Homer-mediated signaling and cocaine addiction

荷马介导的信号传导和可卡因成瘾

• 批准号: 7845577
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 30万
• 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/7845577
• 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; Regimen; 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 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（由申请人提供）：反复的可卡因暴露会导致中皮质边缘谷氨酸传递的持续、不适应变化，这是成瘾表型的核心。因此，可能导致可卡因成瘾神经病理学的分子候选者是那些调节中皮质边缘谷氨酸传递的分子。在过去的5年里，突触后支架蛋白的Homer家族已经成为可卡因诱导的中皮质边缘谷氨酸和行为变化的关键调节器，这些变化可能与成瘾的标志性特征（如复发）的分子基础有关。Homer1多态性与人类可卡因成瘾和反复给药（包括过度自我给药）显著相关，改变中皮质边缘Homer1 mRNA和蛋白的表达。行为遗传学研究表明，可卡因诱导的前额叶皮质（PFC） Homer2蛋白水平的增加是充分的，而伏隔核（NAC） Homer2蛋白水平的降低是充分必要的，用于可卡因寻求行为的表达。该项目将通过功能性检查可卡因诱导的背侧和腹侧PFC-NAC谷氨酸预测中Homer2表达变化的作用，以及在过量（40-60+ mg/kg/天）可卡因摄入后立即、中期或长期戒断期间NAC谷氨酸的相关变化，来扩展这些早期数据。基于我们之前的免疫印迹和行为神经遗传学数据，我们假设过量的可卡因摄入会产生PFC的时间依赖性增加和NAC mGluR-Homer信号通路的减少，这是长期戒断期间药物寻求加剧的基础。本提案的具体目标1将采用免疫印迹和体内微透析来验证特定假设，即在过度可卡因自我给药戒断过程中，可卡因寻求的时间依赖性增强与中脑皮质边缘背侧回路中PFC的时间依赖性增加和NAC - homr介导的信号通路的时间依赖性减少有关，从而导致中脑皮质边缘谷氨酸释放异常。Specific Aim 2将采用位点定向病毒介导的基因传递来检测PFC-NAC预测中增强和预防可卡因诱导的Homer2变化对可卡因配对线索诱导的药物寻找和NAC谷氨酸传递的功能后果。预计获得的结果将大大增加我们对Homer2在调节兴奋性谷氨酸在腹侧和背侧皮质边缘亚回路中的作用的理解，因为它与复发易感性的时间依赖性增加有关。这些知识将指出，可卡因诱导的PFC-NAC谷氨酸传递的突触前和突触后的Homer2调节的改变是调节长期戒断期间复发倾向的关键神经适应性，这与理解成瘾神经病理学及其使用谷氨酸靶向药物治疗具有高度相关性。反复服用可卡因会导致背侧和腹侧皮质边缘亚回路中兴奋性神经递质谷氨酸的持续不适应变化，这些神经适应是可卡因戒断期间复发易感性的核心。因此，了解过量可卡因摄入对中皮质边缘谷氨酸传递的长期影响的分子机制将有助于确定治疗成瘾的新治疗靶点，并有助于筛查“风险”个体或预测个体治疗结果。为此，本项目将采用行为学、神经化学、遗传学和免疫学方法相结合的方法，研究在过度自我服用可卡因的长期戒断过程中，在背侧和腹侧中皮质边缘亚回路中，homer2介导的信号通路在可卡因寻求加剧中所起的作用。