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Heroin-induced plasticity: the role of actin dynamics

海洛因诱导的可塑性：肌动蛋白动力学的作用

基本信息

批准号：
9899969
负责人：
DAVID M DIETZ
金额：
$ 35.77万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9899969
关键词：
Abstinence Actin-Binding Protein Actins Addictive Behavior Attenuated Behavior Behavioral Binding Biological Process Brain Brain region Cells Cellular Morphology Cellular Structures Chronic Cues Data Dendritic Spines Dependence Development Disease Dopamine D2 Receptor Down-Regulation Drug Addiction Epidemic Epigenetic Process Event Functional disorder G Actin Goals Health Heroin Heroin Abuse Heroin Dependence Homeostasis Intervention Intravenous Lead Measures Mediating Messenger RNA MicroRNAs Mission Modeling Molecular Morphology National Institute of Drug Abuse Neurobiology Neuronal Plasticity Neurons Nucleus Accumbens Open Reading Frames Opiate Addiction Opioid Overdose Pharmaceutical Preparations Pharmacotherapy Phenotype Population Predisposition Process Proteins Rattus Recurrent disease Regulation Relapse Research Rewards Role Self Administration Specificity Structure Substance Addiction Synapses Testing Therapeutic Time Transcriptional Regulation Transgenic Organisms United States National Institutes of Health Viral Genes Virus Work addiction behavioral plasticity cell type combat drebrins drug abstinence drug craving drug relapse effective intervention effective therapy experimental study gene therapy knock-down neuroadaptation neurobiological mechanism novel novel therapeutics opioid use overexpression prescription opioid abuse prescription opioid misuse prevent relating to nervous system response substance abuse treatment virtual

项目摘要

ABSTRACT Opiate use, dependence, and addiction have dramatically increased to epidemic proportions in recent years. This is a reflection of the increased misuse of prescription opioids and abuse of illegal opiate drugs, such as heroin. Unfortunately, there are still relatively few effective pharmacotherapeutic interventions available for the treatment of substance abuse and addiction, most of which rely on a replacement therapeutic model. Neuronal plasticity is considered to be a substrate that mediates the long-lasting changes in the brain's reward circuit and a key component of the long-term addiction disease state. These neural adaptations occur in brain regions such as the nucleus accumbens and lead to long-term drug craving and drug relapse. Currently, there is a scarcity of mechanistic evidence that explores the molecular mechanisms of heroin-induced structural plasticity. The overarching focus of this proposal is to determine the functional cellular neurobiological mechanisms of heroin-induced behavioral plasticity. The proposed studies investigate the role of actin dynamics mediated through the actin-binding protein drebrin in heroin-induced plasticity, ultimately resulting in long-term drug craving and relapse behaviors. To this end, we have proposed three Specific Aims that will test the following hypotheses: to determine if heroin self- administration results in a persistent and epigenetically-mediated decrease in the actin-stabilizing protein drebrin, which in turn regulates actin turnover (Aim I); to determine that drebrin is an essential molecular mechanism underlying heroin-induced relapse-like behaviors and structural plasticity following abstinence from heroin self-administration (Aim II); and to determine if drebrin mediates drug seeking and structural plasticity in D1- and in D2-expressing medium spiny neurons following heroin self-administration (Aim III). This application presents an opportunity to determine, for the first time, a causal mechanism—drebrin—in the underlying cellular (actin dynamics; D1/D2 MSN cellular specificity), structural (morphological), and behavioral (reinstatement) plasticity induced by heroin. The findings from the work in this application will elucidate mechanisms by which chronic heroin exposure induces long-term changes in the plasticity of nucleus accumbens neurons and provides new directions for the development of novel therapies for heroin addiction.

抽象的近年来，阿片类药物的使用、依赖和成瘾急剧增加，达到流行的程度。这反映出处方阿片类药物的滥用和非法阿片类药物的滥用增加，例如海洛因。不幸的是，目前有效的药物治疗干预措施仍然相对较少。药物滥用和成瘾的治疗，其中大部分依赖于替代治疗模式。神经元可塑性被认为是介导大脑持久变化的基质奖励回路和长期成瘾疾病状态的关键组成部分。这些神经适应发生在伏隔核等大脑区域会导致长期的药物渴望和药物复发。现在，缺乏探索海洛因诱发结构性中毒的分子机制的证据可塑性。该提案的首要重点是确定功能性细胞神经生物学海洛因诱导的行为可塑性机制。拟议的研究调查了肌动蛋白结合蛋白介导的肌动蛋白动力学的作用 drebrin 参与海洛因诱导的可塑性，最终导致长期的药物渴望和复吸行为。对此最后，我们提出了三个具体目标来检验以下假设：确定海洛因是否自我给药导致肌动蛋白稳定蛋白持续且表观遗传介导的减少 drebrin，进而调节肌动蛋白周转（目标 I）；确定drebrin是一种重要的分子海洛因诱发的复吸样行为和戒断后结构可塑性的潜在机制海洛因自我给药（目标 II）；并确定drebrin是否介导药物寻找和结构可塑性海洛因自我给药后表达 D1 和 D2 的中型多棘神经元（目标 III）。该应用首次提供了确定因果机制——drebrin——的机会。基础细胞（肌动蛋白动力学；D1/D2 MSN 细胞特异性）、结构（形态学）和行为（恢复）海洛因引起的可塑性。本申请工作的结果将阐明长期接触海洛因导致细胞核可塑性长期变化的机制伏隔神经元为海洛因成瘾新疗法的开发提供了新方向。