Psychology Department, Fairfield University, CT, USA.
Behav Pharmacol. 2021 Oct 1;32(7):561-570. doi: 10.1097/FBP.0000000000000650.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social behaviors and communication. In rodents and humans, prenatal exposure to antiepileptic valproic acid is associated with an increased risk for autistic-like characteristics. One potential treatment is oxytocin, a prosocial neuropeptide that can be delivered intranasally. However, the sex-specific effects of valproic acid exposure and intranasal oxytocin treatment on behavior have not been fully explored. Pregnant Long Evans rats were administered valproic acid (500 mg/kg) or saline midday on gestational day 12, and after weaning, male and female pups were assigned to control (saline-saline), valproic acid-saline, or valproic acid-oxytocin groups. Oxytocin (0.8 IU/kg) or saline was delivered intranasally 30-60 min before tests for anxiety-like behaviors (elevated plus maze), social interactions (sociability) and sociosexual behaviors (partner preference, 50 kHz vocalizations and scent marking). Prenatal exposure to valproic acid resulted in sex-specific differences in behavior. When compared to controls, valproic acid males showed enhanced anxiety-like behaviors in adolescence and fewer scent marks in adulthood, while valproic acid females showed reduced sexual (partner) preference as adults. Intranasal oxytocin was anxiolytic for valproic acid males, but moderately anxiogenic for valproic acid females, and in both sexes it surprisingly impaired social interactions in the sociability test. Furthermore, intranasal oxytocin failed to improve sociosexual deficits in valproic acid rats. These findings highlight the importance of conducting preclinical studies in both sexes, and suggest that oxytocin may be an effective treatment in animal models with heightened anxiety-like behaviors.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交行为和沟通方面的缺陷。在啮齿动物和人类中，产前暴露于抗癫痫药物丙戊酸会增加出现类似自闭症特征的风险。一种潜在的治疗方法是催产素，这是一种可以鼻内给药的亲社会神经肽。然而，丙戊酸暴露和鼻内催产素治疗对行为的性别特异性影响尚未得到充分探索。在妊娠第 12 天的中午，给怀孕的长爪沙鼠给予丙戊酸（500mg/kg）或生理盐水，然后在断奶后，雄性和雌性幼崽被分配到对照组（生理盐水-生理盐水）、丙戊酸-生理盐水或丙戊酸-催产素组。在测试焦虑样行为（高架十字迷宫）、社交互动（社交性）和社交性行为（伴侣偏好、50kHz 发声和气味标记）之前 30-60 分钟，鼻内给予催产素（0.8IU/kg）或生理盐水。丙戊酸暴露导致行为出现性别特异性差异。与对照组相比，丙戊酸雄性在青春期表现出增强的焦虑样行为，成年后气味标记减少，而丙戊酸雌性在成年后表现出性（伴侣）偏好减少。鼻内催产素对丙戊酸雄性具有抗焦虑作用，但对丙戊酸雌性具有适度的焦虑作用，并且在两性中，它出人意料地损害了社交性测试中的社交互动。此外，鼻内催产素未能改善丙戊酸大鼠的社交性行为缺陷。这些发现强调了在两性中进行临床前研究的重要性，并表明催产素可能是治疗具有增强的焦虑样行为的动物模型的有效方法。
