CORTICOTROPIN-RELEASING FACTOR IN HORMONAL AND BEHAVIORAL RESPONSES TO STRESS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。研究狨猴脑和垂体中促肾上腺皮质激素释放因子系统的特征，并评估其在内分泌和应激行为反应中的作用。促肾上腺皮质激素释放因子（CRF）是一种神经肽，可调节对应激的行为、激素、自主神经和免疫反应，可能与人类情绪和焦虑障碍的病理生理学有关。为了建立CRF高分泌的内分泌和行为影响的非人灵长类动物模型，我们进行了初步试验，表征了CRF 1型（CRFR1）和2型（CRFR2）受体和CRF结合蛋白（CRF- bp）在狨猴垂体中的表达，并评估了选择性CRFR1拮抗剂安他拉明对CRF和应激的激素和行为反应的影响。绒猴CRFR1、CRFR2和CRF-BP克隆区域的序列在DNA水平上与人类基因同源性为98%，CRFR1和CRFR2的预测蛋白序列与扩增区域的同源性为100%。克隆的绒猴CRF-BP在核酸水平上与人同源96%，在预测蛋白水平上与人同源98%。我们观察到，CRFR1和CRFR2 mrna在绒猴垂体中的丰度几乎相等，这为该物种中这两种CRF受体对促肾上腺皮质激素（ACTH）的产生和分泌提供了潜在的调节。安他拉明降低了ACTH对绵羊CRF的反应以及ACTH和皮质醇对限制性应激源的反应，但没有改变血浆ACTH或皮质醇的基础浓度。这些研究表明，CRF作用于CRFR1刺激绒猴ACTH释放，但提示CRF通过CRFR2和/或其他分泌物作用，也可能在基线条件下调节ACTH释放中发挥重要作用。这些发现将为进一步研究CRF在狨猴应激反应中的作用奠定重要基础。本研究使用WNPRC绒猴群体，化验服务和病理服务。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To characterize the corticotropin-releasing factor system in the brain and pituitary of the marmoset and evaluate its role in endocrine and behavioral responses to stress. Corticotropin-releasing factor (CRF) is a neuropeptide that regulates the behavioral, hormonal, autonomic, and immune responses to stress and may contribute to the pathophysiology of mood and anxiety disorders in humans. To develop a nonhuman primate model of the endocrine and behavioral effects of CRF hypersecretion, we performed pilot tests characterizing the expression of CRF type-1 (CRFR1) and type-2 (CRFR2) receptors and CRF-binding protein (CRF-BP) in the marmoset pituitary, and assessing the effects of antalarmin, a selective CRFR1 antagonist, on hormonal and behavioral responses to CRF and stress. The sequences for the cloned regions of the marmoset CRFR1, CRFR2, and CRF-BP were found to be 98% homologous with the human genes at the DNA level, and for CRFR1 and CRFR2, 100% identity for the predicted protein sequence of the amplified region. The cloned region of the marmoset CRF-BP was found to be 96% homologous to human at the nucleic acid level and 98% identity at the predicted protein level. We observed that the CRFR1 and CRFR2 mRNAs were of nearly equal abundance in the marmoset pituitary, providing for potential regulation of adrenocorticotropin (ACTH) production and secretion by both of these CRF receptors in this species. Antalarmin reduced the ACTH response to ovine CRF as well as the ACTH and cortisol responses to a restraint stressor, but did not alter basal plasma ACTH or cortisol concentrations. These studies indicate that CRF acts on CRFR1 to stimulate ACTH release in the marmoset, but suggest that CRF acting through CRFR2, and/or other secretagogues, may also play a significant role in regulating ACTH release under baseline conditions. These findings will for a crucial basis for further studies of the role of CRF on responses to stress in the marmoset. This research used the WNPRC marmoset colony, Assay Services and Pathology Services.