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: 10551185
• 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/10551185
• 关键词: Abstinence; Actin-Binding Protein; Actins; Addictive Behavior; Attenuated; Behavior; Behavioral; Binding; Biological Process; Brain; Brain region; Cells; 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; Incubated; Intervention; Intravenous; 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; Rat Transgene; Rattus; Recurrent disease; Regulation; Relapse; Research; Rewards; Role; Self Administration; Specificity; Substance Addiction; Synapses; Testing; Therapeutic; Time; Transcriptional Regulation; 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; inducible Cre; knock-down; neural; neuroadaptation; neurobiological mechanism; novel; novel therapeutics; opioid use; overexpression; prescription opioid misuse; relapse prevention; 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.

摘要 近年来，阿片类药物的使用、依赖和成瘾已急剧增加到流行病的程度。 这反映了处方类阿片滥用和非法阿片类药物滥用的增加， 海洛因不幸的是，仍然有相对较少的有效的药物干预措施， 药物滥用和成瘾的治疗，其中大多数依赖于替代治疗模式。 神经元可塑性被认为是介导大脑中的长期变化的基质， 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 大脑区域，如脑桥核，并导致长期的药物渴望和药物复发。目前， 缺乏机制证据来探索海洛因诱导的结构的分子机制， 可塑性这项建议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。 本研究探讨肌动蛋白结合蛋白介导的肌动蛋白动力学的作用 在海洛因诱导的可塑性方面存在障碍，最终导致长期的药物渴望和复发行为。本 最后，我们提出了三个具体的目标，将测试以下假设：以确定是否海洛因自我， 给药导致肌动蛋白稳定蛋白的持续和表观遗传介导的减少 dreplasmid，这反过来又调节肌动蛋白营业额（目的I）;以确定dreplasmid是一个重要的分子 海洛因诱导的复吸样行为和戒断后结构可塑性的机制 海洛因自我给药（目的II）;并确定是否dreplasma介导药物寻求和结构可塑性， D1-和D2-表达介质多刺神经元后，海洛因自我管理（目的III）。 这一应用提供了一个机会，以确定，第一次，一个因果机制-dreplant-在 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 海洛因诱发的可塑性。本申请中的工作结果将阐明 慢性海洛因暴露诱导核可塑性长期变化的机制 神经元，并为海洛因成瘾的新疗法的发展提供了新的方向。