Partial mGlu5 Negative Allosteric Modulators to Prevent Relapse to Cocaine Abuse

项目摘要/摘要 可卡因滥用，目前还没有FDA批准的药物治疗方法，与长期的 情感/动机降低、决策受损的潜在神经生物学和功能改变- 制造、睡眠障碍以及对与可卡因相关的线索的夸大反应 高复发率。人体成像研究报告了一种“额叶下垂”的状态(例如，血氧水平降低 前额叶皮质[PFC]对认知挑战的依赖[大胆]激活)，但增加 戒除可卡因使用者对与可卡因有关的线索的反应(如增加大胆反应)。临床前 研究提供的证据表明，改变的中皮质纹状体谷氨酸(Glu)信号是其中一些信号的基础 改变。例如，在PFC、NAC和腹侧，谷氨酸介导的突触可塑性增加 在延长的可卡因自我给药(SA)后出现被盖区(VTA)。暴露在可卡因中- 相关线索增加谷氨酸(通过皮质-伏隔核)和DA浓度(通过皮质-VTA驱动的DA释放) 在NAC和减弱NAC中这些增强的反应是一种有希望的复发途径 预防。代谢性谷氨酸的负变构调节(NAM)抑制谷氨酸功能 (MGlu)受体亚型mGlu5减弱可卡因自身给药(SA)和线索诱导的恢复 啮齿动物和非人灵长类动物的可卡因寻觅行为。拟议研究的总体目标是 1)了解清醒大鼠安静状态和睡眠状态下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 模型强迫药物使用(6小时长访问SA)；以及2)检验谷氨酸能抑制的假设 通过mGlu5 NAMS的功能将减弱可卡因的行为、功能和神经化学反应- 成对的条件性线索，有助于复发。拟议的研究将系统地评估功能 以及与线索诱导的恢复相关的皮质-伏隔回路的神经化学变化(临床前 通过利用功能磁共振成像和微透析技术在清醒大鼠中建立复发模型。 在K99应用阶段提出的研究将检验完整mGlu5的效果 NAM VU0409106关于线索诱导的恢复、线索诱导的大胆反应的变化(目标1)和关于线索- 微透析诱导PFC和NAC中Glu和DA浓度的变化(目标2)。这些研究 将为申请人提供独立建立和进行觉醒功能磁共振成像和 清醒大鼠的微透析研究。在AIMS 3和4(R00部分)中提出的研究中，申请人将测试 新开发和表征的部分mGlu5NAMS与完整的mGlu5NAMS相比，将 在减弱线索诱导的恢复和潜在的神经化学和功能方面同样有效 在PFC和NAC中相关，但将显示出更广泛的治疗窗口。FULL的治疗指数 MGlu5 NAMS受到不良副作用的限制，包括认知障碍和类精神分裂 效果。以M-5MPEP为代表的部分mGlu5 NAMS，减毒可卡因SA和在 剂量范围也产生抗抑郁和缓解焦虑的效果，但与完整的mGlu5 NAMS形成对比 不能诱导镇静，也不能增强PCP诱导的多动。我们将研究部分和 完整的mGlu5 NAMS M-5MPEP和VU0409106关于注意力、工作记忆、唤醒和睡眠的测量， 戒毒期间可卡因引起的障碍的指标，以检查更广泛的治疗潜力或不良反应 效果。部分mGlu5NAMS的发展为研究这种能力提供了一个前所未有的机会 以减轻与可卡因复发有关的多个行为成分。 此外，这些研究直接与NIDA的使命保持一致，即进行翻译研究 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。正如沃尔科博士和他的同事最近强调的那样， 开发可识别疾病症状、轨迹或治疗反应的翻译生物标记物 对于开发预防复发的治疗方法是不可或缺的(ACS Chem Neurosci 2015)。建议进行的研究 整合CNS功能的两个这样的翻译度量。 建议的研究与申请者在制定成功的 独立研究实验室，将高度翻译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 无疑为直接追踪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障碍提供基础。这个 研究和开发计划概述了实现这些长期目标的连贯战略以及 功能成像培训的短期目标和加强神经科学背景 申请人，以补充强大的行为药理学背景和建立的脑电方法学。 跨多个领域的协作性质和广泛的专业知识，跨越体外化学合成 体内评估、药物发现努力和临床合作提供了一个丰富的环境 培养一名全面发展的首席调查员，具备运行高效和创新的 独立研究实验室。

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.