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.

项目概要摘要：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和调节大多数滥用药物的愉悦感。了解 VTA 神经元的兴奋性如何受突触输入调节，如果要了解多巴胺如何发挥作用，膜特性至关重要释放受到控制。 5'-单磷酸腺苷 (AMP) 激活蛋白激酶 (AMPK) 是一个大师调节细胞代谢的酶。在外周组织中，AMPK 激活生化途径，增加能源产量，同时减少能源消耗。尽管在大脑中广泛表达，但其功能在中枢神经元中的作用很大程度上是未知的。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) 通道引起的超极化电流，减少脱敏多巴胺 D2 自身受体，并抑制 VTA 神经元兴奋性突触传递的影响。这我们提出的研究的总体假设是 AMPK 激活增强了对 VTA 神经元。膜片移液器将用于记录单个 VTA 神经元的全细胞电流和电位大鼠中脑切片。蛋白质免疫印迹将用于量化磷酸化和在存在和不存在 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。目标 #1 将描述 AMPK 激活剂对 K- 引起的电流的影响 ATP 开启剂二氮嗪。目标#2将研究第二信使系统并识别递质受体介导 AMPK 激活剂减少多巴胺 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位点在 VTA 中。目标 #4 将描述 AMPK 激活抑制 VTA 中爆发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治疗策略多巴胺依赖性疾病。