Pharmacological modulation of striatal physiology and repetitive behaviors by M4 PAMs

M4 PAM 对纹状体生理学和重复行为的药理学调节

• 批准号: 10665904
• 负责人: Daniel J Foster
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665904
• 关键词: Animal Model; Antipsychotic Agents; Basal Ganglia; Behavior; Behavior Therapy; Behavioral; Brain; Brain region; CNR2 gene; Cell physiology; Clinical; Clinical Data; Corpus striatum structure; Data; Disease; Dopamine; Electric Stimulation; Electrophysiology (science); Environment; Genetic; Gilles de la Tourette syndrome; Glutamates; Goals; Grooming; Human; Hyperactivity; Impairment; Knockout Mice; Learning; Long-Term Depression; Mediating; Mental disorders; Mus; Muscarinic Acetylcholine Receptor; Mutant Strains Mice; Neurons; Obsessive-Compulsive Disorder; Pathologic; Patients; Periodicity; Phenotype; Physiological; Physiology; Play; Receptor Activation; Refractory; Regulation; Resistance; Role; Scanning; Selective Serotonin Reuptake Inhibitor; Series; Signal Transduction; Social Interaction; Structure; Synapses; Testing; Therapeutic; Therapeutic Agents; Wild Type Mouse; autism spectrum disorder; behavioral study; disabling symptom; endocannabinoid signaling; experimental study; genetic approach; glutamatergic signaling; in vivo; innovation; mouse model; nervous system disorder; neurotransmission; novel; novel strategies; novel therapeutics; optogenetics; pharmacologic; positive allosteric modulator; pre-clinical; presynaptic; receptor; reduce symptoms; repetitive behavior; symptom treatment; tool; transmission process; treatment strategy

Project Summary / Abstract Repetitive behaviors are commonly observed in disorders such as Obsessive-Compulsive Disorder (OCD), Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs). These behaviors can have profound negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy are moderately effective in treating these symptoms, many patients are refractory to these therapies and there is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The striatum is a brain region that plays a key role in integrating information from numerous brain structures and is essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors. Here we provide preliminary data demonstrating that M4 PAMs can reduce excessive grooming in SAPAP3 KO mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available therapies. We hypothesize that repetitive behaviors in multiple animal models displaying repetitive grooming are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis through a series of electrophysiological and behavioral studies using a combination of genetically modified mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important information regarding the physiological role of M4 receptors in regulating basal ganglia function and will elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.

项目概要/摘要 重复行为常见于强迫症 (OCD)、 妥瑞氏综合症 (TS) 和自闭症谱系障碍 (ASD)。这些行为可能会产生深远的影响 对患者的生活产生负面影响，并可能损害他们的学习、社交互动和适应能力 不断变化的环境。选择性血清素再摄取抑制剂、抗精神病药物和行为疗法 对治疗这些症状有一定的效果，许多患者对这些疗法有抵抗力，并且存在 迫切需要确定更好的治疗策略来帮助患有这些致残症状的患者。这 纹状体是一个大脑区域，在整合来自众多大脑结构的信息方面发挥着关键作用， 对于调节习惯性和目标导向的行为至关重要。临床和临床前数据的融合表明 通过纹状体中特定回路的过度活跃的多巴胺能和谷氨酸能神经传递 可能代表异常重复行为的常见机制基础。有趣的是，广泛 我们实验室和其他人的研究发现，毒蕈碱乙酰胆碱受体的 M4 亚型可以发挥 对纹状体多巴胺能和谷氨酸能传递的强大调节控制，提高了可能性 M4 的选择性激活剂可以逆转可能引起重复行为的病理变化。 在这里，我们提供了初步数据，证明 M4 PAM 可以减少 SAPAP3 KO 中的过度修饰 小鼠（一种表现出重复过度梳理表型的遗传小鼠模型）。这可以提供一个 在确定一种治疗对现有药物耐药的致残症状的新方法方面取得了突破 疗法。我们假设多种动物模型中的重复行为表现出重复的梳理行为 与纹状体中过度活跃的谷氨酸和多巴胺释放有关，并且 M4 PAM 治疗 可以通过使这些形式的神经传递正常化来减少重复行为。我们将检验这个假设 通过一系列电生理学和行为学研究，结合使用转基因技术 小鼠、光遗传学方法和新型药理学工具。这些研究将提供重要的 有关 M4 受体在调节基底神经节功能中的生理作用的信息和意志 阐明 M4 PAM 在缓解重复行为方面的治疗潜力。