Imaging the antipsychotic actions of metabotropic glutamate receptor-2 activators

代谢型谷氨酸受体 2 激活剂的抗精神病作用成像

• 批准号: 8547111
• 负责人: Nellie Eunjoo Byun
• 金额: $ 37.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547111
• 关键词: Acute; Address; Adverse effects; Affect; Agonist; Amphetamines; Anhedonia; Animal Model; Antipsychotic Agents; Area; Attention; Behavioral; Biological Assay; Biological Markers; Biological Neural Networks; Blood - brain barrier anatomy; Brain; Brain region; Cerebrum; Chemosensitization; Chronic; Clinical; Clinical Data; Clinical Trials; Cognition; Cognitive deficits; Corpus striatum structure; Data; Delusions; Development; Disease; Dopamine; Dopamine D2 Receptor; Evaluation; Functional Imaging; Functional Magnetic Resonance Imaging; Glutamates; Goals; Hallucinations; Image; Imaging Techniques; Individual; Intervention; Ketamine; Knockout Mice; Ligands; Measurement; Mediating; Memory; Memory impairment; Metabolic; Metabotropic Glutamate Receptors; Modeling; Mood Disorders; Motor; N-Methyl-D-Aspartate Receptors; Output; Patients; Phase; Phase II Clinical Trials; Phencyclidine; Population; Pre-Clinical Model; Prodrugs; Property; Rattus; Refractory; Reporting; Rest; Schizophrenia; Series; Short-Term Memory; Signal Transduction; Site; Symptoms; Techniques; Testing; Thalamic structure; Therapeutic; Therapeutic Agents; Treatment Efficacy; base; diphenyl; executive function; human subject; improved; in vivo; interest; metabotropic glutamate receptor 2; neuroimaging; neuropsychiatry; novel; novel strategies; novel therapeutics; pre-clinical; prepulse inhibition; receptor; relating to nervous system; response; transmission process; treatment effect; treatment strategy

DESCRIPTION (provided by applicant): The overall goals of this proposal are to quantitatively characterize the effects on neural activation and cerebral networks of novel compounds that target metabotropic glutamate receptor subype 2 (mGlu2) using functional neuroimaging techniques, and to correlate these findings with behavioral responses. These agents are of high interest as potential treatments for schizophrenia and other mood disorders. Preclinical and phase II clinical data with LY404039 support the hypothesis that metabotropic glutamate receptor subtype 2/3 (mGlu2/3) agonists are a viable, non-dopaminergic strategy for the treatment of schizophrenia. The clinical findings suggest that mGlu2/3 activation is effective in improving both positive and negative symptoms and a study in ketamine-induced working memory deficits in human subjects suggests that cognition can be improved, too. We have recently reported the development of a novel strategy to selectively activate individual mGlu subtypes, particularly mGlu2, using highly selective positive allosteric modulators (PAMs). These compounds do not activate mGlu2 directly, but dramatically potentiate the response of the receptor to Glu. The development of biphenyl indadone-A (BINA), a systemically active mGlu2 PAM that crosses the blood brain barrier, opens an unprecedented opportunity to investigate whether the antipsychotic-like effects of mGlu2/3 agonists can be recapitulated by targeting mGlu2 with a PAM. Our preliminary studies suggest that BINA has robust efficacy in several animal models used to predict antipsychotic efficacy. In the proposed studies, we will utilize BINA and the mGlu2/3 agonist LY404039 in a series of neuroimaging studies to test the hypothesis that selective potentiation of mGlu2 will have activity in animal models that predict antipsychotic efficacy. We hypothesize that these agents will modulate glutamatergic transmission in corticostriatal and corticothalamic circuits and that direct mGlu2/3 activation wil differentially modulate mesolimbic dopamine transmission compared to mGlu2 potentiation. Using resting state functional MRI as an output in NMDA receptor hypofunction models, we predict mGlu2-mediated normalization of neural network fluctuations. We will correlate the imaging findings with treatment effects on cognition tasks. Normalization of resting state brain fluctuations may be an important biomarker of the therapeutic efficacy of antipsychotic agents.

描述（由申请人提供）：本提案的总体目标是使用功能性神经影像技术定量表征针对代谢型谷氨酸受体亚型 2 (mGlu2) 的新型化合物对神经激活和大脑网络的影响，并将这些发现与行为反应相关联。这些药物作为精神分裂症和其他情绪障碍的潜在治疗方法引起了人们的高度关注。 LY404039 的临床前和 II 期临床数据支持这样的假设：代谢型谷氨酸受体亚型 2/3 (mGlu2/3) 激动剂是治疗精神分裂症的可行的非多巴胺能策略。临床结果表明，mGlu2/3 激活可有效改善阳性和阴性症状，一项针对氯胺酮引起的人类受试者工作记忆缺陷的研究表明，认知能力也可以得到改善。我们最近报道了一种新策略的开发，该策略使用高选择性正变构调节剂（PAM）选择性激活单个 mGlu 亚型，特别是 mGlu2。这些化合物不会直接激活 mGlu2，但会显着增强受体对 Glu 的反应。联苯茚达酮-A (BINA) 是一种具有全身活性的 mGlu2 PAM，可穿过血脑屏障，它的开发为研究是否可以通过用 PAM 靶向 mGlu2 来重现 mGlu2/3 激动剂的抗精神病样作用提供了前所未有的机会。我们的初步研究表明，BINA 在用于预测抗精神病药疗效的几种动物模型中具有强大的功效。在拟议的研究中，我们将在一系列神经影像学研究中利用 BINA 和 mGlu2/3 激动剂 LY404039 来测试 mGlu2 的选择性增强将在预测抗精神病药功效的动物模型中具有活性的假设。我们假设这些药物将调节皮质纹状体和皮质丘脑回路中的谷氨酸能传递，并且与 mGlu2 增强相比，直接 mGlu2/3 激活将差异性地调节中脑边缘多巴胺传递。使用静息态功能 MRI 作为 NMDA 受体功能减退模型的输出，我们预测 mGlu2 介导的神经网络波动正常化。我们将把影像学结果与认知任务的治疗效果联系起来。静息状态下大脑波动的正常化可能是抗精神病药物治疗效果的重要生物标志物。