Role of endocannabinoid signaling in stress-coping behavior

压力有助于成瘾的病因，但这种现象背后的机制仍然是 未知内源性大麻素（eCB）-花生四烯酸和2-花生四烯酸甘油（2-AG）-以及它们的 大麻素（CB）受体被认为在调节应激反应中起重要作用 行为。项目5将研究eCB信号的变化是否有助于神经行为 压力引起的变化。我们假设eCB系统通过以下方式增强压力应对反应： 作为促肾上腺皮质激素释放因子（CRF）的下游调节因子，CRF是一种神经肽， 与压力有关的疾病我们有四个具体目标：1。确定CRF对脑eCB的影响 动员。初步结果表明，大鼠CRF给药可改变脑中eCB水平。我们提出 通过鉴定所涉及的CRF受体亚型，它们的脑定位， 以及它们影响eCB动员的生化机制。2.为了检查角色 在CRF诱导的行为中的eCB系统。初步研究结果表明，大脑eCB动员 调节CRF的神经行为作用。为了验证这个想法，我们将研究是否代理， 增加eCB水平（花生四烯酸降解抑制剂URB 597）或阻断CB受体（ B！拮抗剂利莫那班）影响CRF的三种作用，其与急性应激引起的作用非常相似： 摄食抑制、焦虑相关行为增强和血浆皮质酮升高 程度. 3.为了评估eCB系统对应激诱导行为的贡献， 通用报告格式我们将确定URB 597和利莫那班对三种神经行为结果的影响， CRF介导的急性束缚应激：抑制进食，增强焦虑相关的 行为和血浆皮质酮水平升高。长期暴露在压力下会扰乱行为， 降低了科普通常可管理的压力刺激的能力。为了测试这种干扰是否 是由于CRF和anandamide信号之间的正常平衡在大脑中的破坏，我们将 4.确定慢性应激对大脑eCB信号传导的影响。为此，我们将（i）确定 这种改变的分子机制;以及（ii）确定它们是否与 CB 1受体表达的变化。这些研究的结果应有助于 创新疗法，治疗与压力有关的疾病，如成瘾、焦虑和抑郁。发展 新疗法的出现将大大有利于降低与成瘾有关的公共卫生成本。

Stress contributes to the etiology of addiction, but the mechanisms underlying this phenomenon are still unknown. The endocannabinoids (eCBs) - anandamide and 2-arachidonoylglycerol (2-AG) - and their attending cannabinoid (CB) receptors are thought to play important roles in the regulation of stress-coping behaviors. Project 5 will examine whether changes in eCB signaling contribute to the neurobehavioral alterations induced by stress. We hypothesize that the eCB system enhances stress-coping responses by acting as a downstream regulator of corticotrophin-releasing factor (CRF), a neuropeptide implicated in stress-related disorders. We have four specific aims: 1. To determine the effects of CRF on brain eCB mobilization. Initial results indicate that administration of CRF in rats alters brain eCB levels. We propose to characterize this response by identifying the CRF receptor subtype(s) involved, their brain localization, and the biochemical mechanism through which they influence eCB mobilization. 2. To examine the role of the eCB system in CRF-induced behaviors. Preliminary findings suggest that brain eCB mobilization modulates the neurobehavioral actions of CRF. To test this idea, we will examine whether agents that either increase eCB levels (the anandamide degradation inhibitor URB597) or block CB receptors (the B! antagonist rimonabant) affect three actions of CRF that closely mimic those elicited by acute stress: inhibition of feeding, enhancement of anxiety-related behaviors and elevation of plasma corticosterone levels. 3. To assess the contribution of the eCB system to stress-induced behaviors mediated by CRF. We will determine the effects of URB597 and rimonabant on three neurobehavioral outcomes of acute restraint stress that are mediated by CRF: inhibition of feeding, enhancement of anxiety-related behaviors and elevation of plasma corticosterone levels. Chronic exposure to stress disrupts behavior, reducing the ability to cope with normally manageable stressful stimuli. To test whether such disturbances are due to a disruption in the normal balance between CRF and anandamide signaling in the brain, we will 4. determine the impact of chronic stress on brain eCB signaling. To this end, we will (i) identify the molecular mechanisms underlying such alterations; and (ii) determine whether they are associated with changes in CB1 receptor expression. The results of these studies should facilitate the development of innovative therapies for stress-related disorders such as addiction, anxiety and depression. Development of new therapies will be of great benefit to decreasing the public health costs related to addiction.