During wakefulness, the cerebral cortex, which is responsible for generating mental activities, is activated by brain stem ascending influences. This is evidenced by classic electrophysiological field and unitary activities, gamma range activity and cortical blood flow. However, aminergic ascending neurons exert mainly diffuse inhibitory influences. These two kinds of influences together support reflective and rational psychological activities. During slow wave sleep, both kinds of ascending influences decrease and the mental content comprises low-intensity thought-like activities, similar to the waking mode of functioning, although dreams have been described. During rapid eye movement sleep, the principal dreaming stage, the cortex is activated but significantly disinhibited since all aminergic neurons are silent except the dopaminergic ones. We hypothesize that, in addition to this unusual state, the persistent release of dopamine associated with the specific silence of noradrenergic neurons could explain the characteristics of dream mental activity which are somewhat similar to psychotic symptoms.

Sleep Research Online

In patients with depression, enhanced secretion of ACTH and cortisol, a reduction in slow wave sleep (SWS) and a blunted nocturnal growth hormone (GH) surge have been described and attributed, at least partly, to an elevation of corticotropin-releasing hormone (CRH), hence a shift in the ratio between growth hormone-releasing hormone (GHRH) and CRH. We investigated the effects of pulsatile administration of GHRH (4x50 µg, at hourly intervals between 2200 and 0100 h) on the sleep EEG (2300-0700 h) in patients with depression (16 females, 19 males, age range 19-76 years) and matched controls (20 females, 20 males). In patients compared with controls, NREM sleep and in particular stage 2 sleep was greatly decreased at baseline. GHRH treatment enhanced NREM sleep, and in particular stage 2 sleep in men, regardless of diagnosis, while decreasing it in women (F=6.0 and 7.1, p<0.05). In controls, aging was associated with a decrease in NREM sleep, including both SWS and stage 2 sleep (r= -0.45 r= -0.39, p<0.05), while in patients only SWS declined with age (r= -0.49, p<0.05). The significant decrease in NREM sleep including stage 2 sleep in patients with depression and elderly control subjects is compatible with the suggested role of sleep continuity and stage 2 sleep in cognitive functioning. GHRH promoted NREM sleep, stage 2 sleep and sleep continuity and might prove beneficial for improvement of cognitive function, at least in men. These data support the hypothesis that female gender, aging and depression are associated with a shift in the GHRH/CRH ratio towards CRH.

Sleep Research Online

In depression and aging an increase in nocturnal cortisol secretion and a blunted nocturnal growth hormone (GH) surge have been described. In normal young men, growth hormone-releasing hormone (GHRH) promotes GH release and reduces plasma cortisol. Here, we examined whether GHRH could help to restore sleep-endocrine regulation in patients with depression and aging. GHRH (4x50 µg, at 2200, 2300, 2400 and 0100 h) or saline (placebo) was injected intravenously to 42 patients with depression (19 females, 23 males) and matched controls (age range 19-76 years). Blood samples were withdrawn at 20 min intervals between 2200-0700 h and analysed using Manova (D.F. 1, 72). Patients compared to controls had significantly higher levels of ACTH and cortisol, particularly during the first half of the night (F=9 and F=11.8, each p<0.05). GHRH reduced ACTH during the first and cortisol secretion during the second half of the night in males, regardless of diagnosis, but enhanced it in females (F=5.1 and F=4.0, each p<0.05). ACTH and cortisol secretion were inversely related to NREM and stage 2 sleep in patients (r= -0.42, -0.42 and r= -0.36, -0.39, respectively, each p<0.05) but not in controls. Our data suggest that: 1) female gender, depression and aging add-on to enhance HPA activity, and 2) hyperactivity of the HPA system and the decrease in NREM and in particular stage 2 sleep in depression are interrelated. In men, GHRH can restore some of the sleep-endocrine alterations associated with depression and aging.

Sleep Research Online

Systemic Administration of Hypocretin-1 Reduces Cataplexy and Normalizes Sleep and Waking Durations in Narcoleptic Dogs Joshi John, Ming-Fung Wu and Jerome M. Siegel Recent work has implicated the hypocretin (orexin) system in the genesis of narcolepsy. In the current study we demonstrate that systemically administered hypocretin-1 (Hcrt-1) produces an increase in activity level, longer waking periods, a decrease in REM sleep without change in nonREM sleep, reduced sleep fragmentation and a dose dependent reduction in cataplexy in canine narcoleptics. Repeated administration of single daily doses of Hcrt-1 led to consolidation of waking and sleep periods and to a complete loss of cataplexy for periods of three or more days after treatment in animals that were never asymptomatic under control conditions. Systemic administration of Hcrt-1 may be an effective treatment for narcolepsy. Sleep Research Online

Dorsal Raphe Nucleus Administration of 5-HT1A Receptor Agonist and Antagonists: Effect on Rapid Eye Movement Sleep in the Rat Jaime M. Monti, Héctor Jantos, Daniel Monti and Fernando Alvariño The effect of flesinoxan, a selective 5-HT1A receptor agonist, WAY 100635, a selective 5-HT1A receptor antagonist, and (±)pindolol, a mixed ß-adrenoceptor and 5-HT1A/B receptor antagonist, on spontaneous sleep was studied in adult rats implanted for chronic sleep recordings. Drugs were infused directly into the dorsal raphe nucleus (DRN). Direct application of flesinoxan (25.0 and/or 50.0 ng) into the DRN induced a significant increment of REM sleep (REMS) during the second and third 2 h period of recording. On the other hand, microinjection into the DRN of (±)pindolol (100.0 and/or 200.0 ng), and WAY 100635 (12.5, 25.0 and 50.0 ng) significantly reduced REMS during the first and/or second 2 h recording period . Our findings support previous studies indicating that microdialysis perfusion of the 5-HT1A receptor agonist 8-OHDPAT into the DRN increases REMS. In addition, they favor the proposal that microinjection of 5-HT1A receptor antagonists into the DRN would suppress 5-HT inhibition and reduce REMS. Sleep Research Online

Distribution of Hypocretin-Containing Neurons in the Lateral Hypothalamus and c-Fos-Immunoreactive Neurons in the VLPO Dean Wagner, Rafael Salin-Pascual, Mary Ann Greco and Priyattam J. Shiromani The present study investigated the distribution of neurons implicated in the regulation of sleep in three species generally used in sleep research, i.e., mice, rats and cats. We focused on sleep active neurons in the ventral lateral preoptic (VLPO) area and the hypocretin/orexin-containing neurons in the lateral hypothalamus. The latter groups of neurons were found recently to play an important role in the regulation of REM sleep. The expression of the transcription factor, c-Fos, was used to identify the VLPO. In mice and rats, in response to sleep, a discrete cluster of c-Fos positive cells was found in the VLPO. In mice, this cluster was located more medially compared to the rat, and as in the rat, galanin immunostained neurons were found in the VLPO. In the cat, c-Fos positive cells did not segregate to a specific location but were more diffusely represented in the preoptic area. In all three species, orexin/hypocretin-containing neurons were located only in the lateral hypothalamus with the distribution being more diffuse in the cat. The grouping of sleep-active cells in rodents makes it feasible to extract these cells for tissue culture and molecular analysis. Moreover, given that rodents have a distinct circadian distribution of sleep-wakefulness, the connectivity with the suprachiasmatic nucleus can also be determined. Sleep Research Online