Neuropeptide S Counteracts Reserpine-induced Depression-like Behaviors And Sleep Disorders

Depression is closely associated with paradoxical sleep (PS) disorders, although the causality between depression and sleep disorders is controversial. PS as a biological indicator for diagnosis and treatment is much used in currently depressive research. There are significant contradictions between the efficacy and side effects of antidepressants used in clinical treatment. It is urgently necessary to find the new antidepressants with less side effects. Neuropeptide S (NPS), a endogenous neuromodulator, is newly found to regulate multiple central function. We guess NPS is involved in antidepressant regulation based on its cognate receptor (NPSR) widely distributed in the brain. A depressive model-induced by reserpine (Res) was employed in the present study to evaluate the effects of NPS on depression-like behaviors and sleep disorders in rats.Methods:The forced swimming test was used to detect the immobility time in reserpine (6mg/kg, IP)-, Res (IP)+NPS (1nmol, ICV)-, or Res (IP)+clomipramine (CLI, a tricyclic antidepressants as positive control,50mg/kg, IP)-treated rats, respectively. The sleep-wake cycle in three groups were analyzed by EEG/EMG recording.Results:The immobility time on the second day after Res injection increased (145.27±10.52min vs92.24±9.63min, p<0.001) compared with control group. However, Res+CLI-and Res+NPS-treated rats respectively decreased the immobility time (117.35±6.55min vs145.27±10.52min, p<0.05) and (92.95±10.23min vs142.42±6.12min, p<0.01) compared to Res-treated rats.Res-treated rats induced an increase in PS by63%(p<0.01), in SWS by20%(p<0.05), and a decrease in W by44%(p<0.05) compared to control rats, respectively, from8:00to12:00h on the second day. The analysis of sleep-wakefulness states showed that Res-treated rats respectively increased the stage transition numbers from S to P by1.3-fold (p<0.05) and from P to W by1.4-fold (p<0.05), the mean episode numbers of PS decreased by24%(p<0.05). In the calculation of total amount for12-h light phase, Res induced an increase in PS by24%(p<0.05) and SWS by14%(p<0.05), but a decrease in W by30%(p<0.05). Furthermore, the amount for24h, Res increased PS by14%(p<0.05) and SWS by11%(p<0.05), and decreased W by11%(p<0.05).Res+CLI suppressed PS up to5hours from9:00h to14:00h by100%,100%,78%,69%and69%per hour respectively compared with Res+saline. The PS was rebounded in dark phase while the CLI effect was suggested to diminish. In the calculation of total amount for11-h light phase, PS was reduced by42%(p<0.001), but SWS and W were not different from Res+saline. The architecture of sleep-wakefulness analysis from9:00to14:00h showed that CLI administration in Res-treated rats increased PS latency by494%(p<0.001), decreased the mean episode number by76%(p<0.001) and the mean episode duration by33%(p<0.05) compared with control group.NPS was administered at10:00h on the second day after Res treatment, and then suppressed PS from10:00to12:00h (reduction by79%and61%, respectively). Meanwhile, SWS was decreased, and W was increased. As CLI, PS and SWS were increased in dark phase. The architecture of sleep-wakefulness analysis from10:00to12:00h showed that NPS administration in Res-treated rats increased PS latency by133%(p<0.001), decreased the mean episode number by61%(p<0.001) and the mean episode duration by42%(p<0.05) compared with control group.Conclusions:Res induces depression-like behaviors and sleep disorders characterized with PS increase in rats. NPS, as CLI, counteracts Res-induced depression-like behaviors and sleep disorders. NPS antagonizes depression-like sleep disorders through reducing sleep (PS and SWS) time and increasing W. However, CLI suppresses PS without reducing SWS.