尽管自闭症谱系障碍(ASD)的患病率上升,对于解决其核心症状和相关症状的药物疗法,仍有大量未满足的需求。虽然一些非典型抗精神病药物已被批准用于管理相关的易怒和攻击性,它们的使用受到大量副作用的限制。这项研究的目的首先是开发行为措施来探索挫折,ASD大鼠产前丙戊酸(VPA)模型中的易怒和攻击表型。此外,我们研究了两种新机制的潜力,5-HT1B和TAAR1激动,缓解这些行为。对暴露于产前VPA的雄性后代进行了训练,以在提示的操作任务中实现稳定的表现,然后在操作挫折测试中进行药理学评估,瓶刷试验和居民闯入试验。暴露于VPA的大鼠表现出沮丧和易怒的行为,与对照组相比,攻击性也有所增加。在先前在操作测试中经历挫折事件的动物中,易怒的行为和攻击性进一步加剧。与载体相比,5-HT1B激动剂CP-94253或TAAR1激动剂RO5263397的单次施用减弱了挫折样行为。此外,在正常和挫折条件下,这两种激动剂都能降低易怒样行为。虽然CP-94253在两种条件下都降低了居民入侵者测试中的攻击性,RO5263397仅在先前经历挫折事件的大鼠中产生作用。我们的研究描述了以前未表征的挫折表型,烦躁,ASD大鼠产前VPA模型的侵袭性。给予选择性TAAR1或5-HT1B受体激动剂缓解了这些缺陷,有必要进一步探索ASD治疗中的两个目标。
Despite the rising prevalence of autism spectrum disorder (ASD), there remains a significant unmet need for pharmacotherapies addressing its core and associative symptoms. While some atypical antipsychotics have been approved for managing associated irritability and aggression, their use is constrained by substantial side effects. This study aimed firstly to develop behavioral measures to explore
frustration, irritability and aggression phenotypes in the rat prenatal valproic acid (VPA) model of ASD. Additionally, we investigated the potential of two novel mechanisms, 5-HT1B and TAAR1 agonism, to alleviate these behaviors. Male offspring exposed to prenatal VPA were trained to achieve stable performance on a cued operant task, followed by pharmacological assessment in an operant
frustration test, bottle brush test and resident intruder test. VPA exposed rats demonstrated behaviors indicative of
frustration and irritability, as well as increased aggression compared to controls. The irritability-like behavior and aggression were further exacerbated in animals previously experiencing a frustrative event during the operant test. Single administration of the 5-HT1B agonist CP-94253 or TAAR1 agonist RO5263397 attenuated the
frustration-like behavior compared to vehicle. Additionally, both agonists reduced irritability-like behavior under both normal and frustrative conditions. While CP-94253 reduced aggression in the resident intruder test under both conditions, RO5263397 only produced effects in rats that previously experienced a frustrative event. Our study describes previously uncharacterized phenotypes of
frustration, irritability, and aggression in the rat prenatal VPA model of ASD. Administration of selective TAAR1 or 5-HT1B receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment.