Partial mGlu5 Negative Allosteric Modulators to Prevent Relapse to Cocaine Abuse

部分 mGlu5 负变构调节剂可防止可卡因滥用复发

• 批准号: 10002210
• 负责人: Robert Warren Gould
• 金额: $ 24.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002210
• 关键词: Abstinence; Addictive Behavior; Adverse effects; Affect; Anti-Anxiety Agents; Antidepressive Agents; Architecture; Area; Arousal; Attention; Attenuated; Behavior; Behavioral; Behavioral Model; Biological Markers; Brain; Chemicals; Clinic; Clinical; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Cognitive; Collaborations; Complement; Cues; Decision Making; Development; Development Plans; Discrimination; Disease; Dose; Dose-Limiting; Drug usage; Electroencephalography; Environmental Risk Factor; Exhibits; FDA approved; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; GRM5 gene; Glutamates; Goals; Impaired cognition; Impairment; In Vitro; Laboratory Research; Ligands; Link; Measures; Medial; Mediating; Metabotropic Glutamate Receptors; Methodology; Microdialysis; Mission; Modeling; Motivation; National Institute of Drug Abuse; Nature; Neurobiology; Neurosciences; Nucleus Accumbens; Outcome Study; Pharmacological Treatment; Pharmacotherapy; Phase; Pre-Clinical Model; Prefrontal Cortex; Process; Rattus; Recording of previous events; Regimen; Relapse; Reporting; Research; Research Personnel; Rest; Rewards; Rodent; Running; Sedation procedure; Self Administration; Short-Term Memory; Signal Transduction; Sleep; Sleep disturbances; Synaptic plasticity; Techniques; Testing; Therapeutic; Therapeutic Index; Training; Translational Research; Ventral Tegmental Area; addiction; awake; behavioral pharmacology; blood oxygen level dependent; chemical synthesis; cocaine exposure; cocaine relapse; cocaine relapse prevention; cohesion; comorbidity; disorder later incidence prevention; drug discovery; environmental enrichment for laboratory animals; extracellular; glutamatergic signaling; human imaging; imaging study; in vivo; indexing; innovation; neurobiological mechanism; neurochemistry; neuropsychiatric disorder; nonhuman primate; novel; novel therapeutics; preclinical study; research and development; response; side effect; skills; symptomatology; treatment response

PROJECT SUMMARY/ABSTRACT Cocaine abuse, for which there are no FDA-approved pharmacological treatments, is associated with long- term neurobiological and functional alterations underlying decreased affect/motivation, impaired decision- making, sleep disturbances, and an exaggerated response to cocaine-related cues that are associated with high rates of relapse. Human imaging studies report a state of “hypofrontality” (e.g. reduced blood oxygen level dependent [BOLD] activation in the prefrontal cortex [PFC] in response to cognitive challenge), yet increased response (e.g. increased BOLD response) to cocaine-related cues in abstinent cocaine users. Preclinical studies provide evidence that altered mesocorticostriatal glutamatergic (Glu) signaling underlies some of these changes. For example, increased glutamate-mediated synaptic plasticity in the PFC, NAc and ventral tegmental area (VTA) are present following extended cocaine self-administration (SA). Exposure to cocaine- related cues increases Glu (via cortico-accumbal) and DA concentrations (via cortico-VTA driven DA release) in the NAc and attenuating these enhanced responses in the NAc represents a promising avenue for relapse prevention. Inhibiting Glu function via negative allosteric modulation (NAM) of the metabotropic glutamate (mGlu) receptor subtype, mGlu5 attenuates cocaine self-administration (SA) and cue-induced reinstatement of cocaine-seeking behavior in rodents and nonhuman primates. The overall goals of the proposed studies are to 1) understand functional and neurochemical changes in the PFC and NAc in awake rats at rest and in response to cocaine-related cues during abstinence following a cocaine self-administration (SA) regimen that models compulsive drug use (6-h long access SA); and 2) test the hypothesis that inhibition of glutamatergic function via mglu5 NAMs will attenuate the behavioral, functional and neurochemical response to cocaine- paired conditioned cues that contribute to relapse. The proposed studies will systematically assess functional and neurochemical changes in the cortico-accumbal circuit related to cue-induced reinstatement (preclinical model of relapse), by utilizing fMRI and microdialysis techniques in awake rats. The studies proposed during the K99 phase of the application will examine the effects of the full mGlu5 NAM VU0409106 on cue-induced reinstatement, cue-induced changes in BOLD response (Aim 1) and on cue- induced changes in Glu and DA concentrations in the PFC and NAc using microdialysis (Aim 2). These studies will provide the applicant with the expertise to independently establish and conduct awake fMRI and microdialysis studies in awake rats. In the studies proposed in Aims 3 and 4 (R00 portion) the applicant will test the hypothesis that newly developed and characterized partial mGlu5 NAMs, compared to full mGlu5 NAMs, will be equally effective in attenuating cue-induced reinstatement and the underlying neurochemical and functional correlates in the PFC and NAc, yet will exhibit a broader therapeutic window. The therapeutic index of full mGlu5 NAMs is limited by adverse side effects, including cognitive impairments and psychotomimetic-like effects. Partial mGlu5 NAMs, represented by M-5MPEP, attenuated cocaine SA and discrimination within a dose range that also produced antidepressant- and anxiolytic-like effects, but in contrast to full mGlu5 NAMs did not induce sedation or potentiate PCP-induced hyperlocomotion. We will examine effects of the partial and full mGlu5 NAMs M-5MPEP and VU0409106 on measures of attention, working memory, arousal and sleep, indices of cocaine-induced disorders during abstinence, to examine broader therapeutic potential or adverse effects. Development of partial mGlu5 NAMs represents an unprecedented opportunity to investigate the ability of these ligands to mitigate multiple behavioral components that are associated with cocaine relapse. Furthermore, these studies directly align with NIDA's mission to conduct translational research examining environmental factors that influence the neurobiological mechanisms contributing to addictive behaviors and exploring novel pharmacological treatment approaches. As recently highlighted by Dr. Volkow and colleagues, developing translational biomarkers that can identify disease symptomatology, trajectory or treatment response is integral for developing treatments for relapse prevention (ACS Chem Neurosci 2015). The proposed studies integrate two such translational measures of CNS function. The proposed studies align with the long-term goals of the applicant in developing a successful independent research laboratory integrating highly translational behavioral and functional assessments with the skill set to understand underlying circuitry and neurochemistry. The outcome of these studies will undoubtedly provide compelling support for multiple avenues of research directly pursuing cocaine addiction studies and provide the foundation for researching neuropsychiatric disorders comorbid with addiction. The research and development plan outlines a cohesive strategy to meet these long-term goals as well as the short-term goals of training in functional imaging and to strengthen the neuroscience background for the applicant, to complement the strong behavioral pharmacology background and established EEG methodology. The collaborative nature and extensive expertise across multiple areas spanning chemical synthesis, in vitro and in vivo assessments, drug discovery efforts and clinical collaborations provides an enriching environment to develop a well-rounded principle investigator with the skills to run a highly productive and innovative independent research laboratory.

