Stress and Endocannabinoids in Serotonin Neurons

血清素神经元中的压力和内源性大麻素

• 批准号: 7817101
• 负责人: SAMIR HAJ-DAHMANE
• 金额: $ 33.88万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817101
• 关键词: 2-arachidonylglycerol; Acute; Agonist; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain; CNR1 gene; Corticosterone; Development; Dorsal; Down-Regulation; Endocannabinoids; Etiology; Exposure to; Functional disorder; Genetic; Glucocorticoids; Glutamates; Hormones; Hour; Link; Mediating; Metabolism; Molecular; Mood Disorders; Neurons; Pharmaceutical Preparations; Play; Regulation; Research Personnel; Role; Serotonin; Signal Transduction; Slice; Source; Stress; Swimming; Synaptic Transmission; System; Testing; acute stress; anandamide; biological adaptation to stress; cannabinoid receptor; improved; in vivo; neurochemistry; neurotransmission; novel; programs; receptor; transmission process; uptake

DESCRIPTION (provided by applicant): Alteration in serotonin (5-HT) system is involved in the pathophysiology of stress-related anxiety disorder. Medications that modulate serotonergic transmission are widely used to treat anxiety disorder. Recently, evidence from animal studies indicates that endocannabinoid (eCB) system plays an important role in the regulation of stress responses and anxiety related behaviors. Genetic deletion or pharmacological blockade of type 1 cannabinoid receptors (CB1) results in a marked increase in anxiety-like behaviors and stress responses. These behavioral effects are mediated in part, via the modulation of the 5-HT system. However, the cellular and molecular mechanism by which stress modulates eCB signaling in 5-HT neurons has not been characterized. We have conducted preliminary studies to examine the impact of acute stress hormone corticosterone and severe stress on eCB signaling in dorsal raphe (DR) 5-HT neurons. We find that acute corticosterone enhances eCB synthesis/release, which in turn modulates glutamatergic transmission to DR 5-HT neurons. Our results also show that exposure to severe stress induces a down-regulation of eCB signaling in DR 5-HT neurons 24 hours later. This functional adaptation of eCB signaling in DR 5-HT neurons may play a role in stress-induced anxiety disorder. The long-term objective of this application is to delineate the cellular and molecular mechanisms by which stress modulates eCB signaling in DR 5-HT neurons. In this application, we plan to use a combination of electrophysiological, pharmacological and neurochemical approaches to 1) test the hypothesis that glucocorticoids acutely enhance eCB synthesis/release in DR 5-HT neurons, 2) elucidate the signal transduction mechanisms by which glucocorticoids enhance eCB signaling in DR 5-HT neurons, 3) to determine the mechanisms of severe stress-induced down-regulation of eCB signaling in DR 5-HT neurons. Given the role of 5-HT and eCB systems in the regulation of stress related behaviors, the results from the proposed studies will better our understanding of the etiology of anxiety disorder and may contribute to the development of more effective anxiolytics.

描述（由申请人提供）：5-羟色胺（5-HT）系统的改变参与应激相关性焦虑障碍的病理生理。调节血清素传递的药物被广泛用于治疗焦虑症。近年来，动物实验证据表明，内源性大麻素（eCB）系统在应激反应和焦虑相关行为的调控中起着重要作用。1型大麻素受体（CB1）的基因缺失或药物阻断导致焦虑样行为和应激反应的显着增加。这些行为影响部分是通过5-羟色胺系统的调节来调节的。然而，应激调节5-HT神经元中eCB信号的细胞和分子机制尚未被表征。我们已经进行了初步研究，以检查急性应激激素皮质酮和严重应激对中缝背（DR） 5-HT神经元中eCB信号的影响。我们发现急性皮质酮增强了eCB的合成/释放，这反过来调节了谷氨酸能向DR 5-HT神经元的传递。我们的研究结果还表明，暴露于严重应激下24小时后，DR 5-HT神经元的eCB信号下调。dr5 - ht神经元中eCB信号的功能适应可能在应激性焦虑障碍中起作用。该应用程序的长期目标是描述应激调节DR - 5-HT神经元中eCB信号的细胞和分子机制。在这项应用中，我们计划结合电生理、药理学和神经化学的方法，1)验证糖皮质激素能显著增强DR - 5-HT神经元中eCB的合成/释放的假设，2)阐明糖皮质激素增强DR - 5-HT神经元中eCB信号的信号转导机制，3)确定严重应激诱导下DR - 5-HT神经元中eCB信号下调的机制。鉴于5-HT和eCB系统在调节压力相关行为中的作用，本研究的结果将有助于我们更好地理解焦虑障碍的病因，并可能有助于开发更有效的抗焦虑药物。