Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments

退伍军人中一种令人衰弱的心理健康问题是创伤后应激障碍 （PTSD），这是一种焦虑症（PTSD），随着生活经历而发展 - 威胁性的心理创伤。患有创伤后应激障碍（PTSD）的个体循环水平降低 内源性大麻素 (eCB)，包括 2-AG。由于 2-AG 信号传导的破坏会导致情绪变化 紊乱、记忆力减退和疼痛加剧、逆转压力的能力 2-AG 产生/降解的诱导变化对于治疗 PTSD 具有巨大的潜力。 鉴于 2-AG 信号在压力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 水平持久下降 创伤性应激和相关的 2-AG 减少之间存在的知识差距 内容。啮齿类动物接触自然捕食者的气味会造成心理压力，从而导致 增强联想恐惧学习，因此已被用于模拟 PTSD 的多个方面。 我们之前已经表明，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受体来进行突触传递。这个 对捕食者气味的本能反应和巩固恐惧需要大脑区域 记忆。我们的试验数据表明，暴露在捕食者气味中会减少 2-AG 信号传导 小脑和这种应激源消除了抑制性中间神经元中的 A 型 K 电流。因此 我们的中心假设是捕食者气味应激增强了 GABA 能的兴奋性 中间神经元，从而减少 2-AG 信号传导，因此药物干预 抑制2-AG降解并降低神经元兴奋性可以逆转应激引起的 2-AG水平下降。在目标 1 中，我们将确定心理压力是否会减少 2- AG 音调通过增加 2-AG 降解或减少 2-AG 产生来实现。目标 2 将测试 假设情绪压力通过增加抑制性中间神经元来减少 2-AG 信号传导 活动。我们将测试 FDA 批准的几种减少神经元活动的药物是否可以 逆转压力引起的变化。因为拟议的研究调查了一种新机制 心理压力对 2-AG 代谢的调节是潜在的，这可能表明新的 PTSD 的治疗策略和新的治疗靶点。

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.