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:
- 金额:$ 23.89万
- 依托单位:
- 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:
- 关键词:AcuteAddressAffectAutoreceptorsBehaviorBehavioralBrainCalciumCell NucleusCell physiologyCellsCharacteristicsChronicDendrodendritic SynapseDopamineDrug abuseDrug usageElectrophysiology (science)FoundationsGleanGoalsInjection of therapeutic agentIntakeIntravenousKnowledgeLiteratureLong-Term DepressionMeasuresMediatingMental DepressionMethamphetamineMethamphetamine dependenceMicroinjectionsMusNeuropeptidesNeurotensinNeurotensin ReceptorsPeptidesPharmaceutical PreparationsPharmacologyProcessProgressive DiseasePropertyProtein phosphataseProtocols documentationPsychostimulant dependencePublic HealthRegimenRoleSelf AdministrationSignal TransductionSiteSliceSocietiesSynapsesSynaptic TransmissionTechniquesTestingTherapeuticTherapeutic AgentsTimeVentral Tegmental Areaaddictionbasedesigndopamine transporterdopaminergic neurondrug abuse preventiondrug rewarddrug seeking behaviorexperimental studyextracellularimprovedin vivoinduced pluripotent stem cellmethamphetamine abusemethamphetamine usemouse modelneurophysiologyneuroregulationneurotransmissionpatch clamppostsynapticprotein activationpublic health relevanceresponsetherapeutic targettool
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(METH)成瘾目前是一个巨大的公共卫生问题,但目前还没有治疗药物被批准用于治疗。精神兴奋剂成瘾是一种慢性进行性疾病,由许多持续的神经生理适应驱动。METH自我给药增加了腹侧被盖区(VTA)多巴胺(DA)神经元上神经肽神经降压素的输入,这广泛涉及药物奖励过程。虽然文献证据和我们的初步结果表明,神经降压素减少DA自身受体介导的信号传导,DA D2自身受体在药物自我给药中的作用还没有被描述。我们最近已经确定了什么是DA自身受体和DA介导的突触传递的研究中缺失的工具:抑制性突触后电流(或IPSC)直接介导的树突状DA神经传递在腹侧被盖区。DA IPSC的鉴定使我们能够首次直接解决有关METH滥用和DA神经传递之间关系的突触问题。本申请的目的是确定负责逐步增加METH自我给药的DA细胞体水平的关键突触适应。我们的中心假设是,METH的使用通过神经紧张素依赖性的细胞内钙升高降低腹侧被盖区DA神经元中的D2自身受体信号传导,产生METH自我给药行为的升级。我们将通过将脑切片中的膜片钳电生理学与静脉内METH自我给药和小鼠VTA位点特异性药物显微注射相结合来测试这一点。 目标1中的研究将确定导致DA IPSC长期抑制的机制。待检验的假设是,DA IPSC的长期抑制是通过神经降压素受体依赖性的细胞内钙升高产生蛋白磷酸酶3的活化而产生的。目标2中的研究将确定METH自我给药产生的DA IPSC的变化。待检验的假设是,体内偶然的METH自我给药通过神经紧张素依赖性机制降低自身受体信号传导。目标3中的研究将确定DA自身受体介导的神经传递对METH自我给药升级的作用。待检验的假设是,自身受体信号传导直接限制METH摄入,并且神经降压素诱导的该信号的抑制有助于观察到的自我给药的升级,延长对药物的使用。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,并将确定这种树突状DA神经传递的减少如何产生METH自我给药的升级。这些发现将提供神经降压素,DA神经元活性和METH自我管理之间的关系的详细了解,并将奠定治疗靶向神经降压素和自身受体介导的信号转导的基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Michael J Beckstead其他文献
Michael J Beckstead的其他文献
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{{ truncateString('Michael J Beckstead', 18)}}的其他基金
Plasticity of GABA input to VTA dopamine neurons in opioid use disorders
阿片类药物使用障碍中 VTA 多巴胺神经元 GABA 输入的可塑性
- 批准号:
10259310 - 财政年份:2021
- 资助金额:
$ 23.89万 - 项目类别:
Plasticity of GABA input to VTA dopamine neurons in opioid use disorders
阿片类药物使用障碍中 VTA 多巴胺神经元 GABA 输入的可塑性
- 批准号:
10512049 - 财政年份:2021
- 资助金额:
$ 23.89万 - 项目类别:
Effects of dietary restriction on age-related neurophysiological adaptations: from behavior to single dopaminergic neurons
饮食限制对年龄相关神经生理适应的影响:从行为到单个多巴胺能神经元
- 批准号:
9240155 - 财政年份:2016
- 资助金额:
$ 23.89万 - 项目类别:
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
- 批准号:
8440057 - 财政年份:2013
- 资助金额:
$ 23.89万 - 项目类别:
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
- 批准号:
8617261 - 财政年份:2013
- 资助金额:
$ 23.89万 - 项目类别:
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
- 批准号:
9085629 - 财政年份:2013
- 资助金额:
$ 23.89万 - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7406089 - 财政年份:2007
- 资助金额:
$ 23.89万 - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7254296 - 财政年份:2007
- 资助金额:
$ 23.89万 - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7615534 - 财政年份:2007
- 资助金额:
$ 23.89万 - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7816734 - 财政年份:2007
- 资助金额:
$ 23.89万 - 项目类别:
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