Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide
检查 Zeta 抑制肽导致药物相关记忆擦除的机制
基本信息
- 批准号:10557811
- 负责人:
- 金额:$ 47.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:A kinase anchoring proteinAMPA ReceptorsAbstinenceActinsAffectAnimal ModelBehaviorBehavioralBiologicalBrainCell Culture TechniquesChronicCocaineCocaine AbuseCocaine DependenceCountryCuesDataDendritesDendritic SpinesDiseaseDown-RegulationElectrophysiology (science)ExcisionExtinctionFoodFutureGoalsGrantHealthHealth Care CostsHippocampusImpairmentInfusion proceduresKnock-outLearningLong-Term DepressionLong-Term EffectsMeasuresMedialMediatingMediatorMemoryMolecularMorphogenesisN-MethylaspartateNatureNeuronsNucleus AccumbensPeptidesPharmaceutical PreparationsPharmacological TreatmentPhysiologicalPhysiologyPolymersPrefrontal CortexProcessProtein IsoformsPublic HealthRelapseResearchRoleShapesStimulusSubstrate SpecificitySynapsesSynaptic plasticityTechniquesTherapeuticTherapeutic InterventionTranslationsUnited StatesVertebral columnWorkcocaine relapsecocaine rewardcocaine seekingcocaine self-administrationdensitydesigneffectiveness evaluationexperienceexperimental studyinhibitorinsightnovelpolymerizationpreventprotein kinase C zetareceptortrafficking
项目摘要
.
Examining mechanisms underlying drug-associated memory erasure by zeta-inhibitory peptide.
Project Summary:
Cocaine abuse is a major public health problem in the United States with high rates of relapse and a lack to
pharmacological treatment options. We have recently demonstrated that zeta-inhibitory peptide (ZIP) infused
into the nucleus accumbens blocks cocaine reinstatement, an animal model of relapse. Further, ZIP's effects
persist up to 1 week after the peptide is cleared from the brain and ZIP does not alter food reinstatement.
Recent evidence has called the mechanism of action of ZIP into question. Therefore, the goal of this proposal
is to examine mechanisms by which ZIP affects cocaine-induced behavioral, synaptic and structural plasticity.
We, and others, have shown that cocaine self-administration leads to impaired NMDA-dependent long-term
depression (LTD) within the accumbens. Future learning, such as the extinction of drug-associated cues, could
be occluded without the ability to rescale these synapses. As LTD is dependent upon the removal of GluA2-
containing AMPARs, we hypothesize that ZIP may restore the capacity for LTD following cocaine by preventing
PKC-mediated removal of GluA2-containing AMPARs. Changes in AMPAR trafficking are dynamic and
alterations in structural plasticity, such as changes in spine density, provide a mechanism for persistent
changes at the receptor level. In fact, chronic cocaine has been shown to lead to structural plasticity within the
nucleus accumbens and manipulations that disrupt this structural plasticity decrease cocaine reward
behaviors, including reinstatement behavior. As structural plasticity is dependent upon actin polymerization and
cocaine has been shown to alter this process, we propose that ZIP may reverse cocaine-induced structural
plasticity via disruption of actin dynamics. As the ability of ZIP to eliminate cocaine reinstatement could provide
an avenue to designing potential therapeutics, understanding the mechanism by which these effects occur is
critical. Aim 1 focuses on determining how ZIP administration in the nucleus accumbens affects synaptic
plasticity and AMPAR trafficking. Additionally, this aim will determine whether the effects of ZIP on cocaine
reinstatement are dependent upon the ability to blunt LTD the necessity of the ability of ZIP to reverse this
plasticity in its behavioral effects. Aim 2 will focus on the potential affects of ZIP on cocaine-induced structural
plasticity. Aim 3 focuses on determining whether the effects of ZIP are dependent upon another atypical PKC,
PKCι/λ. Thus, the overall goal of the proposed experiments is to elucidate the mechanisms by which ZIP may
disrupt cocaine-induced plasticity at the level of the receptor and the dendrite.
.
zeta抑制肽对药物相关记忆消除机制的研究。
项目概要:
可卡因滥用在美国是一个主要的公共卫生问题,复发率高,缺乏有效的预防措施。
药物治疗选择。我们最近证明,zeta抑制肽(ZIP)注入
在可卡因复发的动物模型中,此外,ZIP的影响
在肽从大脑中清除后持续长达1周,ZIP不会改变食物恢复。
最近的证据对ZIP的作用机制提出了质疑。因此,本提案的目的
研究ZIP影响可卡因诱导的行为、突触和结构可塑性的机制。
我们和其他人已经表明,可卡因自我管理导致受损的NMDA依赖性长期
抑郁症(LTD)的发生。未来的学习,如药物相关线索的消失,
没有能力重新调整这些突触。由于LTD依赖于GluA 2的去除,
含有AMPAR,我们假设ZIP可以通过防止可卡因后LTD的能力恢复,
PKC介导的含GluA 2的AMPAR的去除。AMPAR贩运的变化是动态的,
结构可塑性的改变,如棘密度的变化,提供了一种持久的机制,
受体水平的变化。事实上,慢性可卡因已被证明会导致大脑中的结构可塑性。
破坏这种结构可塑性的核团和操作会降低可卡因的奖赏
行为,包括恢复行为。由于结构可塑性依赖于肌动蛋白聚合,
可卡因已被证明可以改变这一过程,我们建议ZIP可以逆转可卡因诱导的结构
通过破坏肌动蛋白动力学的可塑性。由于ZIP消除可卡因的能力,
一种设计潜在疗法的途径,了解这些效应发生的机制,
很危险目的1着重于确定在延髓核中给予ZIP如何影响突触的形成。
可塑性和AMPAR运输。此外,这一目标将确定ZIP对可卡因的影响是否
恢复取决于钝化有限责任公司的能力,ZIP的能力,以扭转这一必要性
行为效应的可塑性。目标2将重点关注ZIP对可卡因诱导的结构性
可塑性目的3的重点是确定ZIP的作用是否依赖于另一种非典型PKC,
PKC 1/λ。因此,拟议实验的总体目标是阐明ZIP可能
在受体和树突水平上破坏可卡因诱导的可塑性。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Post-weaning social isolation causes sex-specific alterations to dendritic spine density in subregions of the prefrontal cortex and nucleus accumbens of adult mice.
