The role of nitric oxide in physiological sleep regulation

Nitric oxide is a free radical neurotransmitter that is involved in a number of physiological and pathological processes. Preliminary evidence suggests that nitric oxide could play a role in regulating vigilance. The experiments described in this thesis sought to characterize the involvement of nitric oxide in the homeostatic and circadian process of sleep regulation. To examine the role of nitric oxide in the circadian component of sleep regulation, nitric oxide donors and a nitric oxide synthase inhibitor were microinjected directly to the suprachiasmatic nucleus, a major output of the suprachiasmatic nucleus, the sub-paraventricular zone, or the area surrounding the circadian pacemaker (diencephalic region) and sleep responses were recorded. Anterior diencephalic microinjection of a nitric oxide synthase inhibitor greatly increased rapid-eye-movement sleep, and these effects were also seen after sub-paraventricular zone microinjection of the nitric oxide synthase inhibitor. On the other hand, when the microinjections were aimed at the suprachiasmatic nucleus, nitric oxide donor suppressed rapid-eye-movement sleep. Systemic injection of a nitric oxide synthase inhibitor at dark-onset greatly increased rapid-eye-movement sleep. These findings are consistent with the hypothesis that nitric oxide may have arousal-promoting effects, mediated in part by the suprachiasmatic nucleus. In terms of the homeostatic process of sleep regulation, systemic injection of a nitric oxide synthase inhibitor shortened in length and decreased in amplitude the sleep rebound to sleep deprivation. Also, in response to sleep deprivation, nitric oxide synthase enzyme activity was decreased in brain nuclei involved in sleep-wake cycle regulation. On the other hand, nitric oxide synthase protein amounts were increased following extended wakefulness, especially inducible nitric oxide synthase in the basal forebrain. Systemic injection of a nitric oxide synthase inhibitor at a time when homeostatic sleep pressure is spontaneously highest, at light onset, also decreased sleep amounts, suggesting that and intact nitric oxide-ergic signaling cascade is necessary for proper sleep responses to be mounted after both spontaneous and forced wakefulness. In addition, preliminary studies support the hypothesis that cyclic guanosine monophosphate could be a signaling molecule involved in carrying out at least part of the sleep-modulatory actions of nitric oxide