Oxytocin as a therapeutic target for Schizophrenia

催产素作为精神分裂症的治疗靶点

• 批准号: 8888359
• 负责人: DAVID FEIFEL
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888359
• 关键词: Acute; Address; Advanced Development; Adverse effects; Affinity; Anhedonia; Animal Experimentation; Animal Experiments; Animal Model; Animal Testing; Animals; Antipsychotic Agents; Attention; Biological; Biological Markers; Brain; Brain region; Characteristics; Chronic; Clinical; Clinical Treatment; Cognition; Cognitive; Cognitive deficits; Data; Development; Disease; Dose; Evaluation; Exhibits; Female; Future; Hormones; Human; Individual; Investigation; Knowledge; Literature; Long-Term Effects; Measurement; Mediating; Mental disorders; Modeling; Nature; Oxytocin; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phenotype; Process; Property; Publishing; Randomized Controlled Trials; Rattus; Rattus norvegicus; Receptor Activation; Regimen; Research; Resistance; Rodent; Route; Safety; Schizophrenia; Sex Characteristics; Short-Term Memory; Site; Symptoms; Syndrome; System; Testing; Text; Therapeutic; Therapeutic Effect; Time; Vasopressin Receptor; Withdrawal; base; clinical effect; cognitive neuroscience; design; drug candidate; improved; male; neurobiological mechanism; neuromechanism; novel; novel strategies; pre-clinical; public health relevance; reproductive function; reproductive hormone; research study; sex; social; social cognition; therapeutic target; tool; treatment duration; visual memory

 DESCRIPTION (provided by applicant): There is a tremendous need for improved treatments for schizophrenia (SCZ), especially for its 'negative' symptoms and cognitive deficits. Oxytocin is a reproductive hormone that is also a powerful regulator of brain processes that are very relevant to SCZ. Preliminary research in animals and humans indicate that the oxytocin system may be an auspicious target for developing new SCZ treatments. However, in order for that to occur, a much greater understanding of oxytocin's potential anti-SCZ effects is urgently needed to address inconsistencies and gaps in the existing body of data. Animal studies are an important tool for obtaining information about potential new treatments, but there has been surprisingly little animal research into oxytocin's anti-SCZ potential. The overall aim of this project is to address this critical gap in knowledge. Since it is unclear which specific features f SCZ may be benefited by oxytocin, several experiments have been thoughtfully designed to evaluate its effects in a battery of state-of-the-art animal tests developed to represent the distinct clinical features of SCZ's cognitive and negative symptoms. Other experiments are designed to uncover the biological mechanisms and brain circuits that underlie oxytocin's anti-SCZ effects, something that has not previously been well studied. By testing the effects of long-term oxytocin treatment via the intranasal route, the standard route in human studies, these experiments will provide an understanding of oxytocin's effects that is more relevant to the chronic nature of clinical treatment than the preponderance of previous animal studies on this topic, which have typically examined one-time, peripheral or central oxytocin administration. As it is highly involved in reproductive function, oxytocin's brain effects are likely to differ in maes and females, but animal experiments investigating its SCZ-relevant effects have almost exclusively included only male subjects. By incorporating both female and male animals in experiments, this project will provide much needed information about possible sex differences in oxytocin's anti-SCZ effects. Another important feature of this project is that it will advance the characterization of a promising rat model of relevance to SCZ and facilitate the ultimate assessment of the validity of the tests used to model features of SCZ. This project will greatly expand the current body of scientific knowledge regarding oxytocin's anti-SCZ properties, including important information regarding potential dose-, sex-, and time-dependent aspects of its clinical effects, potential adverse effects, as well as individual characteristics that may hel identify likely responders to oxytocin treatment. These findings will guide future studies in animals and in patients with SCZ, while the findings regarding oxytocin's neurobiological mechanisms will likely guide the design of novel drugs that are based on oxytocin, but that possess improved efficacy and/or safety.

 描述（由申请人提供）：迫切需要改进精神分裂症（SCZ）的治疗方法，特别是针对其“阴性”症状和认知缺陷。催产素是一种生殖激素，也是与大脑过程密切相关的强大调节剂。对动物和人类的初步研究表明，催产素系统可能是开发新的 SCZ 治疗方法的一个有利目标。迫切需要催产素潜在的抗 SCZ 作用来解决现有数据中的不一致和差距。动物研究是获取潜在新疗法信息的重要工具，但令人惊讶的是，对催产素的抗 SCZ 潜力的动物研究却很少。该项目的总体目标是解决这一关键的知识空白，因为尚不清楚 SCZ 的哪些具体特征可能受益于催产素，因此经过深思熟虑设计了几个实验来评估其对一系列药物的影响。最先进的动物测试旨在代表 SCZ 认知和阴性症状的独特临床特征，其他实验旨在揭示催产素抗 SCZ 作用的生物机制和大脑回路，这在以前尚未得到很好的证实。通过测试通过鼻内途径（人体研究中的标准途径）长期催产素治疗的效果，这些实验将提供对催产素效果的了解，这种效果与临床治疗的慢性性质更相关。先前关于这一主题的动物研究大多检查一次性、外周或中枢催产素给药，因为催产素与生殖功能密切相关，催产素对雄性和雌性的大脑影响可能有所不同，但动物实验正在研究其 SCZ。 -相关效应几乎只包括雄性受试者。通过将雌性和雄性动物纳入实验，该项目将提供有关催产素抗 SCZ 效应可能存在的性别差异的急需信息。它将推进与 SCZ 相关的有前途的大鼠模型的表征，并促进用于模拟 SCZ 特征的测试有效性的最终评估。该项目将极大地扩展当前有关催产素抗 SCZ 特性的科学知识体系，包括有关其临床效果的潜在剂量、性别和时间依赖性、潜在不良反应以及可能有助于识别催产素治疗可能反应者的个体特征的重要信息。这些发现将指导未来的动物和体内研究。患者患有SCZ，虽然有关催产素神经生物学机制的发现可能会指导基于催产素的新药物的设计，但这些药物具有更高的功效和/或安全性。