- DOI:10.1016/j.brainres.2021.147755
- 发表时间:2022-02-15
- 期刊:
- 影响因子:2.9
- 作者:McGrath AG;Briand LA
- 通讯作者:Briand LA
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LISA A BRIAND其他文献
LISA A BRIAND的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('LISA A BRIAND', 18)}}的其他基金
The Building Research Independence by Developing Goals and Hands-on Experiences (BRIDGE) Program
通过制定目标和实践经验建立研究独立性(BRIDGE)计划
- 批准号:
10593235 - 财政年份:2023
- 资助金额:
$ 47.78万 - 项目类别:
Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide
检查 Zeta 抑制肽导致药物相关记忆擦除的机制
- 批准号:
10347308 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide
检查 Zeta 抑制肽导致药物相关记忆擦除的机制
- 批准号:
9752721 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide
检查 Zeta 抑制肽导致药物相关记忆擦除的机制
- 批准号:
9905503 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide
检查 Zeta 抑制肽导致药物相关记忆擦除的机制
- 批准号:
10399321 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
AMPA Receptor Trafficking and Cocaine Reinstatement
AMPA 受体贩运和可卡因恢复
- 批准号:
9000679 - 财政年份:2015
- 资助金额:
$ 47.78万 - 项目类别:
AMPA Receptor Trafficking and Cocaine Reinstatement
AMPA 受体贩运和可卡因恢复
- 批准号:
8606840 - 财政年份:2013
- 资助金额:
$ 47.78万 - 项目类别:
AMPA Receptor Trafficking and Cocaine Reinstatement
AMPA 受体贩运和可卡因恢复
- 批准号:
8442554 - 财政年份:2013
- 资助金额:
$ 47.78万 - 项目类别:
The role of CREB in stress-induced reinstatement
CREB 在应激诱导恢复中的作用
- 批准号:
8232158 - 财政年份:2010
- 资助金额:
$ 47.78万 - 项目类别:
The role of CREB in stress-induced reinstatement
CREB 在应激诱导恢复中的作用
- 批准号:
7804995 - 财政年份:2010
- 资助金额:
$ 47.78万 - 项目类别:
相似海外基金
Role of PSD-95-linked PDE4A5 in Regulation of AMPA Receptors
PSD-95 连接的 PDE4A5 在 AMPA 受体调节中的作用
- 批准号:
10829146 - 财政年份:2023
- 资助金额:
$ 47.78万 - 项目类别:
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2022
- 资助金额:
$ 47.78万 - 项目类别:
Discovery Grants Program - Individual
In vivo Probe for ionotropic glutamate signaling system: AMPA receptors
离子型谷氨酸信号系统体内探针:AMPA 受体
- 批准号:
10584340 - 财政年份:2022
- 资助金额:
$ 47.78万 - 项目类别:
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2021
- 资助金额:
$ 47.78万 - 项目类别:
Discovery Grants Program - Individual
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2020
- 资助金额:
$ 47.78万 - 项目类别:
Discovery Grants Program - Individual
Binding of Endophilin Endocytic Proteins to AMPA Receptors and Neuronal Voltage-gated Potassium (Kv) Channels: Regulation of Synaptic Plasticity
内亲素内吞蛋白与 AMPA 受体和神经元电压门控钾 (Kv) 通道的结合:突触可塑性的调节
- 批准号:
RGPIN-2015-03850 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Discovery Grants Program - Individual
The missing link: Opioid modulation of AMPA receptors
缺失的环节:阿片类药物对 AMPA 受体的调节
- 批准号:
2253144 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Studentship
Calcium-permeable AMPA receptors and their auxiliary subunits: pharmacological and molecular intervention in health and disease
钙渗透性 AMPA 受体及其辅助亚基:健康和疾病的药理学和分子干预
- 批准号:
MR/T002506/1 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Research Grant
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Discovery Grants Program - Individual
Life cycle of AMPA receptors under acute metabolic stress
急性代谢应激下 AMPA 受体的生命周期
- 批准号:
411538084 - 财政年份:2018
- 资助金额:
$ 47.78万 - 项目类别:
Research Units