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.