Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, 94304, USA.
Neurotherapeutics. 2023 Mar;20(2):546-563. doi: 10.1007/s13311-022-01328-2. Epub 2022 Dec 21.
Wake-promoting agents are used for the management of excessive daytime sleepiness caused by narcolepsy. Clinical and preclinical data suggests that solriamfetol, a novel dopamine and norepinephrine reuptake inhibitor, is a promising therapeutic option for excessive daytime sleepiness. We provide the first head-to-head comparison of in vivo efficacy between modafinil and solriamfetol in narcoleptic mice. Both compounds induced potent wake-promoting effects in littermate wild-type and orexin-tTA; TetO-DTA mice when dosed at active and resting phases. However, neither modafinil nor solriamfetol alleviated cataplexy. Remarkably, modafinil significantly induced locomotor activity but solriamfetol had small effects. Awake electroencephalogram profiles revealed that modafinil augmented theta oscillation in a dose-dependent manner, but, on the contrary, the response to solriamfetol was blunted, reflecting the differences in their neurochemical properties and anxiogenic effects. Drug-induced anxiety-related behaviors were evaluated at equipotent wake-promoting doses in WT and DTA mice using the elevated plus maze and forced swim tests. Importantly, 100 mg/kg of modafinil significantly produced anxiety-related behaviors in WT mice, whereas 150 mg/kg of solriamfetol did not have anxiogenic effects. On the other hand, DTA mice exhibited trait anxiety and altered drug responses. Our results suggest that solriamfetol potently promotes wakefulness without psychomotor effects and without inducing anxiety-related behaviors.
觉醒促进剂用于治疗嗜睡症引起的日间过度嗜睡。临床前和临床数据表明，新型多巴胺和去甲肾上腺素再摄取抑制剂索利那新是治疗日间过度嗜睡的有希望的治疗选择。我们首次对头对头比较了莫达非尼和索利那新在嗜睡症小鼠中的体内疗效。当在活动期和休息期给药时，这两种化合物都在同窝野生型和食欲素-tTA； TetO-DTA 小鼠中引起了强烈的促醒作用。然而，莫达非尼和索利那新都不能缓解猝倒。值得注意的是，莫达非尼显著诱导运动活动，但索利那新的作用较小。清醒脑电图分析表明，莫达非尼以剂量依赖性方式增强θ振荡，但相反，索利那新的反应被削弱，反映了它们的神经化学特性和焦虑作用的差异。在 WT 和 DTA 小鼠中，使用高架十字迷宫和强迫游泳试验，在等效促醒剂量下评估药物引起的焦虑相关行为。重要的是，100mg/kg 的莫达非尼在 WT 小鼠中显著产生了焦虑相关行为，而 150mg/kg 的索利那新没有焦虑作用。另一方面，DTA 小鼠表现出特质焦虑和改变的药物反应。我们的研究结果表明，索利那新强烈促进觉醒，而没有精神运动作用，也没有引起焦虑相关行为。
