Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor, stimulates GH release, appetite, and weight gain in humans and rodents. Synthetic GHSs modulate sleep electroencephalogram (EEG) and nocturnal hormone secretion. We studied the effect of 4 x 50 microg of ghrelin administered hourly as intravenous boluses between 2200 and 0100 on sleep EEG and the secretion of plasma GH, ACTH, cortisol, prolactin, and leptin in humans (n = 7). After ghrelin administration, slow-wave sleep was increased during the total night and accumulated delta-wave activity was enhanced during the second half of the night. Rapid-eye-movement (REM) sleep was reduced during the second third of the night, whereas all other sleep EEG variables remained unchanged. Furthermore, GH and prolactin plasma levels were enhanced throughout the night, and cortisol levels increased during the first part of the night (2200-0300). The response of GH to ghrelin was most distinct after the first injection and lowest after the fourth injection. In contrast, cortisol showed an inverse pattern of response. Leptin levels did not differ between groups. Our data show a distinct action of exogenous ghrelin on sleep EEG and nocturnal hormone secretion. We suggest that ghrelin is an endogenous sleep-promoting factor. This role appears to be complementary to the already described effects of the peptide in the regulation of energy balance. Furthermore, ghrelin appears to be a common stimulus of the somatotropic and hypothalamo-pituitary-adrenocortical systems. It appears that ghrelin is a sleep-promoting factor in humans.
Aging is associated with dramatic reductions in sleep continuity and sleep intensity. Since gaboxadol, a selective GABA A receptor agonist, has been demonstrated to improve sleep consolidation and promote deep sleep, it may be an effective hypnotic, particularly for elderly patients with insomnia. In the present study, we investigated the effects of subchronic gaboxadol administration on nocturnal sleep and its residual effects during the next days in elderly subjects. This was a randomized, double-blind, placebo-controlled, balanced crossover study in 10 healthy elderly subjects without sleep complaints. The subjects were administered either placebo or 15 mg gaboxadol hydrochloride at bedtime on three consecutive nights. Sleep was recorded during each night from 2300 to 0700 h and tests assessing attention (target detection, stroop test) and memory function (visual form recognition, immediate word recall, digit span) were applied at 0900, 1400, and 1700 h during the following days. Compared with placebo, gaboxadol significantly shortened subjective sleep onset latency and increased self-rated sleep intensity and quality. Polysomnographic recordings showed that it significantly decreased the number of awakenings, the amount of intermittent wakefulness, and stage 1, and increased slow wave sleep and stage 2. These effects were stable over the three nights. None of the subjects reported side effects. Next-day cognitive performance was not affected by gaboxadol. Gaboxadol persistently improved subjective and objective sleep quality and was devoid of residual effects. Thus, at the employed dose, it seems an effective hypnotic in elderly subjects.
The cytokine interleukin (IL)-1 is a key mediator of the somnogenic response to immune challenge. In this vehicle-controlled study we evaluated circadian interference with the sleep-promoting effects of IL-1 beta. In two randomized experiments, rats were injected intracerebroventricularly with 5 ng IL-1 beta either at the beginning of the rest phase or at the beginning of the activity phase. Recordings were made during the 24 h preceding the injections (baseline) and during the first 12 postinjection hours. To avoid masking effects of light, the rats were maintained under a skeleton photoperiod during recording. During both the rest and activity phase, IL-1 beta induced fever and initially promoted non-rapid eye movement sleep (REMS). The effect of IL-1 beta on the duration of non-REMS and electroencephalogram (EEG) power densities within non-REMS was related to circadian phase. During the rest phase, IL-1 beta resulted in a minor increase in non-REMS duration but a prominent enhancement in EEG activity in the delta (0.5-4 Hz) and most other frequency bands. During the activity phase, IL-1 beta evoked a larger increase in the duration of non-REMS but hardly affected EEG activity within this state. Thus the effects of IL-1 beta on non-REMS are strongly influenced by diurnal phase. The alterations in EEG power density are in contrast to those elicited by sleep deprivation, which are largely independent of time of day. It is concluded that IL-1 beta activates EEG regulatory mechanisms mediated by processes that depend on circadian phase.
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