Homer-mediated signaling and cocaine addiction

荷马介导的信号传导和可卡因成瘾

• 批准号: 7686941
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686941
• 关键词: Address; Animal Model; Behavior; Behavioral; Behavioral Genetics; Biochemical; Brain; Brain region; Cocaine; Cocaine Dependence; Cues; Data; Development; Dorsal; Drug Addiction; Drug Exposure; Family; Funding; Gene Delivery; Gene Targeting; Genetic; Genetic Polymorphism; Glutamates; Goals; Homer protein; Human; Immunoblotting; Immunologic Techniques; Individual; Injection of therapeutic agent; Intake; Knowledge; Laboratories; Lipase; Mediating; Messenger RNA; Microdialysis; Molecular; Neurobiology; Neuronal Plasticity; Neurotransmitters; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphatidylinositols; Phospholipase; Phosphotransferases; Prefrontal Cortex; Process; Proteins; Regulation; Relapse; Request for Proposals; Risk; Role; Scaffolding Protein; Screening procedure; Self Administration; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Site; Testing; Time; Training; Treatment Protocols; Treatment outcome; Viral; Virus; Withdrawal; addiction; base; behavioral sensitization; cocaine exposure; craving; drug seeking behavior; in vivo; insight; neuroadaptation; neurochemistry; neurogenetics; neuropathology; new therapeutic target; phosphatidylinositol receptor; preference; prevent; protein expression; receptor; transmission process

DESCRIPTION (provided by applicant): Repeated cocaine exposure induces persistent, maladaptive changes in mesocorticolimbic glutamate transmission that are central to an addicted phenotype. Thus, likely molecular candidates contributing to the neuropathology of cocaine addiction are those regulating mesocorticolimbic glutamate transmission. Over the past 5 years, the Homer family of post-synaptic scaffolding proteins has emerged as a critical regulator of cocaine-induced changes in mesocorticolimbic glutamate and behavior that likely have relevance for the molecular underpinnings of hallmark features of addiction, such as relapse. A Homer1 polymorphism is significantly associated with cocaine addiction in humans and repeated cocaine administration, including excessive cocaine self-administration, alters mesocorticolimbic Homer mRNA and protein expression. Behavioral genetic studies indicated that a cocaine-induced increase in prefrontal cortex (PFC) Homer2 protein levels is sufficient, while a reduction in nucleus accumbens (NAC) Homer2 protein levels is both necessary and sufficient, for the expression of cocaine-seeking behavior, as assessed using place-preference paradigms. This project will extend these earlier data through a functional examination of the role for cocaine-induced changes in Homer2 expression within the dorsal and ventral PFC-NAC glutamate projections upon cocaine- paired cue-induced drug-seeking and associated changes in NAC glutamate during immediate, intermediate or protracted withdrawal from a period of excessive (40-60+ mg/kg/day) cocaine intake. Based on our previous immunoblotting and behavioral neurogenetics data, it is hypothesized that that excessive cocaine intake produces a time-dependent increase in PFC and decrease in NAC mGluR-Homer signaling pathways that underlie the intensification of drug-seeking during protracted withdrawal. Specific Aim 1 of this proposal will employ immunoblotting and in vivo microdialysis to test the specific hypothesis that the time- dependent intensification of cocaine-seeking during withdrawal from excessive cocaine self-administration is associated with time-dependent increases in PFC and decreases in NAC Homer-mediated signaling pathways within the dorsal mesocorticolimbic circuit, resulting in abnormal mesocorticolimbic glutamate release. Specific Aim 2 will employ site-directed viral-mediated gene delivery to examine the functional consequences of augmenting and preventing cocaine-induced changes in Homer2 within PFC-NAC projections for cocaine- paired cue-induced drug-seeking and NAC glutamate transmission. It is anticipated that the results obtained will greatly increase our understanding of the role for Homer2 in regulating excitatory glutamate transmission within the ventral and dorsal mesocorticolimbic subcircuits as it relates to time-dependent increases in relapse vulnerability. Such knowledge will point to cocaine-induced alterations in Homer2 regulation of both pre- and post-synaptic aspects of PFC-NAC glutamate transmission as critical neuroadaptations regulating the propensity to relapse during protracted withdrawal, which has high relevance for understanding addiction neuropathology and its treatment with glutamate-targeting pharmacotherapies. Repeated cocaine administration induces persistent, maladaptive changes in the excitatory neurotransmitter glutamate within the dorsal and ventral mesocorticolimbic subcircuits and these neuroadaptations are central to relapse vulnerability during cocaine withdrawal. Thus, an understanding of the molecular mechanisms involved in the protracted effects of excessive cocaine intake upon mesocorticolimbic glutamate transmission will assist in the identification of novel therapeutic targets for the treatment of addiction, as well as assist in screening "at risk" individuals or predicting individual treatment outcomes. To this end, this project will employ a combination of behavioral, neurochemical, genetic and immunological approaches to examine the role for Homer2-mediated signaling pathways within the dorsal and ventral mesocorticolimbic subcircuits in the intensification of cocaine-seeking observed during protracted withdrawal from excessive cocaine self- administration.

