L-NAME bidirectionally modulates the behavioral consequences of acute sleep restriction in chronically stressed mice:...

This study investigated the mediating role of the nitric oxide (NO) system in the behavioral interplay between chronic stress and acute sleep restriction. Using the hole-board test in mice, we first established that four weeks of chronic restraint stress (CRS) reliably induced an anxiety-like phenotype, characterized by reduced head-dipping, and also decreased grooming behavior. A subsequent 3 h sleep restriction (SR) significantly prevented this anxiety-like suppression of head-dipping, restoring exploratory behavior to control levels, while also reversing the stress-induced reduction in grooming. Pharmacological manipulation revealed a state-dependent role for NO signaling. The NO precursor L-Arginine (25 and 50 mg/kg, i.p.) had no effect in naïve mice but selectively attenuated SR-induced increases in rearing and grooming in CRS mice. In contrast, the nitric oxide synthase inhibitor L-NAME (5 and 10 mg/kg, i.p.) exerted anxiogenic effects in naïve mice (reducing head-dips and increasing grooming) but produced an anxiolytic-like effect in CRS mice by increasing head-dip counts. Furthermore, in sleep-restricted CRS mice, L-NAME synergistically enhanced the SR-induced increase in head-dips, while suppressing the grooming response. Collectively, these findings demonstrate a critical and state-dependent bidirectional modulation by the NO system, highlighting its key role in integrating prior stress experience to shape behavioral responses to subsequent sleep-wake disruption.