Anxiolytic-like effects of the dual orexin receptor antagonist daridorexant in rats

Abstract Dual orexin receptor antagonists (DORAs) belong to a novel class of sleep medications that function by blocking the actions of wakefulness-promoting orexin neuropeptides in sleep-wake centers of the brain. Orexins also transmit signals to brain nuclei that regulate emotions and stress responses. The effects of DORAs on anxiety-like reactions requires further exploration. The hyperarousal theory of insomnia suggests an underlying overactivation of the body’s stress response systems, and a considerable proportion of insomnia patients suffers from concurrent anxiety disorders. Hence, it is important for physicians to be certain that novel insomnia treatments do not exacerbate, but rather alleviate, patients’ anxiety and psychological stress responses. Our aim was to test the effect of the new DORA daridorexant on diverse anxiety- and fear-evoked behavioral and physiological reactions in rats to gain first insight into the drug’s potential in humans. Daridorexant, given orally at 10, 30 and 100 mg/kg 1 h before testing, resulted in a dose-dependent reduction of fear-potentiated acoustic startle (FPS) reactions, schedule-induced polydipsia (SIP) and social stress-induced hyperthermia and tachycardia (SIH/T). Furthermore, under non-stressful, basal conditions, daridorexant also reduced heart rate in spontaneously hypertensive rats, which are a model of endogenous sympathetic hyperactivation that can occur in insomnia or anxiety disorders. Daridorexant had no effect on ultrasound-induced, panic-like, defensive behavior (UIDB). We conclude that daridorexant rather attenuated and did not enhance fear/stress responses in rats. It was effective in models that simulate endophenotypes that are specific for post-traumatic stress, obsessive-compulsive, and social anxiety disorder.