描述（由申请方提供）：重复可卡因暴露诱导中皮质边缘谷氨酸传递的持续性适应不良变化，这些变化是成瘾表型的核心。因此，可能的分子候选人有助于可卡因成瘾的神经病理学是那些调节中皮质边缘谷氨酸传递。在过去的5年中，Homer家族的突触后支架蛋白已经成为可卡因诱导的中皮质边缘谷氨酸变化和行为的关键调节因子，这些变化可能与成瘾的标志性特征的分子基础有关，例如复发。Homer 1多态性与人类可卡因成瘾显著相关，重复可卡因给药，包括过量的可卡因自我给药，改变了中皮质边缘Homer mRNA和蛋白质表达。行为遗传学研究表明，可卡因诱导的前额叶皮层（PFC）Homer 2蛋白水平的增加是足够的，而减少核内（NAC）Homer 2蛋白水平是必要的和足够的，可卡因寻求行为的表达，使用位置偏好范式进行评估。该项目将通过对可卡因诱导的Homer 2表达变化在可卡因配对线索诱导的药物寻求后的背侧和腹侧PFC-NAC谷氨酸投射中的作用以及在从过量（40-60+ mg/kg/天）可卡因摄入期立即、中期或长期戒断期间NAC谷氨酸的相关变化的功能检查来扩展这些早期数据。基于我们先前的免疫印迹和行为神经遗传学数据，假设过量的可卡因摄入产生PFC的时间依赖性增加和NAC mGluR-Homer信号通路的减少，这是长期戒断期间寻求药物的强化的基础。本提案的具体目标1将采用免疫印迹和体内微透析来测试特定假设，即过量可卡因自我给药戒断期间可卡因寻求的时间依赖性增强与PFC的时间依赖性增加和背侧中皮质边缘回路内NAC Homer介导的信号传导途径的减少相关，导致异常中皮质边缘谷氨酸释放。具体目标2将采用定点病毒介导的基因递送来检查增加和预防PFC-NAC投射内可卡因诱导的Homer 2变化的功能后果，用于可卡因配对线索诱导的药物寻求和NAC谷氨酸传递。预计所获得的结果将大大增加我们对Homer 2在调节腹侧和背侧中皮层边缘亚回路内兴奋性谷氨酸传输中的作用的理解，因为它涉及复发脆弱性的时间依赖性增加。这些知识将指向可卡因诱导的Homer 2调节PFC-NAC谷氨酸传递的突触前和突触后方面的改变，作为调节长期戒断期间复发倾向的关键神经适应，这与理解成瘾神经病理学及其谷氨酸靶向药物治疗具有高度相关性。重复可卡因给药诱导持续的，适应不良的变化，兴奋性神经递质谷氨酸在背侧和腹侧mesocorticolimbic子电路和这些神经适应是中央可卡因戒断期间复发的脆弱性。因此，对过量可卡因摄入对中皮质边缘谷氨酸传递的长期影响所涉及的分子机制的理解将有助于确定用于治疗成瘾的新的治疗靶点，以及有助于筛选“有风险”的个体或预测个体治疗结果。为此，该项目将采用行为，神经化学，遗传和免疫学方法的组合来检查Homer 2介导的信号通路在背侧和腹侧中皮质边缘亚回路中的作用，在从过量可卡因自我给药的长期戒断期间观察到的可卡因寻求的强化。