Effects of Chronic Intranasal Oxytocin

描述(申请人提供)：自闭症是一种常见的、损害神经发育的疾病，涉及社会交往和社会交流的缺陷。催产素是9 在下丘脑产生并储存在脑下垂体部的氨基酸。OT调节密切的选择性社会纽带的形成，并与自闭症谱系障碍(ASD)的社会功能障碍有关。最近有大量研究探讨鼻腔催产素对人类行为的影响，包括建议将其用于治疗包括自闭症在内的各种涉及社会缺陷的精神病理学。对12-18岁的儿童使用鼻内OT治疗自闭症的第二阶段试验正在进行中(ClinicalTrials.gov标识符：NCT01256060)，在美国，OT已经经常被开给患有自闭症的儿童。令人担忧的是，我们在动物模型中的初步数据显示，虽然鼻腔给药在短期内对社会行为有积极影响，但某些剂量的长期影响是负面的。除了我们的初步研究外，还没有关于在人类或任何动物模型中慢性鼻腔使用OT的长期研究；这就是我们在这项研究中建议做的。本研究的目的是考察慢性鼻腔注射OT对两种选择性社会行为的动物模型(草原田鼠和Titi猴子)以及一种自闭症社会缺陷的小鼠模型的发育影响。在啮齿动物模型中，给药的剂量、频率和年龄都会有所不同。课程将探讨给药的直接社会影响，以及对社会行为、重复行为和焦虑的长期影响，以及催产素和加压素系统的变化，以及对社会刺激的功能神经变化。在Titi猴子身上，我们将使用临床试验中使用的剂量，并检查对社会行为、重复行为和焦虑的短期和长期影响。最后，我们将通过PET成像检查慢性鼻腔OT或赋形剂治疗的Titi猴子局部脑葡萄糖代谢的变化，重点关注产生或具有OT受体的区域。

DESCRIPTION (provided by applicant): Autism is a common, impairing neurodevelopmental disorder involving deficits in social interaction and social communication. Oxytocin (OT) is a nine amino acid peptide produced in the hypothalamus and stored in the posterior pituitary. OT regulates the formation of close selective social bonds and has been implicated in the social dysfunction found in autism spectrum disorders (ASD). There has been a proliferation of recent research examining the effects of intranasal OT on human behavior, including suggestions for its use as a therapeutic for various psychopathologies involving social deficits, including ASD. Phase 2 trials for use of intranasal OT in autism are underway for children 12-18 years of age (Clinicaltrials.gov identifier: NCT01256060), and OT is already frequently prescribed in the United States to children with ASD. Alarmingly, our preliminary data in animal models show that while administration of intranasal OT has positive effects of social behavior in the short-term, long-term effects at some dosages are negative. Aside from our pilot study, there have been no long-term studies of chronic intranasal OT use in humans or in ANY animal model; that is what we propose to do in this study. The aim of the current study is to examine the developmental effects of chronic intranasal OT administered to two animal models of selective social behavior (prairie voles and titi monkeys), as well as one mouse model of the social deficits of autism. In the rodent models, dosage, frequency, and age of administration will be varied. The immediate social effects of administration, as well as long-term effects on social behavior, repetitive behavior, and anxiety will be explored, as well as changes to the OT and vasopressin systems and functional neural changes in response to social stimuli. In titi monkeys, we will administer the dosage being used in clinical trials and examine the short-term and long-term effects on social behavior, repetitive behavior, and anxiety. Finally, we will examine changes to local cerebral glucose metabolism in titi monkeys treated with chronic intranasal OT or vehicle via PET imaging, with a focus on areas that produce or have receptors for OT.