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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要可卡因滥用，没有FDA批准的药物治疗，与长期有关术语神经生物学和功能变化的影响减少了影响/动机，决策受损与可卡因相关的提示进行制作，睡眠障碍以及夸张的反应继电器率高。人类成像研究报告了“低纤维性”状态（例如，血液氧降低在响应认知挑战时，前额叶皮层[PFC]中的依赖[BOLD]激活），但增加了避免可卡因用户中与可卡因相关的提示的响应（例如增加了大胆响应）。临床前研究提供了改变中皮质纹状体谷氨酸能（GLU）信号传导的证据。更改。例如，PFC，NAC和腹侧的谷氨酸介导的合成可塑性增加延长可卡因自我管理（SA）之后，对段面积（VTA）存在。暴露于可卡因 - 相关线索增加了GLU（通过皮质辅助）和DA浓度（通过Cortico-VTA驱动DA释放）在NAC中，NAC中的这些增强的反应是一种有希望的救济途径预防。通过代谢性谷氨酸的负变构调制（NAM）抑制GLU功能（mglu）受体亚型，mglu5减弱可卡因自我给药（SA）和提示诱导的恢复原状啮齿动物和非人类隐私的寻求可卡因行为。拟议研究的总体目标是 1）了解静止和静止大鼠的PFC和NAC的功能和神经化学变化可卡因自我管理（SA）方案后，对可卡因相关的提示的反应强迫毒品使用（6小时长的访问SA）； 2）检验抑制谷氨酸能的假设通过MGLU5 NAM的功能将减弱对可卡因的行为，功能和神经化学反应有助于继电器的配对条件提示。拟议的研究将系统地评估功能与提示诱导的恢复（临床前）有关的皮质辅助电路的神经化学变化退休模型），通过在清醒大鼠中使用fMRI和微透析技术。在应用程序的K99阶段提出的研究将检查完整MGLU5的影响 NAM VU0409106在提示引起的恢复，提示引起的大胆响应变化（AIM 1）和提示上的变化使用微透析（AIM 2），PFC和NAC中GLU和DA浓度的诱导变化。这些研究将向申请人提供专业知识，以独立建立和进行清醒的fMRI和清醒大鼠的微透析研究。在目标3和4（r00部分）中提出的研究中，申请人将测试与完整的MGLU5 NAM相比，新开发和表征部分MGLU5 NAM的假设将同样有效地衰减提示引起的恢复和基础神经化学和功能在PFC和NAC中相关，但将退出更广泛的治疗窗口。完整的理论索引 MGLU5 NAMS受到不利副作用的限制，包括认知障碍和类似精神的副作用效果。部分MGLU5 NAM，由M-5MPEP代表，可卡因SA衰减和歧视剂量范围也产生了抗抑郁药和抗焦虑样作用，但与完整的MGLU5 NAM相反不影响镇静或潜在的PCP诱导的超塑料。我们将研究部分的影响完整的MGLU5 NAMS M-5MPEP和VU0409106关于注意，工作记忆，唤醒和睡眠的测量可卡因诱导的戒酒期间的指标，以检查更广泛的治疗潜力或不良的疾病效果。部分MGLU5 NAMS的开发代表了调查能力的前所未有的机会这些配体以减轻与可卡因继电器相关的多种行为成分。此外，这些研究直接与NIDA进行转化研究考试的使命保持一致影响神经生物学机制的环境因素，导致加性行为和探索新型的药理治疗方法。最近由Volkow博士及其同事强调的那样开发可以识别疾病症状，轨迹或治疗反应的转化生物标志物是开发预防救济治疗方法不可或缺的一部分（ACS Chem Neurosci 2015）。提出的研究集成了CNS功能的两个这样的翻译测量。拟议的研究与申请人的长期目标保持一致独立研究实验室将高度翻译的行为和功能评估与了解基础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令人信服的支持研究并为研究神经精神疾病的合并症提供了基础。这研发计划概述了一个凝聚力的策略，以实现这些长期目标以及功能成像中训练的短期目标，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脑电图方法。跨越化学合成的多个领域的协作性质和广泛的专业知识，体外以及体内评估，药物发现工作和临床合作提供了丰富的环境为了开发一个全面的主要调查员独立研究实验室。