Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA; Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
Neuropharmacology. 2019 Jan;144:301-311. doi: 10.1016/j.neuropharm.2018.10.036. Epub 2018 Nov 3.
Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.
目前，尚无有效的药物治疗策略可以有效治疗自闭症谱系障碍（ASD）中的社交缺陷。神经激素催产素在多种类型的社交行为中发挥作用，被认为是治疗 ASD 中社交障碍和其他症状的一种潜在方法。然而，从药物治疗的角度来看，催产素有几个缺点，无法作为标准的临床治疗方法，包括快速代谢、脑穿透率低以及与加压素（抗利尿激素）受体的活性。本研究描述了一个临床前筛选项目的研究结果，该项目旨在评估催产素受体（OXTR）激动剂和催产素代谢物作为更优化治疗的潜在临床用途。我们首先使用基于细胞的体外测定法和 BALB/cByJ 自闭症样社交缺陷小鼠模型的行为测试，研究了两种合成催产素类似物 TC-OT-39 和卡贝缩宫素。虽然 TC-OT-39 和 carbetocin 均可选择性地激活 OXTR，但这两种合成激动剂在 BALB/cByJ 模型中均无促进社交的作用。我们随后评估了两种催产素代谢物：OT(4-9)和 OT(5-9)。虽然 OT(5-9) 不能改善社交缺陷，但代谢物 OT(4-9) 以剂量依赖性方式导致 BALB/cByJ 模型中出现明显的社交偏好。在结束 OT(4-9)（2.0mg/kg）亚慢性治疗方案后的 24 小时和 12 天，均可观察到社交能力增强。总之，这些结果表明，催产素的社交作用可能是通过催产素代谢物的下游活性介导的，这为针对 ASD 的药物发现提供了新的靶点。
