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

• 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
• 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

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，依赖性和成瘾已大大增加了流行比例。 这反映了对处方阿片类药物的遗物增加和滥用非法鸦片药物的反映，例如 海洛因。不幸的是，仍然有相对较少的有效的药物治疗干预措施 治疗药物滥用和添加的治疗，其中大多数依赖于替代治疗模型。 神经元可塑性被认为是介导大脑持续变化的底物 奖励电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 大脑区域（如伏隔核），并导致长期的药物渴望和药物缓解。现在， 机械证据稀缺，探讨了海洛因引起的结构的分子机制 可塑性。该提案的总体重点是确定功能性细胞神经生物学 海洛因引起的行为可塑性的机制。 提出的研究研究了肌动蛋白动力学通过肌动蛋白结合蛋白介导的作用 Drebrin在海洛因诱导的可塑性中，最终导致了长期的毒品渴望和继电器行为。对此 最后，我们提出了三个具体目标，这些目标将检验以下假设：确定海洛因是否自我 给药会导致稳定蛋白的持续且表观遗传介导的降低 德雷布林（Drebrin）反过来调节肌动蛋白的周转率（AIM I）；确定DREBRIN是必不可少的分子 戒酒后，海洛因引起的类似继电器的行为和结构可塑性的基础机制 海洛因自我管理（AIM II）；并确定Drebrin是否介导了寻求药物和结构可塑性 海洛因自我给药后的D1和表达D2培养基神经元（AIM III）。 该应用程序提供了第一次确定一种因果机制（杀死）的机会 潜在的细胞（肌动蛋白动力学； D1/D2 MSN细胞特异性），结构（形态）和行为 （恢复）海洛因引起的可塑性。此应用程序中工作的发现将阐明 慢性海洛因暴露诱导核可塑性的长期变化的机制 ac伏氏神经元，并为开发海洛因成瘾的新疗法提供了新的方向。