Neuroadaptive changes in dendritically targeted mRNAs in cocaine abstinence

可卡因戒断中树突状靶向 mRNA 的神经适应性变化

• 批准号: 7334266
• 负责人: Terri Schochet
• 金额: $ 4.96万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7334266
• 关键词: Abstinence; Acute; Adaptive Behaviors; Behavior; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Chromosome Pairing; Chronic; Cocaine; Cues; Data; Dendrites; Dendritic Spines; Down-Regulation; Drug Addiction; Drug Exposure; Drug abuse; Exposure to; Gene Expression; Glutamates; Goals; Golgi Apparatus; Image; Immunohistochemistry; In Situ Hybridization; Infusion procedures; Intake; Interneurons; Laboratories; Localized; Long-Term Effects; Messenger RNA; Metabolic; Modification; Molecular; Molecular Profiling; Morphology; Nucleus Accumbens; Output; Parahippocampal Gyrus; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Public Health; Pyramidal Cells; Radioactive; Rattus; Relapse; Reporting; Research; Resolution; Rewards; Rodent; Saline; Self Administration; Self-Administered; Staining method; Stains; Structure; Structure of molecular layer of cerebellar cortex; Synapses; Synaptic plasticity; System; Testing; Therapeutic Intervention; Training; Transcriptional Regulation; Up-Regulation; Vertebral column; Week; addiction; cell type; day; density; dentate gyrus; drug abuse prevention; drug addict; drug withdrawal; hippocampal pyramidal neuron; insight; mRNA Expression; neural circuit; neurotransmission; novel; prevent; response; spinophilin

DESCRIPTION (provided by applicant): In drug addiction, the functioning of motivational and reward neural circuitry normally used to guide adaptive behaviors becomes biased towards continued drug abuse. These persistent neuroadaptive changes encompass alterations in molecular components at the synapse, changes in gene expression, and altered behavioral output. Even after cessation of drug intake, a large proportion of recovering drug addicts will relapse into drug abuse following weeks or months of abstinence (Kalivas and Volkow, 2005). One of the brain regions in which these changes take place is the prefrontal cortex (RFC), a critical region for goal- directed behaviors and impulse control. Imaging studies of addicts have revealed decreased basal activity during drug withdrawal (Goldstein and Volkow, 2001), and large increases in metabolic activity following exposure to drug cues in the PFC (Childress et al., 1999). It is a goal to correlate these functional modifications with altered molecular substrates to identify novel potential targets for therapeutic intervention. Examination of the PFC and regions that provide input to and output from the PFC following both acute and chronic drug exposure implicate changes in glutamate neurotransmission as a key factor in the addicted brain (McFarland and Kalivas, 2003). Increased branching and dysmorphic dendritic spines have been reported in the nucleus accumbens and PFC in rats one month after cessation of cocaine self administration (Robinson et al., 2001), however the molecular cascades underlying these responses have not been elaborated. This study will examine a cluster of dendritic mRNAs, identified by analysis of gene expression profiles in the PFC, that may contribute to the drug-induced synaptic plasticity in the PFC during a period of cocaine abstinence. These candidate genes, including staufen 2, and spinophilin, may underlie long-lasting physical modifications at the synapse. The overall goal of these studies is to yield insight into potential mechanisms that can be targeted to provide novel treatment opportunities for the prevention of drug abuse and relapse. The relevance of this research to public health is in gaining further understanding of the changes that occur in the brain in addiction. Knowing how long-term effects of drugs are stamped into the system even after drugs are no longer present may help generate new strategies for developing treatments to prevent drug abuse.

描述（由申请人提供）：在药物成瘾中，通常用于指导自适应行为的动机和奖励神经回路的功能变得有偏见。这些持续的神经适应性变化包括突触处分子成分的变化，基因表达的变化和行为输出改变。即使停止药物摄入量，大部分康复的吸毒者也会在禁欲后几周或几个月（Kalivas and Volkow，2005年）复发为药物滥用。发生这些变化的大脑区域之一是前额叶皮层（RFC），这是目标行为和冲动控制的关键区域。对吸毒者的成像研究表明，在药物戒断期间的基础活性降低（Goldstein and Volkow，2001），并且在PFC中暴露于药物线索后代谢活性大幅增加（Childress等，1999）。它的目标是将这些功能修饰与改变的分子底物相关联，以鉴定治疗干预的新型潜在靶标。急性和慢性药物暴露后，对PFC提供输入和输出的PFC和区域的检查暗示谷氨酸神经传递的变化是上瘾大脑的关键因素（McFarland和Kalivas，2003）。在停止可卡因自我给药后一个月的大鼠中，已经报道了在伏伏核和PFC中分支和畸形的树突状棘的增加（Robinson等，2001），但是尚未阐明这些反应的分子级联。这项研究将检查一组树突状mRNA，通过对PFC中基因表达谱的分析鉴定，这可能会导致在可卡因弃戒时PFC中药物诱导的突触可塑性。这些候选基因，包括Staufen 2和Spinophilin，可能是突触时长期持久的身体修饰的基础。这些研究的总体目的是洞悉可能针对预防药物滥用和复发的新型治疗机会的潜在机制。这项研究与公共卫生的相关性是进一步了解成瘾中大脑中发生的变化。知道即使在药物不再存在之后，也知道药物的长期影响如何在系统中盖章，这可能有助于产生新的策略来制定治疗方法以防止药物滥用。