Benzodiazepine treatment induced neuroplasticity

苯二氮卓治疗诱导神经可塑性

基本信息

批准号：
10308069
负责人：
Tija C. Jacob
金额：
$ 39.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308069
关键词：
Address Adverse effects Alcohol withdrawal syndrome Anxiety Anxiety Disorders Benzodiazepine Receptor Benzodiazepines Binding Binding Proteins Biochemical Biosensor Brain Chemosensitization Chronic Data Dependence Development Disease Drug Targeting Electrophysiology (science)Epilepsy Evaluation Event Excitatory Synapse FDA approved Family member Flumazenil Functional disorder Genetic Glutamates Goals Imaging Techniques In Vitro Inhibitory Synapse Knowledge MK801 MPP2 gene Mass Spectrum Analysis Mediating Memantine Mental Depression Methods Modification Molecular Mus N-Methyl-D-Aspartate Receptors Neuronal Plasticity Neurons Neurotransmitter Receptor Optical Methods Optics Overdose Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphorylation Play Post-Translational Protein Processing Property Protein Isoforms Proteins Proteome Proteomics Public Health Publishing Receptor Signaling Research Resolution Rodent Role Scaffolding Protein Schizophrenia Sedation procedure Seizures Signal Transduction Sleeplessness Slice Surface Synapses Synaptic Receptors Testing Therapeutic Time Ubiquitination Up-Regulation Withdrawal Work antagonist behavioral pharmacology calmodulin-dependent protein kinase II gamma-Aminobutyric Acid gephyrin high resolution imaging imaging approach improved in vivo in vivo evaluation innovation neuroadaptation neurotransmission novel patient tolerability prevent receptor receptor upregulation scaffold sedative therapeutic development tool trafficking

项目摘要

Benzodiazepines (BZs) are therapeutic drugs widely used to treat anxiety, insomnia and seizure disorders and as additional drug therapy in schizophrenia and depression. BZs bind and potentiate the inhibitory activity of specific subtypes of GABA type A receptors (GABAARs). Despite the efficacy of BZs, their prolonged use is severely limited by tolerance, dependence and withdrawal. Very little is mechanistically known about the neuroadaptations that underlie a BZ tolerant brain state. Chronic BZ treatment results in a decrease in BZ potentiation of GABA activity at GABAARs, suggesting changes in receptor subunit composition and/or function at inhibitory synapses. Furthermore, the neuroplasticity occurring during BZ treatment is also dependent on excitatory glutamatergic N-methyl-D-aspartate receptors (NMDAR), as co-administration of NMDAR antagonists can prevent BZ tolerance. Using a high throughput quantitative proteomic approach to investigate BZ sedative tolerance-induced changes in the rodent cortex our data show for the first time significant upregulation of key excitatory synapse components. Together with our prior work showing that sustained BZ exposure decreases synaptic levels of BZ sensitive GABAARs, these findings generated the central hypothesis: Benzodiazepine treatment reduces benzo-sensitive GABAAR subtype signaling concomitant with enhancing excitatory synapse strength. The proposed research capitalizes on the use of novel optical methods and quantitative proteomics to address the critical knowledge gap in how prolonged BZ use induces neuroplasticity in both inhibitory GABAAR and excitatory NMDAR signaling. Two independent and complementary Aims are proposed to test these mechanistic components of BZ tolerance. The first aim will use quantitative mass spectrometry, electrophysiology, behavioral and pharmacological methods to define and functionally assess in vivo BZ treatment induced changes in both inhibitory and excitatory synapses of the rodent cortex. The second aim will apply high resolution imaging techniques and an innovative optical biosensor for BZ sensitive GABAAR in vitro and in vivo, combined with genetic, biochemical and electrophysiological approaches to identify BZ treatment induced GABAAR post translational modifications and cellular mechanisms leading to rapid BZ uncoupling and the progression to BZ sedative tolerance. These findings will provide new directions for the development of therapeutic approaches to mitigate or avoid BZ tolerance, addressing a significant unmet public health need.

苯二氮卓类 (BZ) 是广泛用于治疗焦虑、失眠和癫痫症的治疗药物，作为精神分裂症和抑郁症的额外药物治疗。 BZs 结合并增强抑制活性 GABA A 型受体 (GABAAR) 的特定亚型。尽管 BZ 具有功效，但长期使用会影响受到耐受性、依赖性和退缩的严重限制。人们对它的机械原理知之甚少神经适应是 BZ 耐受大脑状态的基础。慢性 BZ 治疗会导致 BZ 减少 GABAARs 上的 GABA 活性增强，表明受体亚基组成和/或功能发生变化在抑制性突触处。此外，BZ 治疗期间发生的神经可塑性还取决于兴奋性谷氨酸 N-甲基-D-天冬氨酸受体 (NMDAR)，与 NMDAR 共同给药拮抗剂可以阻止 BZ 耐受。使用高通量定量蛋白质组学方法研究我们的数据首次显示 BZ 镇静耐受引起的啮齿动物皮层变化关键兴奋性突触成分的显着上调。与我们之前的工作一起表明持续的 BZ 暴露会降低 BZ 敏感 GABAAR 的突触水平，这些发现产生了中心假设：苯二氮卓治疗可减少苯并敏感的 GABAAR 亚型信号传导同时增强兴奋性突触强度。拟议的研究利用了新颖的光学方法和定量蛋白质组学，以解决 BZ 延长时间的关键知识差距使用会诱导抑制性 GABAAR 和兴奋性 NMDAR 信号传导的神经可塑性。两个独立且建议采用补充目标来测试 BZ 公差的这些机械组件。第一个目标将使用定量质谱、电生理学、行为和药理学方法来定义和功能评估体内 BZ 治疗诱导的抑制性和兴奋性突触变化啮齿动物皮质。第二个目标将应用高分辨率成像技术和创新光学体外和体内 BZ 敏感 GABAAR 生物传感器，结合遗传、生化和电生理学方法识别 BZ 治疗诱导的 GABAAR 翻译后修饰和导致 BZ 快速解偶联和 BZ 镇静耐受进展的细胞机制。这些研究结果将为减轻或避免 BZ 的治疗方法的开发提供新的方向宽容，解决重大的未满足的公共卫生需求。