Solriamfetol enhances alertness and cognitive performance in mice

Solriamfetol [(R)-2-amino-3-phenylpropylcarbamate hydrochloride], a phenylalanine derivative initially developed as potential antidepressant, was shown by our group in 2009 to have potent, dose-dependent wake-promoting activity in mice. Solriamfetol (Sunosi(R)) is used since 2019 to counteract excessive daytime sleepiness (EDS) in patients with narcolepsy and obstructive sleep apnea (OSA). It has several advantages over other stimulants, notably that it is not associated with strong psychomotor activity, does not induce behavioral stereotypies and anxiety-related behaviors, in contrast to amphetamines and modafinil. Its mode-of-action remains incompletely solved. It was reported to act as dual dopamine-and-noradrenaline-reuptake-inhibitor (DNRI), and more recently, to have TAAR1 agonist activity. In our early mouse study, we showed that, at 150 mg/kg, Solriamfetol induces a state of wakefulness featuring a dramatic upregulation of EEG gamma activity, a cognitive biomarker, and the expression of genes implicated in neural plasticity, learning and memory. Besides being prescribed to treat EDS, central nervous system stimulants are commonly used as smart drugs to enhance cognition in normal individuals. Therefore, based on Solriamfetols ability to potently induce wakefulness, EEG and molecular markers of learning and memory, we aimed to determine whether it could improve the cognitive performance of wild-type mice. Because at doses of 50-150 mg/kg, Solriamfetol induced an alert waking state associated with low mobility, thus precluding behavioral testing, we used lower doses (1-3 mg/kg) to assess cognition in a battery of tests evaluating short- or long-term memory and spatial navigation. We found that compared to saline, Solriamfetol 3 mg/kg consistently improves sustained attention for a novel object, as well as spatial memory. Next, to determine the brain activity correlates of enhanced cognition, we performed EEG/EMG recording while the mice performed the novel object recognition (NOR) task. Power spectral density (PSD) analysis revealed that 3 mg/kg Solriamfetol reduced EEG delta (an index of sleepiness) during exposure to a novel context, and enhanced EEG fast-gamma (an index of mental concentration) during execution of the NOR task. Taken together, our data demonstrate that low-dose Solriamfetol improves memory and attentional performance in wild-type mice.