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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：
LISA A BRIAND
金额：
$ 47.78万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
https://reporter.nih.gov/project-details/10557811
关键词：
A kinase anchoring protein AMPA Receptors Abstinence Actins Affect Animal Model Behavior Behavioral Biological Brain Cell Culture Techniques Chronic Cocaine Cocaine Abuse Cocaine Dependence Country Cues Data Dendrites Dendritic Spines Disease Down-Regulation Electrophysiology (science)Excision Extinction Food Future Goals Grant Health Health Care Costs Hippocampus Impairment Infusion procedures Knock-out Learning Long-Term Depression Long-Term Effects Measures Medial Mediating Mediator Memory Molecular Morphogenesis N-Methylaspartate Nature Neurons Nucleus Accumbens Peptides Pharmaceutical Preparations Pharmacological Treatment Physiological Physiology Polymers Prefrontal Cortex Process Protein Isoforms Public Health Relapse Research Role Shapes Stimulus Substrate Specificity Synapses Synaptic plasticity Techniques Therapeutic Therapeutic Intervention Translations United States Vertebral column Work cocaine relapse cocaine reward cocaine seeking cocaine self-administration density design effectiveness evaluation experience experimental study inhibitor insight novel polymerization prevent protein kinase C zeta receptor trafficking

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.

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