Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments

心理压力降低内源性大麻素张力：机制和可能的治疗方法

• 批准号: 9452362
• 负责人: Siqiong June Liu
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9452362
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Adrenergic Agents; Adrenergic Receptor; Affect; Animal Model; Anxiety; Anxiety Disorders; Applications Grants; Attenuated; Behavioral; Brain region; Cerebellum; Chronic stress; Data; Development; Emotional Stress; Endocannabinoids; Enzymes; Exhibits; Extinction (Psychology); FDA approved; Foxes; Fright; General Population; Genetic Transcription; Impairment; Individual; Interneurons; Intervention; Investigation; Knowledge; Learning; Life; Life Experience; LoxP-flanked allele; Membrane; Memory; Memory impairment; Mental Depression; Mental Health; Metabolism; Modeling; Monoacylglycerol Lipases; Mood Disorders; Mus; Neurons; Norepinephrine; Odors; Pain; Pharmaceutical Preparations; Pharmacology; Phenotype; Post-Traumatic Stress Disorders; Potassium Channel; Production; Psychological Stress; Purkinje Cells; Receptor Signaling; Regulation; Research; Rodent; Role; Signal Pathway; Stress; Structure of molecular layer of cerebellar cortex; Synaptic Transmission; Testing; Urine; Veterans; anxiety-like behavior; biological adaptation to stress; conditioned fear; designer receptors exclusively activated by designer drugs; endocannabinoid signaling; experience; experimental study; fear memory; gamma-Aminobutyric Acid; in vivo; lipoprotein lipase; locus ceruleus structure; memory consolidation; memory retention; neural circuit; neuronal excitability; new therapeutic target; novel; novel strategies; novel therapeutic intervention; presynaptic; prevent; psychological trauma; reduce symptoms; response; stressor; synthetic enzyme; transmission process; traumatic event; treatment strategy

One debilitating mental health problem among veterans is post-traumatic stress disorder (PTSD), which is an anxiety disorder (PTSD) and develops following the experience of life- threatening psychological trauma. Individuals with PTSD have reduced circulating levels of endocannabinoids (eCB) including 2-AG. Since disruption of 2-AG signaling leads to mood disorders, impaired memory extinction and enhanced pain, the ability to reverse the stress- induced change in 2-AG production/degradation holds great potential for the treatment of PTSD. Given the importance of 2-AG signaling in the stress response and associative fear learning, an understanding of how stress produces a lasting decrease in 2-AG levels is needed to bridge the knowledge gap that exists between traumatic stress and the associated reduction in 2-AG content. Exposure of rodents to natural predator odors causes psychological stress, leading to enhanced associative fear learning and thus has been used to model several aspects of PTSD. We have previously shown that fox urine exposure produced a lasting increase in excitatory synaptic transmission via the activation of adrenergic receptors in the mouse cerebellum. This brain region is required for the innate response to predator odor and for the consolidation of fear memory. Our pilot data show that predator odor exposure reduced 2-AG signaling in the cerebellum and this stressor abolished A-type K currents in inhibitory interneurons. Therefore our central hypothesis is that predator odor stress enhances excitability of GABAergic interneurons and thereby reduces 2-AG signaling, thus pharmacological interventions that inhibit 2-AG degradation and reduce neuronal excitability would reverse the stress-induced decrease in 2-AG levels. In Aim 1, we will determine whether a psychological stress reduces 2- AG tone by increasing 2-AG degradation or by reducing 2-AG production. Aim 2 will test the hypothesis that emotional stress reduces 2-AG signaling by increasing inhibitory interneuron activity. We will test whether several FDA approved drugs that reduce neuronal activity can reverse the stress-induced change. Because the proposed study investigates a new mechanism underlying the regulation of 2-AG metabolism by psychological stress, it could suggest novel treatment strategies for PTSD and new therapeutic targets.

退伍军人中一个令人衰弱的心理健康问题是创伤后应激障碍 创伤后应激障碍（PTSD），这是一种焦虑症（PTSD），并发展以下的生活经验- 可能造成心理创伤患有PTSD的人循环中的 内源性大麻素（eCB），包括2-AG。由于2-AG信号的中断导致情绪 障碍，记忆力减退和疼痛加剧，逆转压力的能力- 诱导的2-AG产生/降解的变化对于治疗PTSD具有很大的潜力。 鉴于2-AG信号在应激反应和联想恐惧学习中的重要性， 需要了解压力如何导致2-AG水平持续下降， 创伤应激和相关的2-AG减少之间存在的知识差距 内容啮齿动物暴露于自然捕食者的气味会引起心理压力，导致 增强的联想恐惧学习，因此已被用于模拟创伤后应激障碍的几个方面。 我们之前已经证明，接触狐狸尿液会导致兴奋性持续增加 通过激活小鼠小脑中的肾上腺素能受体的突触传递。这 对捕食者气味的先天反应和恐惧的巩固需要大脑区域 记忆我们的试验数据表明，捕食者的气味暴露减少了2-AG信号， 小脑和这种应激废除了抑制性中间神经元的A型K电流。因此 我们的中心假设是捕食者气味应激增强GABA能神经元的兴奋性， 从而减少2-AG信号传导，因此药理学干预， 抑制2-AG降解和降低神经元兴奋性将逆转应激诱导的 2-AG水平下降。在目标1中，我们将确定心理压力是否会降低2- 通过增加2-AG降解或减少2-AG产生来调节AG。目标2将测试 情绪应激通过增加抑制性中间神经元而减少2-AG信号传导的假说 活动我们将测试几种FDA批准的减少神经元活动的药物是否能 扭转压力引起的变化。因为这项研究调查了一种新的机制， 作为心理应激对2-AG代谢调节的基础，它可能提示新的 PTSD的治疗策略和新的治疗靶点。