The Role of the Dopamine Transporter in Psychostimulant Abuse
多巴胺转运蛋白在精神兴奋剂滥用中的作用
基本信息
- 批准号:10529326
- 负责人:
- 金额:$ 53.17万
- 依托单位:
- 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:2014-07-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AmericanAmino AcidsAmphetamine AbuseAmphetaminesAnimal ModelBIN1 geneBehaviorBehavioralBehavioral AssayBiochemistryBiological ModelsBrainCell membraneCessation of lifeCytoplasmDataDiseaseDistalDopamineDrosophila genusElectrophysiology (science)ElementsEventFamily memberGeographyGroomingHospitalizationHumanImpairmentLocomotionMeasuresMediatingMembrane ProteinsMethamphetamineMississippiModificationMolecularMolecular ConformationMotivationNeuronsOutcomePharmaceutical PreparationsPharmacotherapyPhasePhosphorylationPhosphotransferasesPost-Translational Protein ProcessingProcessPropertyRegulationReportingRewardsRoleSNAP receptorStimulantSystemTestingTranslatingUnited StatesUnited States Substance Abuse and Mental Health Services Administrationabuse liabilityamphetamine usebehavioral phenotypingbehavioral studybiophysical analysisdopamine transporterdopaminergic neuronextracellularflymolecular targeted therapiesneuropsychiatric disorderneurotransmissionopioid epidemicpreferencepsychostimulantreceptorstimulant abusesyntaxin 1
项目摘要
Project Summary/Abstract: Amphetamines (AMPHs) are psychostimulants commonly used for the
treatment of neuropsychiatric disorders. They are also abused, with devastating outcomes. The abuse potential
of AMPHs has been associated with their ability to cause mobilization of cytoplasmic dopamine (DA), leading to
an increase in extracellular DA levels. This increase is mediated, at least in part, by the reversal of the DA
transporter (DAT) function, which causes non-vesicular DA release (DA efflux). This DA efflux is thought to be
essential for the psychomotor stimulant properties of AMPHs, a notion supported by evidence that specific
inhibition of DA efflux impairs the ability of AMPH to cause locomotor behaviors. To date, no pharmacotherapies
are available for the treatment of AMPHs abuse. Therefore, it is essential to understand: a) the molecular
mechanisms targeted by AMPH to promote DA efflux; b) whether DA efflux disrupts DA functions in brain, and
whether these disruptions support AMPH-induced behaviors; and c) how we can target these mechanisms to
impair DA efflux to regulate AMPH behaviors.
Previously, using a combination of biochemistry, electrophysiology, as well as behavioral assays, we and
others have shown that the DAT N-Terminus (NT) is a critical structural domain for the ability of AMPH to promote
specific behaviors. This is because AMPH stimulates DAT NT phosphorylation, which is vital for its ability to
cause DA efflux. Furthermore, we provided the first evidence that the human DAT (hDAT) NT engages in direct
associations with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein, syntaxin 1
(Stx1), and that this interaction, in addition to hDAT phosphorylation, regulates AMPH-induced DA efflux and
behaviors. This was the first demonstration that the interaction of a plasma membrane protein with Stx1 is
essential for psychostimulant behaviors. Noteworthy is that our data suggest that the strength of this interaction
is regulated by AMPH-induced phosphorylation of Stx1.
We hypothesize that the functional and behavioral role of the hDAT NT phosphorylation is dictated by its
interactions with the plasma membrane protein, Stx1, a process regulated by the phosphorylation status of Stx1.
We propose to test this hypothesis through the following specific aims: 1) to determine how hDAT interacts
with Stx1; 2) to determine the involvement of Stx1 in AMPH-induced DA efflux. The molecular discoveries of
S.A. #1 and S.A. #2 will be evaluated in neurons, in isolated Drosophila brains, and behaviorally, by using
Drosophila as an animal model to study AMPH actions. We are now able to “humanize” flies by expressing hDAT
in DA neurons of Drosophila lacking the endogenous DAT (KO). In this system, we have established that AMPH-
associated behaviors, such as locomotion and grooming, are DAT-dependent. Also, in this animal model, we
can now determine preference (reward) and avoidance for AMPH. Thus, specific aim 3) is to determine whether
hDAT NT-Stx1 interactions are required for AMPH-induced behaviors.
