanding of amphetamine (AMPH)- induced dopamine transporter (DAT) and serotonin transporter (SERT) trafficking in the AMPH sensitized mouse. Repeated AMPH in humans and laboratory animals leads to a behavioral and neurochemical sensitization which may underlie the incentive salience of drugs, e.g., "drug wanting". Understanding the effect of drugs on a sensitized animal is of significant clinical relevance given that human drug addicts, often already sensitized to drugs, repeatedly take drugs. Since AMPH exerts its effect by binding to surface DAT, DAT trafficking is important for the strength and duration of DAT substrate (AMPH and dopamine) action. DAT trafficking is primarily induced by DAT substrate (e.g. AMPH) and D2R agonist (e.g. quinpirole). AMPH is also a substrate for SERT, and SERT is importantly involved in AMPH reinforcement and sensitization. SERT trafficking is regulated by substrates. An alteration in repeated AMPH-induced DAT and SERT trafficking will affect dopaminergic and serotonergic signaling, which may contribute to the cellular mechanisms of AMPH sensitization or tolerance upon repeated AMPH exposure. This proposal will expand upon my present non-NIH funded grant to analyze three specific aims: 1) characterize AMPH- and quinpirole-induced DAT internalization and recycling in AMPH sensitized vs. saline- treated mice and determine whether PKC2 plays a role; 2) determine if repeated AMPH will alter SERT trafficking and enhance serotonin efflux, and whether or not PKC2 plays a role; and 3) determine if repeated AMPH alters syntaxin 1A association with DAT and SERT. This will be the first study to investigate DAT and SERT trafficking in AMPH sensitized state in rodents, and may shed light on different phases of drug responses in humans upon drug exposure and during withdrawal. This study has a broad application because DAT and/or SERT are implicated in many other neuropsychiatric diseases such as schizophrenia, bipolar disorder and depression, which are commonly comorbid with drug abuse. 1 PUBLIC HEALTH RELEVANCE: Human drug craving and abuse is modeled by amphetamine sensitization in rodents induced by repeated amphetamine treatment. Understanding the trafficking of dopamine transporter and serotonin transporter in the animal model of amphetamine sensitization will provide pertinent information about the dopaminergic and serotonergic signaling in the state of drug sensitization in drug addicts, and provide a new cellular avenue for potential drug intervention. The changes found in dopamine and serotonin trafficking will also be relevant to schizophrenia bipolar disorder and depression, which are often comorbid with substance abuse.

描述（由申请人提供）：该提案将首次提供对 AMPH 致敏小鼠中安非他明 (AMPH) 诱导的多巴胺转运蛋白 (DAT) 和血清素转运蛋白 (SERT) 运输的表征和理解。人类和实验动物中重复的 AMPH 会导致行为和神经化学过敏，这可能是药物显着性的诱因，例如“药物需求”。鉴于人类吸毒者通常已经对药物过敏并反复吸毒，了解药物对致敏动物的影响具有重要的临床意义。由于 AMPH 通过与表面 DAT 结合来发挥其作用，因此 DAT 运输对于 DAT 底物（AMPH 和多巴胺）作用的强度和持续时间非常重要。 DAT 运输主要由 DAT 底物（例如 AMPH）和 D2R 激动剂（例如喹吡罗）诱导。 AMPH 也是 SERT 的底物，SERT 重要地参与 AMPH 强化和敏化。 SERT 运输受底物调节。重复 AMPH 诱导的 DAT 和 SERT 运输的改变将影响多巴胺能和血清素能信号传导，这可能有助于重复 AMPH 暴露时 AMPH 敏化或耐受的细胞机制。该提案将扩展我目前非 NIH 资助的拨款，以分析三个具体目标：1）表征 AMPH 致敏小鼠与盐水处理小鼠中 AMPH 和喹吡罗诱导的 DAT 内化和再循环，并确定 PKC2 是否发挥作用； 2) 确定重复的 AMPH 是否会改变 SERT 运输并增强血清素流出，以及 PKC2 是否发挥作用； 3) 确定重复的 AMPH 是否会改变语法蛋白 1A 与 DAT 和 SERT 的关联。这将是第一项调查啮齿动物 AMPH 敏感状态下 DAT 和 SERT 贩运的研究，并可能揭示人类在药物暴露和戒断期间药物反应的不同阶段。这项研究具有广泛的应用，因为 DAT 和/或 SERT 与许多其他神经精神疾病有关，例如精神分裂症、双相情感障碍和抑郁症，这些疾病通常与药物滥用共存。 1 公共健康相关性：人类对毒品的渴望和滥用是通过重复安非他明治疗引起的啮齿类动物对安非他明过敏来模拟的。了解安非他明致敏动物模型中多巴胺转运蛋白和血清素转运蛋白的转运，将为吸毒者药物致敏状态下的多巴胺能和血清素信号传导提供相关信息，并为潜在的药物干预提供新的细胞途径。多巴胺和血清素运输中发现的变化也与精神分裂症、双相情感障碍和抑郁症有关，这些疾病通常与药物滥用共存。