The Orexin System as a Target for PTSD and Comorbid Psychosis

食欲素系统作为创伤后应激障碍和共病精神病的目标

基本信息

批准号：
10454782
负责人：
Daniel Lodge
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454782
关键词：
Adverse effects Anatomy Autoradiography Behavior Behavioral Cognitive Data Delusions Development Disease Dopamine Dopamine D2 Receptor Dose Electrophysiology (science)Enterobacteria phage P1 Cre recombinase FDA approved Functional disorder Hallucinations Herpesviridae High Prevalence Human Hypothalamic structure Individual Intervention Ligands Locomotion LoxP-flanked allele Major Depressive Disorder Measures Mediating Medicine Mood Disorders Motor Names Neurons Nucleus Accumbens Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacology Physiological Population Positioning Attribute Positron-Emission Tomography Post-Traumatic Stress Disorders Psychoses Rattus Reporting Research Rodent Rodent Model Role Sensory Shock Sleeplessness Stimulant Stress Structure of paraventricular nucleus of thalamus Symptoms System Testing Thalamic structure Therapeutic Ventral Tegmental Area Virus Work antagonist base brain pathway comorbidity designer receptors exclusively activated by designer drugs dopamine system dopaminergic neuron effective therapy experience flexibility hypocretin information processing nerve supply neurochemistry neurophysiology new therapeutic target novel prepulse inhibition presynaptic psychiatric comorbidity psychotic symptoms receptor therapeutic target transmission process traumatic event

Adverse effects Anatomy Autoradiography Behavior Behavioral Cognitive Data Delusions Development Disease Dopamine Dopamine D2 Receptor Dose Electrophysiology (science)Enterobacteria phage P1 Cre recombinase FDA approved Functional disorder Hallucinations Herpesviridae High Prevalence Human Hypothalamic structure Individual Intervention Ligands Locomotion LoxP-flanked allele Major Depressive Disorder Measures Mediating Medicine Mood Disorders Motor Names Neurons Nucleus Accumbens Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacology Physiological Population Positioning Attribute Positron-Emission Tomography Post-Traumatic Stress Disorders Psychoses Rattus Reporting Research Rodent Rodent Model Role Sensory Shock Sleeplessness Stimulant Stress Structure of paraventricular nucleus of thalamus Symptoms System Testing Thalamic structure Therapeutic Ventral Tegmental Area Virus Work antagonist base brain pathway comorbidity designer receptors exclusively activated by designer drugs dopamine system dopaminergic neuron effective therapy experience flexibility hypocretin information processing nerve supply neurochemistry neurophysiology new therapeutic target novel prepulse inhibition presynaptic psychiatric comorbidity psychotic symptoms receptor therapeutic target transmission process traumatic event

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项目摘要

Project Summary/Abstract: Psychotic symptoms are highly prevalent in PTSD patients and are typically treated with dopamine D2 receptor antagonists; however, these drugs are associated with significant adverse effects. We have novel preliminary data demonstrating that the paraventricular nucleus of the thalamus (PVT) regulates dopamine neuron activity. We posit that the PVT therefore represents a potential therapeutic target for the treatment of PTSD as well as comorbid psychosis. The PVT receives a particularly dense innervation from orexin containing neurons in the hypothalamus. Thus, the orexin system is well positioned to regulate PVT activity and may be a novel target for pharmacological intervention. One such drug, Suvorexant, an orexin receptor antagonist, is currently FDA- approved for the treatment of insomnia. We will test the hypothesis that Suvorexant can reverse deficits in rodents displaying circuit level alterations and corresponding behavioral deficits relevant to comorbid psychosis in PTSD. Specifically, we will examine whether orexin receptor antagonists can reverse stress-induced behavioral (Aim 1) or neurophysiological/neurochemical (Aim 2) deficits associated with PTSD. We will then determine the role of discrete PVT projections to the nucleus accumbens in comorbid psychosis (Aim 3). This proposal with therefore identify a potential novel therapeutic target and inform the development of more effective treatment approaches for PTSD and comorbid psychosis.

项目摘要/摘要：精神病症状在PTSD患者中高度普遍，通常用多巴胺D2受体治疗对手；但是，这些药物与重大不良反应有关。我们有新颖的初步数据表明，丘脑（PVT）的室室核调节多巴胺神经元活性。我们认为PVT因此代表了治疗PTSD以及合并精神病。 PVT从含有OREXIN的神经元中的神经神经支配下丘脑。因此，Orexin System在调节PVT活性方面处于良好状态，可能是药理干预。一种这样的药物，一种suvorexant，一种奥雷敦素受体拮抗剂，目前为FDA- 批准治疗失眠。我们将检验以下假设，即suvorexant可以逆转不足显示电路水平改变和相应的行为缺陷的啮齿动物与合并症有关在PTSD中。具体而言，我们将检查Orexin受体拮抗剂是否可以反向应力诱导行为（AIM 1）或神经生理/神经化学（AIM 2）与PTSD相关的缺陷。然后我们会确定对伏隔核在合并症精神病中的离散PVT投影的作用（AIM 3）。这因此，提出了一个潜在的新型治疗靶标，并告知开发更有效 PTSD和合并症的治疗方法。