Regulation of VTA dopamine neurons by AMP kinase

AMP 激酶对 VTA 多巴胺神经元的调节

• 批准号: 8752624
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 31.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752624
• 关键词: 5' -AMP-activated protein kinase; AMPA Receptors; Action Potentials; Adenosine Monophosphate; Affect; Autoreceptors; Behavior; Biochemical Pathway; Brain; Brain region; Data; Dependence; Diazoxide; Disease; Dopamine; Dopamine D2 Receptor; Drug abuse; Energy Metabolism; Enzymes; Generations; Glutamates; Homeostasis; Human; Incubated; Ion Channel; Learning; Learning Disorders; Long-Term Potentiation; Mediating; Membrane; Metabolism; Midbrain structure; Mood Disorders; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Na(+)-K(+)-Exchanging ATPase; Neurons; Output; Peripheral; Pharmacology; Phosphotransferases; Physiologic pulse; Physiology; Process; Production; Property; Protein Kinase; Rattus; Regulation; Reporting; Rewards; Role; Second Messenger Systems; Site; Slice; Synapses; Synaptic Transmission; Testing; Tissues; Ventral Tegmental Area; Western Blotting; Whole-Cell Recordings; behavioral sensitization; desensitization; disability; dopaminergic neuron; drug of abuse; gamma-Aminobutyric Acid; goal oriented behavior; improved; inhibitor/antagonist; interest; neuronal excitability; public health relevance; receptor; receptor sensitivity; research study; transmission process; treatment strategy

Project summary abstract: Dopamine release from ventral tegmental area (VTA) neurons assists in learning goal-oriented behaviors and mediates the pleasurable aspects of most drugs of abuse. Understanding how the excitability of VTA neurons is regulated by synaptic inputs and membrane properties is crucial if one is to understand how dopamine release is controlled. 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a master enzyme that regulates cellular metabolism. In peripheral tissues, AMPK activates biochemical pathways that increase energy production while reducing energy expenditure. Although widely expressed in brain, its function in central neurons is largely unknown. Preliminary data from our lab suggest that activators of AMPK potentiate the hyperpolarizing current evoked by ATP-sensitive K+ (K-ATP) channels, reduce the desensitization of dopamine D2 autoreceptors, and inhibit the influence of excitatory synaptic transmission in VTA neurons. The over-arching hypothesis of our proposed studies is that AMPK activation augments inhibitory influences on VTA neurons. Patch pipettes will be used to record whole-cell currents and potentials in single VTA neurons in slices of rat midbrain. Western immunoblot will be used to quantify levels of phosphorylated and unphosphorylated AMPK in midbrain slices that have been incubated in the presence and absence of AMPK activators and/or inhibitors. Aim #1 will characterize the effect of AMPK activators on currents evoked by the K- ATP opener diazoxide. Aim #2 will investigate second messenger systems and identify transmitter receptors that mediate the ability of AMPK activators to reduce dopamine D2 autoreceptor desensitization. Aim #3 will investigate mechanisms and sites of action by which AMPK inhibits glutamate-mediated synaptic transmission in the VTA. Aim #4 will characterize mechanisms by which AMPK activation inhibits burst firing in VTA dopamine neurons. Results of these studies may suggest new pharmacological strategies for treating dopamine-dependent disorders.

项目摘要： 腹侧被盖区（VTA）神经元释放多巴胺有助于学习目标导向行为， 调节了大多数药物滥用的快感了解腹侧被盖区神经元的兴奋性 是由突触输入和膜的性质是至关重要的，如果一个人要了解如何多巴胺 释放是受控的。 5 '-一磷酸腺苷（AMP）激活蛋白激酶（AMPK）是一个大师 调节细胞新陈代谢的酶。 在外周组织中，AMPK激活生物化学途径， 增加能源生产，同时减少能源消耗。虽然在脑中广泛表达， 在中枢神经元中的作用尚不清楚。我们实验室的初步数据表明，AMPK的激活剂增强了 ATP敏感性K+（K-ATP）通道诱发的超极化电流，减少 多巴胺D2自身受体，并抑制腹侧被盖区神经元兴奋性突触传递的影响。的 我们提出的研究的一个过度假设是AMPK激活增强了对 腹侧被盖区神经元。将使用膜片移液管记录单个VTA神经元的全细胞电流和电位， 大鼠中脑的切片。 蛋白质免疫印迹将用于定量磷酸化和磷酸化的水平。 在存在和不存在AMPK的情况下孵育的中脑切片中未磷酸化AMPK 活化剂和/或抑制剂。目的#1将表征AMPK激活剂对由K- ATP开放剂二氮嗪。 目标2将研究第二信使系统并识别递质受体 介导AMPK激活剂降低多巴胺D2自身受体脱敏的能力。 目标#3将 研究AMPK抑制谷氨酸介导的突触传递的机制和作用部位 在VTA。 目标4将描述AMPK激活抑制VTA爆发性放电的机制 多巴胺神经元 这些研究的结果可能会提出新的药理学治疗策略， 多巴胺依赖性疾病