Autophagic regulation of cocaine abuse
可卡因滥用的自噬调节
基本信息
- 批准号:10503559
- 负责人:
- 金额:$ 54.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AttenuatedAutophagocytosisAutoreceptorsBehaviorBehavior TherapyBehavioralBindingBiochemicalCatabolismCell Surface ReceptorsCellular biologyCocaineCocaine AbuseComplexCorpus striatum structureDataDegradation PathwayDevelopmentDopamineDopamine D2 ReceptorDoseDrug abuseFDA approvedFutureGPRASP1 geneGenesGeneticHomologous GeneImageIntravenousKnock-outKnockout MiceLinkLocomotionMass Spectrum AnalysisMetabolismMolecularMusMutateMutationNeuronsNeurotransmittersOutputPathogenicityPathway interactionsPharmaceutical PreparationsPharmacologyPhenocopyPlayProteinsRegulationRelapseResearchRewardsRoleSelf AdministrationSignal TransductionStressSystemTestingTimeVps34 Phosphatidylinositol 3 KinaseWild Type MouseWorkbasecocaine useconditioned place preferencecravingdopaminergic neurondrug of abuseextracellularnoveloverdose deathpresynapticpreventreceptorresponsereuptaketargeted treatmenttooltraffickingupstream kinase
项目摘要
Project Summary/Abstract
The objective of this multi-PI R01 application is to determine how the autophagy machinery regulates the
development of cocaine abuse. Cocaine is one of the most widely abused drugs, and produces a variety of
behaviors including reward, craving, and relapse. Although many pharmacological targets and behavioral
interventions have been explored, there are no FDA-approved medications for reducing cocaine use or treating
relapse in cocaine addicts. Autophagy is a key lysosomal degradation pathway that targets cargos for
degradation either selectively or non-selectively, and is temporally and spatially controlled by more than 30
autophagy genes. Autophagy occurs constitutively at a basal level, and can be further induced by stress. We
recently discovered that an autophagy-related protein Becn2/Beclin 2, which forms a complex with the
autophagy-inducing class III phosphatidylinositol 3-kinase Vps34, is a novel regulator of acquisition of cocaine
reward behaviors via dopamine (DA) D2 receptors (D2Rs). Knockout of Becn2 (but not its homolog Becn1)
globally or specifically in DA neurons protects mice from cocaine-induced locomotor stimulation, conditioned
place preference, and intravenous self-administration. UPLC/mass spectrometry profiling indicates that cocaine-
induced accumulation of DA, but not other neurotransmitters, is attenuated by Becn2 depletion. In addition,
pharmacologically inhibiting autophagy kinases upstream of Becn2, including ULK1 and Vps34, mimics the
effects of Becn2 depletion/mutation on cocaine-induced reward behaviors and DA accumulation, suggesting the
existence of a ULK1-Vps34-Becn2 axis in the regulation of cocaine responses. Furthermore, biochemical
analyses reveal that D2R is a degradation target of Becn2 via binding to a Becn2-associated protein GASP1.
Genetic inhibition of Becn2 or pharmacological inhibition of ULK1 similarly increases striatal presynaptic D2Rs.
Based on these preliminary data, we propose to investigate the hypothesis that the ULK1-Vps34-Becn2
autophagy axis controls vulnerability to cocaine abuse by selectively regulating D2R autoreceptor endolysosomal
trafficking and degradation in DA neurons. Using a combination of genetic, imaging, biochemical, cellular and
behavioral approaches, we aim to answer the following questions: How does Becn2 function in DA neurons to
regulate acquisition of cocaine-taking, dose response, reinstatement of cocaine-seeking, and D2R catabolism
(Aim 1)? Is there a ULK1-Vps34-Becn2 autophagy pathway in DA neurons regulating these cocaine reward
behaviors, and if so, how does it work (Aim 2)? We anticipate that with these two fundamentally related aims,
our study will establish the function and mechanism of a Becn2-centered autophagy axis in the regulation of D2
receptor metabolism, DAergic function, and cocaine-related reward behaviors. A better understanding of this
novel molecular mechanism may provide new options for developing treatments for cocaine abuse and additional
types of drug abuse.
