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）：该提案将提供对Amph敏化小鼠中苯丙胺（AMPH）（AMPH）的首次表征和理解 - 诱导的多巴胺转运蛋白（DAT）和5-羟色胺转运蛋白转运蛋白（SERT）运输。在人类和实验动物中反复的AMPH导致行为和神经化学敏化，这可能是药物激励显着性的基础，例如“想要的药物想要”。鉴于人们通常已经对药物敏感，反复服用药物，了解药物对敏化动物的影响具有显着的临床相关性。由于Amph通过与表面DAT结合发挥作用，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很重要。 DAT运输主要由DAT底物（例如AMPH）和D2R激动剂（例如奎因螺螺；）诱导。 AMPH也是SERT的底物，SERT重要地参与了AMPH的增强和敏化。 SERT贩运受底物的监管。重复AMPH诱导的DAT和SERT运输的改变会影响多巴胺能和5-羟色胺能信号传导，这可能有助于重复AMPH暴露后AMPH敏化或耐受性的细胞机制。该提案将扩大我目前的非NIH资助的赠款，以分析三个具体目的：1）表征Amph和奎因螺氏诱导的DAT内部化和AMPH敏感性与盐水治疗的小鼠的DAT内部化和回收利用，并确定PKC2是否起作用； 2）确定重复的AMPH是否会改变SERT运输并增强5-羟色胺外排，以及PKC2是否起作用； 3）确定重复AMPH是否改变了语法1A与DAT和SERT的关联。这将是第一项研究啮齿动物中Amph敏化状态的DAT和SERT贩运的研究，并可能在药物暴露和戒断期间揭示人类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，躁郁症和抑郁症，这些疾病通常与药物滥用合并。 1 公共卫生相关性：人类的渴望和滥用是通过苯丙胺反复治疗引起的啮齿动物的敏感性来建模的。了解苯丙胺致敏动物模型中多巴胺转运蛋白和5-羟色胺转运蛋白的运输将提供有关吸毒者药物敏化状态的多巴胺能和血清素能信号的相关信息，并为潜在的药物干预提供了新的细胞大道。多巴胺和5-羟色胺运输中发现的变化也将与精神分裂症双相情感障碍和抑郁症有关，这些疾病和抑郁症通常与药物滥用。