Regulation of VTA dopamine neurons by AMP kinase

AMP 激酶对 VTA 多巴胺神经元的调节

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

项目摘要摘要：从腹侧对盖区域（VTA）神经元释放多巴胺的有助于学习目标的行为和调解大多数滥用药物的愉悦方面。了解VTA神经元的兴奋性如果要了解多巴胺，则由突触输入调节，膜特性至关重要释放是控制的。 5'-腺苷单磷酸（AMP）活化蛋白激酶（AMPK）是主人调节细胞代谢的酶。在外围组织中，AMPK激活生化途径增加能源生产，同时减少能源消耗。虽然在大脑中广泛表达，但其功能在中央神经元中，基本上未知。我们实验室的初步数据表明AMPK的激活剂增强 ATP敏感的K+（K-ATP）通道引起的超极化电流，减少多巴胺D2自身受体，并抑制VTA神经元中兴奋性突触传播的影响。这我们提出的研究的过度假设是AMPK激活增强了对抑制性的影响 VTA神经元。贴片移液器将用于记录单细胞电流和电势中的单个VTA神经元中大鼠中脑的切片。西方免疫印迹将用于量化磷酸化水平和在存在和不存在AMPK的情况下孵育的中脑切片中未磷酸化的AMPK 激活剂和/或抑制剂。 AIM＃1将表征AMPK激活剂对K-引起的电流的影响 ATP开瓶器二氮氧化物。 AIM＃2将调查第二通信系统并识别发射机受体介导AMPK激活剂降低多巴胺D2自身受体脱敏的能力。 AIM＃3 Will 研究AMPK抑制谷氨酸介导的突触传播的机制和作用位置在VTA中。 AIM＃4将表征AMPK激活抑制VTA中爆发的机制多巴胺神经元。这些研究的结果可能提出治疗的新药理策略多巴胺依赖性疾病。