The role of vasopressin in the social deficits of autism

加压素在自闭症社交缺陷中的作用

• 批准号: 8706972
• 负责人: ANTONIO HARDAN
• 金额: $ 19.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706972
• 关键词: Acute; Address; Adolescent; Adult; Adverse effects; Aftercare; Animals; Antipsychotic Agents; Argipressin; Autistic Disorder; Basic Science; Behavioral; Biology; Blood specimen; Brain; Child; Clinical Medicine; Cognitive; Complex; Cooperative Behavior; Cues; DSM-IV; Data; Development; Diabetes Insipidus; Diagnostic Procedure; Disease; Dose; Double-Blind Method; Early Intervention; Emotional; Emotions; Enuresis; Exhibits; Eye; Face; Family member; Female; Foundations; Funding; Goals; Human; Impairment; Individual; International Unit; Intervention; Intranasal Administration; Laboratories; Lead; Learning; Measures; Memory; Mind; Names; Neuropeptides; Outcome; Outcome Measure; Oxytocin; Oxytocin Receptor; Parents; Participant; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Plasma; Play; Pre-Clinical Model; Process; Quality of life; Questionnaires; Randomized; Research; Role; Secure; Severities; Social Behavior; Social Functioning; Social Identification; Societies; Subgroup; Symptoms; Testing; Time; Vasopressins; Weight Gain; Wing; aged; argipressin receptor; base; cohort; design; effective therapy; efficacy testing; gaze; head-to-head comparison; improved; male; meetings; mouse model; novel; pre-clinical; pre-clinical research; preclinical study; primary outcome; public health relevance; receptor; secondary outcome; social; social cognition; theories; tool; treatment response

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.

描述（由申请人提供）：自闭症的特点是核心社交障碍，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（例如烦躁），具有不利的副作用（例如嗜睡、体重增加），并且在治疗这种疾病的社会特征方面仍然无效。因此，开发专门针对社会功能的新药物将解决未满足的关键需求。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发挥着关键作用。例如，药物或转基因引起的 AVP 或 OT 损伤会在动物中产生各种社会缺陷。重要的是，单剂量鼻内施用的 OT 可以改善自闭症患者的多种复杂的社会功能（例如，社会信息处理、情绪识别）。尽管鼻内注射 AVP 可改善神经正常个体的社会认知和记忆，并且多年来已安全用于治疗尿崩症和夜间遗尿症，但尚无研究测试 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 OT 受体缺失 (Oxtr-/-) 的自闭症小鼠模型中，社交行为是通过大脑 AVP V1a 受体选择性调节的，并且 AVP 给药可以挽救这些动物的社交缺陷。此外，在其他临床前模型中，AVP 通过 V1a 受体发挥作用，比 OT 更有选择性地增强男性社会行为。相比之下，OT 通过 OT 受体发挥作用，更有选择性地增强女性的社会行为。鉴于自闭症是一种主要偏向男性的疾病，在动物中，AVP 对于男性社会行为比 OT 更重要，即便如此，急性 OT 确实对男性自闭症患者有帮助，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 是否可以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。我们将使用双盲、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 岁患有自闭症的高功能男性和女性的社交缺陷的影响。研究结果衡量的是家长对社会反应量表（SRS）评分的改进以及基于实验室的社会行为和认知评估（即面部情绪识别、对社会线索的目光注视、社会记忆和社会感知能力）。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启动 AVP 和 OT 治疗的头对头比较。这项研究很有可能开发出针对自闭症患者社交障碍的第一种有效治疗方法和早期干预措施。