Does diminished oxytocin modulate stress vulnerability in Schizophrenia

描述（由申请人提供）：我们的研究表明，患有水失衡的精神分裂症患者在心理压力下，下丘脑-垂体-肾上腺（HPA）轴和抗利尿激素（精氨酸加压素：AVP）的活性增强。此外，这些发现似乎归因于海马功能障碍，这可能反过来与潜在的精神障碍直接相关。AVP异常可能导致危及生命的水中毒，HPA轴异常可能是海马介导的心理应激易感性的一部分。我们的初步研究结果表明，在这些患者中，密切相关的神经激素催产素也存在缺陷，这可能有助于增强AVP和HPA轴对心理压力的反应，以及以极端社交缺陷为特征的一种特别致命的精神分裂症（即缺陷综合征）。本研究的目的是确认催产素调节的假设缺陷，并开始确定催产素治疗可以恢复神经内分泌和行为功能的程度。目的1将证实或反驳催产素水平在水分失衡的患者中较低。目的II将评估血浆催产素与社交缺陷和缺陷综合征之间的关系。目的III将评估鼻内催产素是否使水平衡患者对应激的AVP和HPA轴反应增强正常化。目的四将确定鼻内催产素是否改善低血浆催产素患者的社交缺陷。这些探索性研究具有创新性，可以直接为严重精神疾病的难治性和毒性特征带来新的治疗方式。公共卫生相关性：精神分裂症是人类已知的最具破坏性的疾病之一。我们理解和治疗这种疾病的努力是基于最近对大脑调节的激素如何决定我们对压力和社会状况的反应的见解。我们研究了一组精神分裂症患者，他们在这些激素的调节方面表现出异常，我们的数据表明，这与他们较差的压力耐受性和受损的情绪判断有关。我们想看看能否通过鼻腔喷雾剂注入其中一种激素（催产素）来逆转这些缺陷。这项工作有可能增加我们对精神分裂症病因的理解，并确定新的治疗方法。

DESCRIPTION (provided by applicant): Our work indicates that schizophrenic patients with water imbalance have enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis and the antidiuretic hormone (arginine vasopressin: AVP) in response to psychological stress. Furthermore, these findings appear attributable to hippocampal dysfunction, which may in turn be directly related to the underlying psychiatric disorder. The AVP abnormality likely contributes to life threatening water intoxication and the HPA axis abnormality may be part of a more general hippocampal-mediated vulnerability to psychological stress. Our pilot findings indicate that there is also a deficit in the closely related neurohormone, oxytocin, in these patients that may contribute to enhanced AVP and HPA axis responses to psychological stress, as well as to a particularly virulent form of schizophrenia (i.e. deficit syndrome) characterized by extreme social deficits. The goal of this study is to confirm the putative deficits in oxytocin regulation, and begin to determine the extent that neuroendocrine and behavioral functions can be restored with oxytocin treatment. Aim I will confirm or disprove that oxytocin levels are lower in patients with water imbalance. Aim II will assess the association between plasma oxytocin versus social deficits and the deficit syndrome. Aim III will assess if intranasal oxytocin normalizes the enhanced AVP and HPA axis responses to stress in patients with water balance. Aim IV will determine if intranasal oxytocin ameliorates social deficits in patients with low plasma oxytocin. These exploratory studies are innovative and could directly lead to new therapeutic modalities for intractable and virulent features of severe mental illness. PUBLIC HEALTH RELEVANCE: Schizophrenia is one of the most devastating illnesses known to man. Our efforts to understand and treat this disease are based on recent insights into how hormones regulated by the brain determine our responses to stress and to social situations. We study a group of people with schizophrenia who exhibit abnormalities in the regulation of these hormones, which our data suggest, are related to their poor stress tolerance and impaired emotional judgment. We want to see if we can reverse these deficits by giving one of the hormones (oxytocin) by a nasal spray. This work has the potential to increase our understanding of what causes schizophrenia, as well as to identify novel therapies.