The role of dendrodendritic dopamine neurotransmission in methamphetamine abuse

树突状多巴胺神经传递在甲基苯丙胺滥用中的作用

基本信息

批准号：
9187450
负责人：
Michael J Beckstead
金额：
$ 23.89万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187450
关键词：
Acute Address Affect Autoreceptors Behavior Behavioral Brain Calcium Cell Nucleus Cell physiology Cells Characteristics Chronic Dendrodendritic Synapse Dopamine Drug abuse Drug usage Electrophysiology (science)Foundations Glean Goals Injection of therapeutic agent Intake Intravenous Knowledge Literature Long-Term Depression Measures Mediating Mental Depression Methamphetamine Methamphetamine dependence Microinjections Mus Neuropeptides Neurotensin Neurotensin Receptors Peptides Pharmaceutical Preparations Pharmacology Process Progressive Disease Property Protein phosphatase Protocols documentation Psychostimulant dependence Public Health Regimen Role Self Administration Signal Transduction Site Slice Societies Synapses Synaptic Transmission Techniques Testing Therapeutic Therapeutic Agents Time Ventral Tegmental Area addiction base design dopamine transporter dopaminergic neuron drug abuse prevention drug reward drug seeking behavior experimental study extracellular improved in vivo induced pluripotent stem cell methamphetamine abuse methamphetamine use mouse model neurophysiology neuroregulation neurotransmission patch clamp postsynaptic protein activation public health relevance response therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Methamphetamine (METH) addiction currently presents an enormous public health issue, and yet no therapeutic agent is currently approved for its treatment. Psychostimulant addiction is a chronic, progressive disease driven by numerous persistent neurophysiological adaptations. METH self-administration increases input of the neuropeptide neurotensin onto dopamine (DA) neurons in the ventral tegmental area (VTA), which are extensively implicated in drug reward processes. While literature evidence and our preliminary results suggest that neurotensin decreases DA autoreceptor-mediated signaling, the role of DA D2 autoreceptors in drug self-administration has not been described. We have recently identified what had been a missing tool in the study of DA autoreceptors and DA-mediated synaptic transmission: an inhibitory postsynaptic current (or IPSC) mediated directly by dendrodendritic DA neurotransmission in the VTA. The identification of the DA IPSC allows us, for the first time, to directly address synaptic questions concerning the relationship between METH abuse and DA neurotransmission. The goal of this application is to determine key synaptic adaptations at the level of the DA cell body that are responsible for escalating METH self-administration. Our central hypothesis is that METH use decreases D2 autoreceptor signaling in VTA DA neurons through a neurotensin-dependent rise in intracellular calcium, producing an escalation of METH self-administration behavior. We will test this by combining patch clamp electrophysiology in brain slices with intravenous METH self-administration and VTA site-specific drug microinjections in mice. The studies in Aim 1 will determine the mechanisms responsible for long-term depression of the DA IPSC. The hypothesis to be tested is that that long term depression of DA IPSCs is produced by a neurotensin receptor-dependent rise in intracellular calcium producing the activation of protein phosphatase 3. The studies in Aim 2 will determine the changes in the DA IPSC produced by METH self-administration. The hypothesis to be tested is that in vivo contingent METH self-administration decreases autoreceptor signaling through a neurotensin-dependent mechanism. The studies in Aim 3 will determine the role of DA autoreceptor-mediated neurotransmission on the escalation of METH self-administration. The hypothesis to be tested is that autoreceptor signaling directly limits METH intake, and that neurotensin-induced depression of this signal contributes to the escalation of self-administration observed with prolonged access to the drug. The results of these studies will identify key cellular mechanisms responsible for decreased autoreceptor signaling, and will determine how this decrease in dendrodendritic DA neurotransmission produces escalation of METH self-administration. These findings will provide a detailed understanding of the relationship between neurotensin, DA neuron activity and METH self-administration and will lay the foundation for therapeutics targeting neurotensin- and autoreceptor-mediated signaling.

描述（由申请人提供）：甲基苯丙胺（甲基苯丙胺）成瘾目前提出了一个巨大的公共卫生问题，但目前尚未批准治疗剂进行治疗。精神刺激成瘾是一种由许多持续的神经生理适应的驱动的慢性，进行性疾病。甲基化的自我给药增加了神经肽神经素的输入到腹侧段区域（VTA）中的多巴胺（DA）神经元上，这些神经元（VTA）广泛涉及药物奖励过程。尽管文献证据和我们的初步结果表明，神经素蛋白降低了自身受体介导的信号传导，但尚未描述DA D2自感受器在药物自我管理中的作用。我们最近确定了DA自感受器和DA介导的突触传播的研究中缺少的工具：抑制性突触后电流（或IPSC）在VTA中直接介导的Dendrodendendritic DA神经传递。 DA IPSC的识别使我们首次可以直接解决有关甲基滥用与DA神经传递之间关系的突触问题。该应用的目的是确定负责升级甲基甲基自加入的DA细胞体水平的关键突触适应。我们的中心假设是，通过神经素依赖性的细胞内钙中的神经素依赖性升高，甲基化的使用降低了D2自身受体信号传导，从而导致甲基自加入行为的升级。我们将通过将贴片夹在脑切片中的电夹电生理与静脉内甲基甲基化和VTA位点特异性药物微型注射在小鼠中进行测试。 AIM 1中的研究将确定导致DA IPSC长期抑郁症的机制。要检验的假说是，DA IPSC的长期抑郁是由神经素受体依赖性升高在细胞内钙中产生的，从而产生蛋白质磷酸酶3的激活。AIM 2中的研究将确定由METH自我分配产生的DA DA IPSC的变化。要检验的假设是，体内偶然的甲基化自动给药通过神经素依赖性机制降低了自身受体信号传导。 AIM 3中的研究将确定DA自动受体介导的神经传递对甲基甲基递增的自身给药的作用。要检验的假设是自动受体信号直接限制了甲基甲基苯丙胺的摄入，而神经素诱导的该信号的抑郁症有助于随着延长吸毒的途径观察到的自我管理的升级。这些研究的结果将确定负责减少自身受体信号传导的关键细胞机制，并确定树突状da神经传递的减少如何产生甲基甲基自加入的升级。这些发现将详细了解神经素，DA神经元活性和METH自我给药之间的关系，并为靶向神经肌蛋白和自身受体介导的信号传导的治疗剂奠定基础。