Nitric oxide and sleep in the rat: a puzzling relationship.

To date, only a few studies indicate that nitric oxide may play a role in the regulation of the sleep-wake cycle. However, data reported are controversial and the part played by nitric oxide in sleep-wake cycle regulation still remains uncertain. In the present report, we studied the effects on sleep amounts of two different nitric oxide synthase inhibitors: N-nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, and 7-nitro-indazole, a specific inhibitor of neuronal nitric oxide synthase. The above compounds were administered via two routes, i.e. intraperitoneally or locally in the dorsal raphe nucleus, a structure involved in sleep regulation. In order to evaluate their efficiency to inhibit nitric oxide synthesis in the rat brain, they were first administered intraperitoneally to a group of animals, and the cortical release of nitric oxide was determined by means of voltammetric measurements. N-Nitro-L-arginine methyl ester (100 mg/kg, i.p.) did not affect the cortical release of nitric oxide, whereas it increased both slow-wave sleep and paradoxical sleep durations. On the contrary, 7-nitro-indazole (40 mg/kg, i.p.) significantly decreased the cortical release of nitric oxide (-25%) and paradoxical sleep duration. Furthermore, following microinjection of either N-nitro-L-arginine methyl ester or 7-nitro-indazole at 100 ng/0.20 microl into the nitric oxidergic cell area of the dorsal raphe nucleus, decreases in paradoxical sleep duration were obtained (-32.8% and -25.3%, respectively). The results obtained support the existence of a duality in the sleep regulation modalities exerted by nitric oxide, i.e. a peripheral inhibiting influence and a central facilitating role for the nitric oxide-serotoninergic neurons of the dorsal raphe nucleus.