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: 10227987
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227987
• 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; cocaine self-administration; 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.

项目总结/摘要 可卡因滥用，没有FDA批准的药物治疗，与长期- 长期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夸大反应， 复发率高。人体成像研究报告了“前额叶功能减退”的状态（例如，血氧水平降低 前额叶皮层（PFC）对认知挑战的依赖性（BOLD）激活），但增加 反应（例如增加BOLD反应）可卡因相关线索在禁欲可卡因用户。临床前 研究提供了证据表明，改变的中皮质纹状体谷氨酸能（Glu）信号转导是其中一些的基础。 变化例如，在PFC，NAc和腹侧皮层中谷氨酸介导的突触可塑性增加， 被盖区（VTA）是存在延长可卡因自我管理（SA）。接触可卡因- 相关线索增加Glu（通过皮质-VTA）和DA浓度（通过皮质-VTA驱动的DA释放） 减弱NAc中这些增强的反应代表了一种有希望的复发途径 预防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，mGlu 5减弱可卡因自我给药（SA）和线索诱导的恢复， 啮齿动物和非人类灵长类的可卡因寻找行为。拟议研究的总体目标是 1)了解清醒大鼠在休息时PFC和NAc的功能和神经化学变化， 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， 模型强迫性药物使用（6小时长的访问SA）;和2）测试的假设，抑制多巴胺能 通过mglu 5 NAM的功能将减弱对可卡因的行为、功能和神经化学反应， 导致复发的成对条件暗示。拟议的研究将系统地评估功能 与线索诱导的恢复相关的皮质-肾上腺回路中的神经化学变化（临床前 复发模型），通过利用清醒大鼠的fMRI和微透析技术。 在申请的K99阶段期间提出的研究将检查完整mGlu 5 NAM VU 0409106对提示诱导的恢复、提示诱导的BOLD反应变化（目标1）和提示- 使用微透析诱导PFC和NAc中Glu和DA浓度的变化（目的2）。这些研究 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， 清醒大鼠的微透析研究。在目标3和4（R 00部分）中拟定的研究中，申请方将测试 假设新开发和表征的部分mGlu 5 NAM与完整mGlu 5 NAM相比， 同样有效地减弱线索诱导的恢复和潜在的神经化学和功能 PFC和NAc的相关性，但将表现出更宽的治疗窗口。治疗指数 mGlu 5 NAMs受到不良副作用的限制，包括认知障碍和拟精神病样 方面的影响.部分mGlu 5 NAMs（由M-5 MPEP表示）减弱了可卡因SA，并在一个受试者中区分。 也产生抗抑郁和抗焦虑样作用的剂量范围，但与全mGlu 5 NAM相反 不诱导镇静或增强PCP诱导的过度运动。我们将研究部分和 完整mGlu 5 NAM M-5 MPEP和VU 0409106对注意力、工作记忆、觉醒和睡眠的测量， 可卡因引起的疾病的指数，以检查更广泛的治疗潜力或不良反应， 方面的影响.部分mGlu 5 NAM的开发代表了研究其能力的前所未有的机会。 这些配体来减轻与可卡因复吸相关的多种行为成分。 此外，这些研究直接与NIDA的使命，进行翻译研究检查 影响成瘾行为神经生物学机制的环境因素， 探索新的药物治疗方法。正如最近由Dr. Baukow和他的同事们所强调的， 开发可以识别疾病病理学、轨迹或治疗反应的翻译生物标志物 是开发预防复发治疗的必要条件（ACS Chem Neurosci 2015）。拟议的研究 整合CNS功能的两种这样的翻译测量。 拟议的研究符合申请人的长期目标， 独立的研究实验室，将高度转化的行为和功能评估与 了解潜在电路和神经化学的技能。这些研究的结果将 无疑为直接追求可卡因成瘾的多种研究途径提供了有力的支持 为研究成瘾共病的神经精神障碍提供了基础。的 研究和发展计划概述了一个连贯的战略，以实现这些长期目标，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既定的EEG方法。 跨多个领域的协作性质和广泛的专业知识，涵盖化学合成，体外 体内评估、药物发现工作和临床合作提供了丰富的环境， 培养一个全面的主要调查员的技能，运行一个高效和创新的 独立研究实验室。