项目概要/摘要 可卡因滥用（尚无 FDA 批准的药物治疗方法）与长期 术语神经生物学和功能改变导致情感/动机下降、决策受损 制造、睡眠障碍以及对可卡因相关线索的过度反应 人类影像学研究报告了“额叶功能低下”的状态（例如血氧水平降低）。 前额皮质 [PFC] 中响应认知挑战的依赖性 [BOLD] 激活），但增加 临床前戒断可卡因使用者对可卡因相关线索的反应（例如增加 BOLD 反应）。 研究提供的证据表明，中皮质纹状体谷氨酸（Glu）信号的改变是其中一些的基础 例如，PFC、NAc 和腹侧谷氨酸介导的突触可塑性增加。 长期自我施用可卡因 (SA) 后会出现被盖区 (VTA)。 相关线索增加 Glu（通过皮质累积）和 DA 浓度（通过皮质 VTA 驱动的 DA 释放） 在 NAc 中并减弱 NAc 中这些增强的反应代表了复发的有希望的途径 通过代谢型谷氨酸的负变构调节 (NAM) 抑制 Glu 功能。 (mGlu) 受体亚型，mGlu5 减弱可卡因自我给药 (SA) 和提示诱导的恢复 啮齿动物和非人类灵长类动物的可卡因寻求行为拟议研究的总体目标是 1) 了解清醒大鼠在休息和休息时 PFC 和 NAc 的功能和神经化学变化 在可卡因自我给药（SA）方案后戒断期间对可卡因相关线索的反应 建立强迫性药物使用模型（6 小时长接触 SA）；2) 检验谷氨酸能抑制的假设 通过 mglu5 NAM 的功能将减弱对可卡因的行为、功能和神经化学反应 拟议的研究将系统地评估功能性的成对条件线索。 和与提示诱导恢复相关的皮质累积回路中的神经化学变化（临床前 复发模型），通过在清醒的大鼠中利用功能磁共振成像和微透析技术。 在申请的 K99 阶段提出的研究将检查完整 mGlu5 的效果 NAM VU0409106 关于提示诱导的恢复、提示诱导的 BOLD 反应变化（目标 1）以及提示- 使用微透析诱导 PFC 和 NAc 中 Glu 和 DA 浓度的变化（目标 2）。 将为申请人提供独立建立和进行清醒功能磁共振成像的专业知识， 在目标 3 和 4（R00 部分）中提出的研究中，申请人将进行测试。 假设与完整的 mGlu5 NAM 相比，新开发和表征的部分 mGlu5 NAM 将 在减弱线索诱导的恢复以及潜在的神经化学和功能方面同样有效 与 PFC 和 NAc 相关，但将表现出更广泛的治疗指数。 mGlu5 NAM 受到不良副作用的限制，包括认知障碍和拟精神病样 以 M-5MPEP 为代表的部分 mGlu5 NAM，可减弱可卡因 SA 和体内歧视。 剂量范围也产生抗抑郁和抗焦虑样作用，但与全 mGlu5 NAM 不同 不会引起镇静或增强 PCP 引起的过度运动。我们将检查部分和 完整的 mGlu5 NAM M-5MPEP 和 VU0409106，用于测量注意力、工作记忆、觉醒和睡眠， 戒断期间可卡因引起的疾病指数，以检查更广泛的治疗潜力或不良反应 部分 mGlu5 NAM 的开发为研究这种能力提供了前所未有的机会。 这些配体可以减轻与可卡因复发相关的多种行为成分。 此外，这些研究直接符合 NIDA 的使命，即进行转化研究检查 影响导致成瘾行为的神经生物学机制的环境因素和 正如 Volkow 博士及其同事最近强调的那样，探索新的药物治疗方法。 开发可识别疾病症状、轨迹或治疗反应的转化生物标志物 对于开发预防复发的治疗方法至关重要（ACS Chem Neurosci 2015）。 整合中枢神经系统功能的两种此类转化测量。 拟议的研究符合申请人开发成功的长期目标 独立研究实验室，将高度转化的行为和功能评估与 了解基础电路和神经化学的技能将成为这些研究的结果。 无疑为直接追求可卡因成瘾的多种研究途径提供了令人信服的支持 研究并为研究与成瘾共存的神经精神疾病提供基础。 研究和开发计划概述了实现这些长期目标以及 功能成像培训的短期目标，并加强神经科学背景 申请人，以补充强大的行为药理学背景和已建立的脑电图方法。 跨化学合成、体外等多个领域的协作性质和广泛的专业知识 体内评估、药物发现工作和临床合作提供了一个丰富的环境 培养一名全面的首席研究员，具备运行高生产力和创新能力的技能 独立研究实验室。