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：
9279101
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279101
关键词：
AMPA Receptors Action Potentials Adenosine Monophosphate Affect Autoreceptors Behavior Biochemical Pathway Brain Brain region Cells Data Dependence Diazoxide Disease Dopamine Dopamine D2 Receptor Dopaminergic Agents Drug abuse Energy Metabolism Enzymes Generations Glutamates Homeostasis Human Incubated Individual 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 Whole-Cell Recordings behavioral sensitization desensitization disability dopaminergic neuron drug of abuse experimental study goal oriented behavior improved induced pluripotent stem cell inhibitor/antagonist interest neuronal excitability pleasure public health relevance receptor receptor sensitivity transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：从腹侧段区域（VTA）神经元释放多巴胺，有助于学习面向目标的行为，并介导大多数滥用药物的愉悦方面。如果要理解如何控制多巴胺释放，那么了解通过突触输入和膜特性调节VTA神经元的兴奋性是至关重要的。 5'-腺苷单磷酸（AMP）活化的蛋白激酶（AMPK）是一种调节细胞代谢的主酶。在外围组织中，AMPK激活了增加能量产生的生化途径，同时减少了能量消耗。尽管在大脑中广泛表达，但其在中央神经元中的功能在很大程度上未知。我们实验室的初步数据表明，AMPK激活剂会增强ATP敏感的K+（K-ATP）通道引起的超极化电流，减少多巴胺D2自身受体的脱敏，并抑制VTA神经元中兴奋性突触传递的影响。我们提出的研究的架构假设是AMPK激活增强了对VTA神经元的抑制作用。斑块移液器将用于记录大鼠中脑切片中单个VTA神经元中的全细胞电流和电势。西部免疫印迹将用于量化中脑切片中磷酸化和未磷酸化的AMPK水平，这些磷酸化和无磷酸化的AMPK在存在和不存在AMPK激活剂和/或抑制剂的情况下已孵育。 AIM＃1将表征AMPK激活剂对K- ATP开瓶器二氮氧化物诱发的电流的影响。 AIM＃2将调查第二质体系统，并确定介导AMPK激活剂减少多巴胺D2自感受脱敏的能力的发射机受体。 AIM＃3将研究AMPK抑制VTA中谷氨酸介导的突触传递的机制和作用部位。 AIM＃4将表征AMPK激活抑制VTA多巴胺神经元中爆发的机制。这些研究的结果可能表明治疗多巴胺依赖性疾病的新药理策略。