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

• 批准号: 10618914
• 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
• 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/10618914
• 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; Genetic; Genetic study; Hallucinations; Herpesviridae; High Prevalence; Human; Hypothalamic structure; Individual; Intervention; Ligands; Locomotion; LoxP-flanked allele; Major Depressive Disorder; Measures; Mediating; Medicine; Mental disorders; Mood Disorders; Motor; Names; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; 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; 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; pharmacologic; prepulse inhibition; presynaptic; psychiatric comorbidity; psychotic symptoms; receptor; synaptic function; therapeutic target; transmission process; traumatic event

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.

项目总结/文摘: