Homer-mediated signaling and cocaine addiction

荷马介导的信号传导和可卡因成瘾

• 批准号: 8274891
• 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/8274891
• 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; abstracting; 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

Abstract/Project Summary 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.

摘要/项目摘要 重复可卡因暴露诱导中皮质边缘谷氨酸持续性适应不良变化 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调节中皮质边缘谷氨酸传递的那些。来 在过去的5年里，Homer家族的突触后支架蛋白已经成为一个关键的调节因子， 可卡因诱导的中皮质边缘谷氨酸和行为的变化可能与 成瘾标志性特征的分子基础，如复发。Homer 1多态性是 与人类可卡因成瘾和重复服用可卡因显著相关，包括 过量的可卡因自我给药，改变中皮质边缘Homer mRNA和蛋白质表达。 行为遗传学研究表明，可卡因诱导的前额叶皮层（PFC）Homer 2蛋白的增加， 水平是足够的，而降低核内转录因子（NAC）Homer 2蛋白水平是必要的， 足够的，可卡因寻求行为的表达，如使用位置偏好范式评估。 该项目将通过对可卡因诱导的神经元的作用进行功能检查来扩展这些早期数据。 在可卡因作用下，背侧和腹侧PFC-NAC谷氨酸投射内Homer 2表达的变化， 配对线索诱导的药物寻求和相关的变化，在NAC谷氨酸的立即，中间或 长期戒断过量（40-60+ mg/kg/天）可卡因摄入。基于我们之前 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毒品加剧的基础。具体目标1 该提案将采用免疫印迹和体内微透析来测试特定的假设，即时间- 在从过量可卡因自我给药中戒断期间， 与PFC的时间依赖性增加和NAC Homer介导的信号通路的减少相关 在背侧中皮质边缘回路内，导致异常的中皮质边缘谷氨酸释放。具体 目的2将采用定点病毒介导的基因传递来检查 在可卡因的PFC-NAC预测中增强和预防可卡因诱导的Homer 2变化- 配对线索诱导的药物寻求和NAC谷氨酸传输。预计所获得的结果 将大大增加我们对Homer 2在调节兴奋性谷氨酸传递中的作用的理解 在腹侧和背侧中皮质边缘亚回路内，因为它与复发的时间依赖性增加有关 易损性.这些知识将指向可卡因诱导的Homer 2调节的改变， PFC-NAC谷氨酸传递的突触后方面作为调节神经细胞的关键神经适应， 在长期戒断期间复发的倾向，这与理解成瘾具有高度相关性 神经病理学及其用谷氨酸靶向药物疗法的治疗。

项目成果

Incubation of cocaine-craving relates to glutamate over-flow within ventromedial prefrontal cortex.

• DOI: 10.1016/j.neuropharm.2015.10.038
• 发表时间: 2016-03
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Shin CB;Serchia MM;Shahin JR;Ruppert-Majer MA;Kippin TE;Szumlinski KK
• 通讯作者: Szumlinski KK

The motivational valence of methamphetamine relates inversely to subsequent methamphetamine self-administration in female C57BL/6J mice.

• DOI: 10.1016/j.bbr.2020.112959
• 发表时间: 2021-02-01
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Shab G;Fultz EK;Page A;Coelho MA;Brewin LW;Stailey N;Brown CN;Bryant CD;Kippin TE;Szumlinski KK
• 通讯作者: Szumlinski KK

Kinase interest you in treating incubated cocaine-craving? A hypothetical model for treatment intervention during protracted withdrawal from cocaine.

• DOI: 10.1111/gbb.12440
• 发表时间: 2018-03
• 期刊: Genes, brain, and behavior
• 作者: Szumlinski KK;Shin CB
• 通讯作者: Shin CB

Endogenous glutamate within the prelimbic and infralimbic cortices regulates the incubation of cocaine-seeking in rats.

内核和输液性皮质中的内源性谷氨酸调节大鼠可卡因寻求可卡因的孵化。

• DOI: 10.1016/j.neuropharm.2017.10.024
• 发表时间: 2018-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Shin CB;Templeton TJ;Chiu AS;Kim J;Gable ES;Vieira PA;Kippin TE;Szumlinski KK
• 通讯作者: Szumlinski KK

Prolonged-access to cocaine induces distinct Homer2 DNA methylation, hydroxymethylation, and transcriptional profiles in the dorsomedial prefrontal cortex of Male Sprague-Dawley rats.

• DOI: 10.1016/j.neuropharm.2018.09.029
• 发表时间: 2018-12
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Ploense KL;Li X;Baker-Andresen D;Carr AE;Woodward N;Bagley J;Szumlinski KK;Bredy TW;Kippin TE
• 通讯作者: Kippin TE