Homer-mediated signaling and cocaine addiction

荷马介导的信号传导和可卡因成瘾

• 批准号: 7591439
• 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/7591439
• 关键词: Address; Animal Model; Behavior; Behavioral; Behavioral Genetics; Biochemical; Brain; Brain region; Cocaine; Cocaine Dependence; Condition; 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; Synapses; Testing; Time; Training; Treatment Protocols; Treatment outcome; Viral; Virus; Withdrawal; addiction; base; behavioral sensitization; craving; day; drug seeking behavior; in vivo; inositol-1,4,5-triphosphate receptor; insight; neuroadaptation; neurochemistry; neurogenetics; neuropathology; novel therapeutics; preference; prevent; protein expression; receptor; therapeutic target; 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）：反复接触可卡因会导致中皮质边缘谷氨酸传输发生持续的、适应不良的变化，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候选分子是那些调节中皮质边缘谷氨酸传递的分子。在过去的五年里，突触后支架蛋白的 Homer 家族已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标志性特征（例如复发）的分子基础相关。 Homer1 多态性与人类可卡因成瘾显着相关，重复服用可卡因（包括过量自我服用可卡因）会改变中皮质边缘 Homer mRNA 和蛋白质表达。行为遗传学研究表明，可卡因诱导的前额皮质 (PFC) Homer2 蛋白水平的增加就足够了，而伏隔核 (NAC) Homer2 蛋白水平的降低对于可卡因寻求行为的表达既是必要的也是充分的，如使用地点偏好范式进行评估。该项目将通过对可卡因诱导的背侧和腹侧 PFC-NAC 谷氨酸预测中 Homer2 表达变化的作用进行功能检查来扩展这些早期数据，这些变化对可卡因配对提示诱导的药物寻找以及 NAC 谷氨酸的相关变化在立即、从过量（40-60+毫克/公斤/天）可卡因摄入期间中度或长期戒断。根据我们之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会导致 PFC 随时间增加，并导致 NAC mGluR-Homer 信号通路减少，从而导致长期戒断期间药物寻求加剧。该提案的具体目标 1 将采用免疫印迹和体内微透析来检验特定假设，即在过量可卡因自我给药戒断期间可卡因寻求的时间依赖性强化与 PFC 的时间依赖性增加和 NAC Homer 的减少相关背侧皮质边缘回路内介导的信号通路，导致皮质边缘谷氨酸释放异常。具体目标 2 将采用定点病毒介导的基因传递来检查在 PFC-NAC 预测内增强和防止可卡因诱导的 Homer2 变化对可卡因配对线索诱导的药物寻找和 NAC 谷氨酸传输的功能后果。预计所获得的结果将极大地增加我们对 Homer2 在调节腹侧和背侧皮质边缘亚回路内兴奋性谷氨酸传输中的作用的理解，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引起的 Homer2 对 PFC-NAC 谷氨酸传输的突触前和突触后方面的调节的改变，作为调节长期戒断期间复发倾向的关键神经适应，这对于理解成瘾神经病理学及其治疗具有高度相关性谷氨酸靶向药物疗法。重复给予可卡因会引起背侧和腹侧皮质边缘亚回路内兴奋性神经递质谷氨酸的持续性、适应不良的变化，这些神经适应是可卡因戒断期间容易复发的核心。因此，了解过量可卡因摄入对中皮质边缘谷氨酸传输的长期影响所涉及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“高危”个体或预测个体治疗结果。为此，该项目将结合行为、神经化学、遗传和免疫学方法来研究背侧和腹侧皮质边缘亚回路内 Homer2 介导的信号通路在长期戒断过量可卡因期间观察到的可卡因寻求加剧中的作用自我管理。