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）：腹侧被盖区（VTA）神经元释放的多巴胺有助于学习目标导向的行为并调节大多数滥用药物的愉悦感。如果要了解如何控制多巴胺的释放，那么了解 VTA 神经元的兴奋性如何受到突触输入和膜特性的调节至关重要。 5'-单磷酸腺苷 (AMP) 激活蛋白激酶 (AMPK) 是调节细胞代谢的主酶。在外周组织中，AMPK 激活生化途径，增加能量产生，同时减少能量消耗。尽管在大脑中广泛表达，但其在中枢神经元中的功能很大程度上未知。我们实验室的初步数据表明，AMPK 激活剂可增强 ATP 敏感 K+ (K-ATP) 通道诱发的超极化电流，减少多巴胺 D2 自身受体的脱敏，并抑制 VTA 神经元兴奋性突触传递的影响。我们提出的研究的总体假设是 AMPK 激活增强了对 VTA 神经元的抑制影响。贴片移液管将用于记录大鼠中脑切片中单个 VTA 神经元的全细胞电流和电位。 Western 免疫印迹将用于量化中脑切片中磷酸化和非磷酸化 AMPK 的水平，这些切片已在存在和不存在 AMPK 激活剂和/或抑制剂的情况下孵育。目标#1 将描述 AMPK 激活剂对 K-ATP 开启剂二氮嗪引起的电流的影响。目标 #2 将研究第二信使系统并识别介导 AMPK 激活剂减少多巴胺 D2 自身受体脱敏能力的递质受体。目标#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位点。目标 #4 将描述 AMPK 激活抑制 VTA 多巴胺神经元爆发放电的机制。这些研究的结果可能提出治疗多巴胺依赖性疾病的新药理学策略。