项目概要/摘要:安非他明(AMPH)是一种精神兴奋剂,通常用于
神经精神疾病的治疗。它们也被滥用,造成毁灭性的后果。滥用可能性
AMPH的作用与其引起细胞质多巴胺(DA)动员的能力有关,
细胞外DA水平的增加。这种增加是介导的,至少部分是通过逆转DA
多巴胺转运蛋白(DAT)功能,其引起非囊泡DA释放(DA流出)。这种DA外排被认为是
对AMPH的精神兴奋特性至关重要,这一概念得到了证据的支持,
DA流出的抑制削弱了AMPH引起运动行为的能力。迄今为止,没有药物治疗
可用于治疗AMPH滥用。因此,有必要了解:a)分子
由AMPH靶向以促进DA流出的机制; B)DA流出是否破坏脑中的DA功能,以及
这些干扰是否支持AMPH诱导的行为;以及c)我们如何将这些机制靶向于
损害DA外排以调节AMPH行为。
以前,使用生物化学,电生理学以及行为测定的组合,我们和
其他人已经表明DAT N-末端(NT)是AMPH促进细胞增殖的能力的关键结构域。
具体行为。这是因为AMPH刺激DAT NT磷酸化,这对于AMPH的能力至关重要。
引起DA外排。此外,我们提供了人类DAT(hDAT)NT直接参与
与可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体蛋白syntaxin 1的相关性
(Stx 1),这种相互作用,除了hDAT磷酸化,调节AMPH诱导的DA流出,
行为。这是第一次证明质膜蛋白与Stx 1的相互作用是
对精神刺激行为至关重要值得注意的是,我们的数据表明,这种相互作用的强度
由AMPH诱导的Stx 1磷酸化调节。
我们假设hDAT NT磷酸化的功能和行为作用是由其磷酸化水平决定的。
与质膜蛋白Stx 1相互作用,这是一个由Stx 1磷酸化状态调节的过程。
我们建议通过以下具体目标来验证这一假设:1)确定hDAT如何相互作用
与Stx 1; 2)以确定Stx 1在AMPH诱导的DA流出中的参与。分子发现
S.A. #1和S。#2将在神经元中,在分离的果蝇大脑中进行评估,并通过使用
果蝇作为研究AMPH作用的动物模型。我们现在能够通过表达hDAT来“人性化”苍蝇
在缺乏内源性DAT(KO)的果蝇DA神经元中。在这个系统中,我们已经建立了AMPH-
相关的行为,如运动和梳理,是DAT依赖性的。在这个动物模型中,我们
现在可以确定对AMPH的偏好(奖励)和回避。因此,具体目标3)是确定是否
AMPH诱导的行为需要hDAT NT-Stx 1相互作用。
项目成果
期刊论文数量(0)
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AURELIO GALLI其他文献
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{{ truncateString('AURELIO GALLI', 18)}}的其他基金
The Role of the Dopamine Transporter in Psychostimulant Abuse
多巴胺转运蛋白在精神兴奋剂滥用中的作用
- 批准号:
10402705 - 财政年份:2021
- 资助金额:
$ 53.17万 - 项目类别:
The dopamine transporter's lipid interactions: understanding transporter function
多巴胺转运蛋白的脂质相互作用:了解转运蛋白的功能
- 批准号:
9601228 - 财政年份:2017
- 资助金额:
$ 53.17万 - 项目类别:
The Role of the Dopamine Transporter in Psychostimulant Abuse
多巴胺转运蛋白在精神兴奋剂滥用中的作用
- 批准号:
10527164 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
GLP-1 Receptors and Psychostimulant Addiction
GLP-1 受体和精神兴奋剂成瘾
- 批准号:
8840923 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
The dopamine transporter's lipid interactions: understanding transporter function
多巴胺转运蛋白的脂质相互作用:了解转运蛋白的功能
- 批准号:
8808750 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
The dopamine transporter's lipid interactions: understanding transporter function
多巴胺转运蛋白的脂质相互作用:了解转运蛋白的功能
- 批准号:
9755714 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
The dopamine transporter's lipid interactions: understanding transporter function
多巴胺转运蛋白的脂质相互作用:了解转运蛋白的功能
- 批准号:
9903264 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
The dopamine transporter's lipid interactions: understanding transporter function
多巴胺转运蛋白的脂质相互作用:了解转运蛋白的功能
- 批准号:
10545756 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
The Role of the Dopamine Transporter in Psychostimulant Abuse
多巴胺转运蛋白在精神兴奋剂滥用中的作用
- 批准号:
9330133 - 财政年份:2014
- 资助金额:
$ 53.17万 - 项目类别:
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