Wang Lien, Clark Erin A, Hanratty Lynsey, Koblan Kenneth S, Foley Andrew, Dedic Nina, Bristow Linda J
Sumitomo Pharma America, Inc., Marlborough, MA, USA.
Berand Neuropharmacology, Ltd., Dublin, Ireland.
Pharmacol Biochem Behav. 2024 Dec;245:173862. doi: 10.1016/j.pbb.2024.173862. Epub 2024 Aug 26.
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-HT 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-HT 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-HT receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment.
尽管自闭症谱系障碍（ASD）的患病率不断上升，但针对其核心症状和相关症状的药物治疗仍存在重大未满足需求。虽然一些非典型抗精神病药物已被批准用于治疗相关的易怒和攻击行为，但其使用受到大量副作用的限制。本研究旨在首先开发行为学方法，以探索ASD大鼠产前丙戊酸（VPA）模型中的挫败感、易怒和攻击行为表型。此外，我们研究了两种新机制，即5-羟色胺（5-HT）和痕量胺相关受体1（TAAR1）激动作用，减轻这些行为的潜力。将暴露于产前VPA的雄性后代训练至在提示操作性任务中达到稳定表现，随后在操作性挫败试验、瓶刷试验和住家入侵者试验中进行药理学评估。与对照组相比，暴露于VPA的大鼠表现出表明挫败感和易怒的行为，以及攻击性增加。在操作性试验中先前经历过挫败事件的动物中，类似易怒的行为和攻击性进一步加剧。与赋形剂相比，单次给予5-HT激动剂CP-94253或TAAR1激动剂RO5263397可减轻类似挫败的行为。此外，两种激动剂在正常和挫败条件下均降低了类似易怒的行为。虽然CP-94253在两种条件下的住家入侵者试验中均降低了攻击性，但RO5263397仅在先前经历过挫败事件的大鼠中产生作用。我们的研究描述了ASD大鼠产前VPA模型中先前未描述的挫败感、易怒和攻击行为表型。给予选择性TAAR1或5-HT受体激动剂可减轻这些缺陷，这为在ASD治疗中进一步探索这两个靶点提供了依据。
