Role of Neuropeptides in Anxiety

描述(申请人提供)：焦虑症是美国最常见的精神障碍形式，影响着近4000万美国成年人，需要更有效的药物治疗。该项目将由波士顿大学在波士顿丰富的神经科学社区进行，涉及神经肽垂体腺苷环化酶激活多肽(PACAP)，它是促胰液素/胰高血糖素/VIP超家族的成员，以及一种对神经内分泌和行为系统具有显著中枢作用的多效性分子。尽管人们对这种迷人的多肽的兴趣继续呈指数级增长，但这种神经肽在应激反应调节中的作用及其在杏仁核的功能尚不清楚，杏仁核是应激行为表现的关键大脑部位。这种差距的持续存在阻碍了通过了解PACAP在压力和焦虑症中的作用而获得的潜在好处。我们的初步数据表明，PACAP在调节应激行为反应中发挥作用，这似乎是由大脑主要应激肽受体-促肾上腺皮质激素释放因子(CRF)介导的。因此，我们的长期目标是阐明神经肽系统在应激相关疾病的神经生物学中的作用。这项应用的目的是了解PACAP系统如何参与对压力的行为反应，长期目标是为压力和焦虑症的管理提供新的治疗策略。在这项提议中测试的中心假设是，在暴露于压力后，延伸的杏仁核中的内源性PACAP系统被招募，PAC1受体拮抗剂发挥类似焦虑的作用。一个亚假设是PACAP的焦虑效应是通过下丘脑外CRF系统的募集而介导的。这一假设将通过追求三个特定目标来检验；对于PACAP引起焦虑效应重要的大脑部位将在特定目标1中进行表征，使用脑内微量注射PACAP-38。具体目标2将通过研究PAC1拮抗剂的潜在抗焦虑作用以及应激源对不同脑区PACAP和PAC1受体水平的影响，来探索内源性脑PACAP系统在焦虑样行为中的作用。最后，特殊目标3将使用药理学和分子方法研究下丘脑和下丘脑外CRF在PACAP效应中的作用。通过这种多学科方法，拟议的实验结果将为这种神经肽系统作为调节焦虑样行为的机制提供新的见解，并最终可能导致一类用于治疗焦虑样障碍的新的治疗剂。

DESCRIPTION (provided by applicant): Anxiety disorders are the most common form of mental disorders in the United States, affecting nearly 40 million American adults and more efficacious pharmacological treatments are needed. This project, to be conducted at Boston University in the rich neuroscience community of Boston, concerns the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/glucagon/VIP superfamily, and a pleiotropic molecule with remarkable central actions on neuroendocrine and behavioral systems. Although the interest towards this fascinating polypeptide continues to increase exponentially, the role of this neuropeptide in the modulation of stress response and its function in the extended amygdala, a key brain site for the behavioral manifestations of stress, are yet to be elucidated. Continued existence of this gap represents an obstacle to the potential benefits that can derive by understanding the role of PACAP in stress and anxiety disorders. Our preliminary data suggest a role for PACAP in the modulation of behavioral response to stress, which seems to be mediated by the receptors of the major brain stress peptide, corticotropin-releasing factor (CRF). Our long-term goal is therefore to elucidate the role of neuropeptide systems in the neurobiology of stress- related disorders. The objective of this application is to understand how the PACAP system is involved in the behavioral response to stress, with the long-term goal to provide novel therapeutic strategies for the management of stress and anxiety disorders. The central hypothesis under test in this proposal is that the endogenous PACAP system in the extended amygdala is recruited following exposure to stress and that PAC1 receptor antagonists exert an anxiolytic-like action. A sub-hypothesis is that the anxiogenic effects of PACAP are mediated by the recruitment of the extra-hypothalamic CRF system. This hypothesis will be tested by pursuing three specific aims; the brain sites important for the anxiogenic effects of PACAP will be characterized in Specific Aim 1, using intracranial microinjection of PACAP-38. The role of endogenous brain PACAP system in anxiety-like behavior will be explored in Specific Aim 2, through the investigation of the potential anxiolytic effect of a PAC1 antagonist and of the effects of stressors on PACAP and PAC1 receptor levels in discrete brain regions. Finally Specific Aim 3 will investigate the role of hypothalamic and extrahypothalamic CRF in the effects of PACAP using a pharmacological and molecular approach. The results of the proposed experiments, through this multidisciplinary approach, will provide novel insights into this neuropeptide system as a mechanism for modulating anxiety-like behavior, and may ultimately lead to the a new class of therapeutic agents for the treatment of anxiety-like disorders.