Stress and Endocannabinoids in Serotonin Neurons

描述（由申请人提供）：5-羟色胺（5-HT）系统的改变涉及应激相关焦虑症的病理生理学。调节肾上腺素能传递的药物被广泛用于治疗焦虑症。近年来，动物实验研究表明，内源性大麻素（endocannabinoid，eCB）系统在应激反应和焦虑相关行为的调节中发挥重要作用。1型大麻素受体（CB 1）的遗传缺失或药理学阻断导致焦虑样行为和应激反应显着增加。这些行为效应部分通过5-HT系统的调节来介导。然而，应激调节5-HT神经元中eCB信号传导的细胞和分子机制尚未被表征。我们已经进行了初步的研究，以检查急性应激激素皮质酮和严重的压力对中缝背核（DR）5-HT神经元的eCB信号的影响。我们发现，急性皮质酮增强eCB的合成/释放，这反过来又调节多巴胺能传递到DR 5-HT神经元。我们的研究结果还表明，暴露于严重的压力诱导下调eCB信号在DR 5-HT神经元24小时后。DR 5-HT神经元中eCB信号的这种功能适应可能在应激诱导的焦虑障碍中发挥作用。本申请的长期目标是描绘应激调节DR 5-HT神经元中eCB信号传导的细胞和分子机制。在本申请中，我们计划使用电生理学、药理学和神经化学方法的组合来1）测试糖皮质激素急性增强DR 5-HT神经元中eCB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信号传导的信号转导机制，（3）探讨严重应激引起DR 5-HT神经元eCB信号下调的机制。鉴于5-HT和eCB系统在应激相关行为调节中的作用，拟议研究的结果将更好地理解焦虑症的病因，并可能有助于开发更有效的抗焦虑药物。

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.