Phosphatidylinositol 3 Kinase Signaling Regulates the Amphetamine Actions

磷脂酰肌醇 3 激酶信号传导调节安非他明作用

• 批准号: 7480735
• 负责人: Nicole Kathryn Speed
• 金额: $ 2.56万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480735
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Amphetamines; Attenuated; Behavior; Biochemistry; Biophysics; Cell membrane; Cell surface; Cocaine; Diabetes Mellitus; Disease; Dopamine; Drug abuse; Eating Disorders; Feeding behaviors; Insulin; Insulin Resistance; Lead; Modification; Morbidity - disease rate; Reducing diet; Signal Transduction; Synapses; addiction; base; dopamine transporter; extracellular; in vivo; insulin signaling; neurotransmission; psychostimulant; research study; trafficking; transmission process

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand how changes in insulin signaling regulate the actions of amphetamine (AMPH). Dopamine (DA) transporters (DATs), which largely control DA clearance, are targets for psychostimulants such as AMPH and cocaine. By acting on the DAT, AMPH attenuates DA clearance efficiency and induces reverse transport of DA. As a consequence, AMPH increases synaptic DA levels and enhances dopaminergic transmission, with profound effects on behavior. Exciting new experiments demonstrate that insulin, through phosphatidylinositol 3 kinase (PI3K) signaling, regulates DA clearance by fine-tuning DAT plasma membrane expression. This project will combine biochemistry, biophysics to elucidate the relationships between changes in PI3K signaling and changes in AMPH-induced increase in extracellular DA. Therefore, the key issues to resolve include how PI3K signaling regulates AMPH-induced DA efflux and to determine, ex vivo, whether perturbations in PI3K signaling caused by changes in feeding behaviors and disease states such as diabetes regulate DAT cell surface expression. The proposed studies address the following Specific Aims: 1) To define how PI3K signaling regulates AMPH-induced DA efflux. 2) To demonstrate, in vivo, that hypoinsulinemia or insulin resistance induced by changes in diet, reduce DA clearance and AMPH-induced DA efflux and, that these modifications are a consequence of DAT trafficking. This proposal will analyze how perturbations of insulin signaling regulate the ability of amphetamine to increase extracellular dopamine levels, which can lead to addiction. In turn, defining how insulin signaling affects dopamine neurotransmission may help to explain the mechanistic basis for the high co-morbidity of eating disorders and drug abuse.

描述（由申请人提供）：该项目的长期目标是了解胰岛素信号传导的变化如何调节安非他明（AMPH）的作用。多巴胺 (DA) 转运蛋白 (DAT) 主要控制 DA 清除，是 AMPH 和可卡因等精神兴奋剂的目标。通过作用于 DAT，AMPH 会降低 DA 清除效率并诱导 DA 反向转运。因此，AMPH 会增加突触 DA 水平并增强多巴胺能传递，对行为产生深远影响。令人兴奋的新实验表明，胰岛素通过磷脂酰肌醇 3 激酶 (PI3K) 信号转导，通过微调 DAT 质膜表达来调节 DA 清除。该项目将结合生物化学、生物物理学来阐明 PI3K 信号传导的变化与 AMPH 诱导的细胞外 DA 增加的变化之间的关系。因此，需要解决的关键问题包括 PI3K 信号传导如何调节 AMPH 诱导的 DA 流出，以及在体外确定摄食行为和糖尿病等疾病状态的变化引起的 PI3K 信号传导扰动是否调节 DAT 细胞表面表达。拟议的研究涉及以下具体目标：1) 明确 PI3K 信号传导如何调节 AMPH 诱导的 DA 流出。 2) 在体内证明饮食变化引起的低胰岛素血症或胰岛素抵抗，减少 DA 清除和 AMPH 诱导的 DA 流出，并且这些修饰是 DAT 运输的结果。该提案将分析胰岛素信号传导的扰动如何调节安非他明增加细胞外多巴胺水平的能力，从而导致成瘾。反过来，定义胰岛素信号如何影响多巴胺神经传递可能有助于解释饮食失调和药物滥用的高并发发病率的机制基础。