项目摘要/摘要
此多PI R01应用程序的目标是确定自噬机制如何调节
可卡因滥用的发展。可卡因是滥用最广泛的药物之一,它会产生多种
行为包括奖励、渴望和故态复萌。尽管许多药理靶点和行为
已经探索了干预措施,没有FDA批准的药物来减少可卡因的使用或治疗
可卡因成瘾者的复发。自噬是溶酶体降解的关键途径,它以货物为靶点
选择性或非选择性地退化,并在时间和空间上受到30多个
自噬基因。自噬在基础水平上发生,并可被压力进一步诱导。我们
最近发现一种自噬相关蛋白Becn2/Beclin 2,它与
自噬诱导的III类磷脂酰肌醇3-激酶Vps34是一种新的可卡因获取调节因子
奖励行为通过多巴胺(DA)D2受体(D2Rs)实现。Becn2基因敲除(但不是其同源基因Becn1)
整体或特异性DA神经元保护小鼠免受可卡因诱导的条件性运动刺激
偏爱位置,静脉给药。UPLC/MS图谱显示可卡因-
诱导的DA积累,但不是其他神经递质,会因Becn2耗竭而减弱。此外,
药物抑制Becn2上游的自噬激酶,包括ULK1和Vps34,模拟
Becn2缺失/突变对可卡因诱导的奖赏行为和DA蓄积的影响
在可卡因反应的调节中存在ULK1-Vps34-Becn2轴。此外,生化
分析表明,D2R是Becn2通过与Becn2相关蛋白GASP1结合而降解的靶点。
BECn2的遗传抑制或ULK1的药物抑制类似地增加纹状体突触前D2Rs。
基于这些初步数据,我们建议调查ULK1-Vps34-Becn2的假设
自噬轴通过选择性调节D2R自身受体内溶酶体来控制对可卡因滥用的易感性
多巴胺神经元的运输和降解。使用遗传、成像、生化、细胞和
行为方法,我们旨在回答以下问题:Becn2是如何在DA神经元中发挥作用的
调节可卡因的获得、剂量反应、恢复寻找可卡因和D2R分解代谢
(目标1)?在DA神经元中是否存在调节这些可卡因奖赏的ULK1-Vps34-Becn2自噬通路
行为,如果是,它是如何运作的(目标2)?我们预计,有了这两个根本上相关的目标,
我们的研究将建立以Becn2为中心的自噬轴在D2调节中的功能和机制
受体代谢、多巴能功能和可卡因相关的奖赏行为。更好地理解这一点
新的分子机制可能为开发治疗可卡因滥用和其他
药物滥用的类型。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Congcong He', 18)}}的其他基金
Autophagy-facilitated secretion in metabolic maintenance
自噬促进代谢维持中的分泌
- 批准号:
10367132 - 财政年份:2021
- 资助金额:
$ 54.54万 - 项目类别:
Autophagy-facilitated secretion in metabolic maintenance
自噬促进代谢维持中的分泌
- 批准号:
10490364 - 财政年份:2021
- 资助金额:
$ 54.54万 - 项目类别:
Autophagy-facilitated secretion in metabolic maintenance
自噬促进代谢维持中的分泌
- 批准号:
10665778 - 财政年份:2021
- 资助金额:
$ 54.54万 - 项目类别:
Mechanism of autophagy activation in exercise-induced anti-diabetic benefits
自噬激活在运动引起的抗糖尿病益处中的机制
- 批准号:
10522769 - 财政年份:2017
- 资助金额:
$ 54.54万 - 项目类别:
Mechanism of autophagy activation in exercise-induced anti-diabetic benefits
自噬激活在运动引起的抗糖尿病益处中的机制
- 批准号:
10704114 - 财政年份:2017
- 资助金额:
$ 54.54万 - 项目类别:
A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity
新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖
- 批准号:
8774357 - 财政年份:2014
- 资助金额:
$ 54.54万 - 项目类别:
A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity
新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖
- 批准号:
8989093 - 财政年份:2014
- 资助金额:
$ 54.54万 - 项目类别:
A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity
新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖
- 批准号:
8538967 - 财政年份:2012
- 资助金额:
$ 54.54万 - 项目类别: