Homer-mediated signaling and cocaine addiction

荷马介导的信号传导和可卡因成瘾

• 批准号: 8078935
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 29.1万
• 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/8078935
• 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; Microdialysis; Molecular; Neurobiology; Neuronal Plasticity; Neurotransmitters; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphatidylinositols; Phospholipase; Phosphotransferases; Prefrontal Cortex; Process; Proteins; Regimen; Regulation; Relapse; Request for Proposals; Risk; Role; Scaffolding Protein; Screening procedure; Self Administration; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Site; Synapses; Testing; Time; Training; Treatment outcome; Viral; Virus; Withdrawal; addiction; base; behavioral sensitization; cocaine exposure; craving; drug seeking behavior; in vivo; insight; mRNA Expression; 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（由申请人提供）：重复的可卡因暴露会引起中型谷氨酸谷氨酸传播的持续性，不良适应性变化，这是上瘾表型的核心。因此，可能导致可卡因成瘾神经病理学的分子候选者是调节中皮质糖谷氨酸传播的分子候选者。在过去的五年中，荷马家族的突触后脚手架蛋白家族已成为可卡因诱导的中皮质糖谷氨酸的变化的关键调节剂，并且可能与成瘾的标志特征的分子基础相关，例如成瘾的人（例如复发）。 HOMER1多态性与人类可卡因成瘾显着相关，并反复使用可卡因，包括过度可卡因自我给药，改变了中皮质胶质的Homer mRNA和蛋白质表达。行为遗传研究表明，可卡因诱导的前额叶皮层（PFC）HOMER2蛋白水平的增加足够，而使用可卡因促进行为的表达，使用占位偏见的范围的表达既是必要且足够的HOMER2 HOMER2蛋白水平，既是必要且充分的，则足以表达。该项目将通过对可卡因诱导的HOMER2表达变化的作用来扩展这些早期数据，在背侧和腹侧PFC-NAC谷氨酸谷氨酸谷氨酸谷氨酸投影中对可卡因配对的提示诱导的药物寻求药物和相关的NAC Glutamate的相关变化，直接在中间或中等，中等或proTRACTAIMET或PRTRACTER ADERIPERIVE（40- kg）（40- kg）/kg kg/kg/kg 60- kg/kg。根据我们以前的免疫印迹和行为神经遗传学数据，假设可卡因的摄入过多会产生PFC的时间依赖性增加，而NAC MGlur-Homer信号传导途径的减少是基于戒断过程中药物抢断的强化的基础。该提案的具体目的1将采用免疫印迹和体内微透析来检验以下具体假设：从过度可卡因自我分配中撤出的时间依赖于时间依赖的可卡因寻求可卡因与PFC的时间依赖性增加以及NAC Homer介导的信号介导的室内的含有时间依赖性的增加有关中皮质糖谷氨酸释放异常。具体目标2将采用定位的病毒介导的基因输送来检查增强和防止可卡因诱导的可卡因NAC投影中可卡因的可卡因提示诱导的寻求药物寻求药物和NAC谷氨酸盐传播的功能后果。可以预料，获得的结果将大大增加我们对HOMER2在调节腹侧和背质质体内边缘的兴奋性谷氨酸传播中的作用的理解，因为它与复发脆弱性相关的时间相关的增加。这种知识将指出可卡因诱导的HOMER2调节PFC-NAC谷氨酸传播前和突触后方面的变化，这是关键的神经适应性的关键神经适应性，可以调节持久戒断期间复发的倾向，这在理解粘性神经病理学及其对胶氨酸治疗的治疗中具有很高的相关性。反复的可卡因给药会引起背侧和腹侧中质质体的亚电路内兴奋性神经递质谷氨酸的持续性不良变化，而这些神经适应在可卡因戒断期间对于复发性脆弱性至关重要。因此，对可卡因摄入过度摄入对中皮质糖谷氨酸传播的长期影响的分子机制的理解将有助于鉴定成瘾治疗的新型治疗靶标，并有助于筛查“在风险”个人或预测个体治疗态度的“处于风险”中。为此，该项目将采用行为，神经化学，遗传和免疫学方法的结合，以检查Homer2介导的信号传导途径在背侧和腹腹中皮质上的子循环中的作用，从而在可卡因戒断期间观察到的可卡因促进性的促进性促进性超细胞促进了过多的自我cocaine cocain cocain from frompractive feeking feeking。