The role of vasopressin in the social deficits of autism

描述（由申请人提供）：自闭症的特征是核心社会障碍，限制了患者形成和维持有意义的社会关系的能力。目前，抗精神病药物是唯一被批准用于治疗自闭症的药物治疗选择。然而，这些药物主要针对相关症状（如易怒），有不良副作用（如嗜睡、体重增加），并且对治疗该障碍的社交特征无效。因此，开发专门针对社会功能的新药物将解决一个关键的未满足需求。大量研究表明，密切相关的神经肽精氨酸-加压素（AVP）和催产素（OT）在适应性社会功能中起着关键作用。例如，药理学或转基因诱导的AVP或OT损伤会在动物中产生各种社会缺陷。重要的是，单剂量鼻内给药可以改善自闭症患者的几种复杂的社会功能（例如，处理社会信息，情绪识别）。虽然鼻内给药AVP可以改善神经正常个体的社会认知和记忆，并且多年来一直安全地用于治疗尿崩症和夜间遗尿症，但没有研究测试AVP治疗对自闭症个体社会功能的影响。然而，临床前研究表明，在一个OT受体缺失（Oxtr-/-）的自闭症小鼠模型中，社会行为是通过脑AVP V1a受体选择性调节的，AVP给药可以挽救这些动物的社会缺陷。此外，在其他临床前模型中，AVP通过V1a受体起作用，比OT更有选择性地增强了男性的社会行为。相比之下，OT通过OT受体起作用，更有选择性地增强了女性的社会行为。鉴于自闭症主要是一种男性偏见的疾病，在动物中，AVP比OT对男性社会行为更重要，即使如此，急性OT确实有助于男性自闭症患者，我们假设AVP在治疗自闭症的社会症状方面特别有效。第一步是测试AVP是否能改善自闭症患者的社交障碍，以及男性对AVP的反应是否比女性更强烈。我们将采用双盲、随机、安慰剂对照、平行设计，测试单剂量（20 IU）和4周（20 IU BID）鼻内AVP给药对50名6至12岁自闭症高功能男性和女性的社会缺陷的影响。研究结果测量了父母对社会反应量表（SRS）的评分和基于实验室的社会行为和认知评估（即面部情绪识别、对社会线索的眼神注视、社会记忆和社会感知能力）的改善。与临床前证据一致，我们预测AVP将改善自闭症患者的社会功能。这项研究的数据将用于获得额外的资金，以在更大的自闭症队列中进行AVP和OT治疗的正面比较。这项研究具有很高的潜力，可以为自闭症患者的社会障碍提供第一批有效的治疗方法和早期干预措施。

DESCRIPTION (provided by applicant): Autism is characterized by core social impairments which limit patients' ability to form and maintain meaningful social relationships. At present, antipsychotic medications are the only pharmacotherapeutic option approved to treat autism. However, these agents mainly target associated symptoms (e.g., irritability), have unfavorable side-effects (e.g., lethargy, weight gain), and remain ineffective in treating the social features f this disorder. Developing new medications that specifically target social functioning thus will address a critical unmet need. A large body of research has shown that the closely related neuropeptides arginine-vasopressin (AVP) and oxytocin (OT) play critical roles in adaptive social functioning. For instance, AVP or OT impairments induced pharmacologically or transgenically produce a variety of social deficits in animals. Importantly, single-doses of intranasally administered OT improve several complex social functions (e.g., processing of social information, emotion recognition) in people with autism. Although intranasally administered AVP improves social cognition and memory in neurotypical individuals, and has been used safely for years to treat diabetes insipidus and nocturnal enuresis, no studies have tested the effects of AVP treatment on social functioning in individuals with autism. However, preclinical research has shown that in an OT receptor null (Oxtr-/-)mouse model of autism, social behavior is modulated selectively through brain AVP V1a receptors and that AVP administration rescues social deficits in these animals. Moreover, in other preclinical models, AVP, acting via V1a receptors, more selectively enhances male social behavior than does OT. In contrast, OT, acting via OT receptors, more selectively enhances female social behavior. Given that autism is a predominantly male-biased disorder, that in animals AVP is more important than OT for male social behavior, and that even so, acute OT does help male autistic patients, we hypothesize that AVP will be particularly effective in treating social symptoms in autism. The first step is to test whether AVP ameliorates social impairments in autism and whether males respond more robustly to AVP than females. We will test the effects of single-dose (20 IU) and 4-week (20 IU BID) intranasal AVP administration on social deficits in 50 high functioning males and females with autism aged 6 to 12 years using a double-blind, randomized, placebo controlled, parallel design. Study outcome measures are improvements on parent ratings of the Social Responsiveness Scale (SRS) and laboratory-based assessments of social behavior and cognition (i.e., facial emotion recognition, eye gaze to social cues, social memory, and social perceptual abilities). Consistent with preclinical evidence, we predict that AVP will improve social functioning in individuals with autism. Data from this study will be leveraged to secure additional funding to initiate head-to-head comparisons of AVP and OT treatment in a larger autism cohort. This research has high potential to lead to the development of the first effective treatments and earlier interventions for social impairments in individuals wth autism.