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: 9339560
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339560
• 关键词: AMPA Receptors; Action Potentials; Adenosine Monophosphate; Affect; Amphetamines; Autoreceptors; Behavior; Biochemical Pathway; Brain; Brain region; Cells; Cognitive; Data; Dependence; Diazoxide; Disease; Dopamine; Dopamine D2 Receptor; Dopaminergic Agents; Drug abuse; Emotional; Energy Metabolism; Enzymes; Generations; Glutamates; Homeostasis; Human; Incubated; Individual; Learning; Learning Disorders; Long-Term Potentiation; Mediating; Membrane; Metabolism; Methods; Midbrain structure; Mood Disorders; Morphine; 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; Research; Rewards; Rodent; Role; Second Messenger Systems; Site; Slice; Structure; Synapses; Synaptic Transmission; Testing; Tissues; Ventral Tegmental Area; Whole-Cell Recordings; behavioral sensitization; desensitization; disability; dopaminergic neuron; drug of abuse; experimental study; falls; goal oriented behavior; improved; induced pluripotent stem cell; inhibitor/antagonist; interest; neuronal excitability; neurophysiology; pleasure; public health relevance; receptor; receptor sensitivity; sensor; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Dopamine release from neurons in the ventral tegmental area (VTA) 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. When activated by a falling AMP/ATP ratio, AMPK promotes biochemical pathways that increase energy production while reducing energy expenditure. Although AMPK is widely regarded as an energy sensor, recent studies suggest it also influences neuronal excitability. 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 total 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）中释放出多巴胺的释放，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。当通过AMP/ATP比率下降激活时，AMPK促进了增加能量产生的生化途径，同时减少能量消耗。尽管AMPK被广泛认为是能量传感器，但最近的研究表明它也会影响神经元兴奋性。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在存在和不存在AMPK激活剂和/或抑制剂的情况下孵育的中脑切片中磷酸化和总AMPK水平。 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。