Aging is associated with decreased sleep continuity, slow wave sleep (SWS), growth hormone (GH) release and an increased hypothalamo-pituitary-adrenocortical (HPA) system activity. Total sleep deprivation (TSD) is a strong stimulus for sleep. To determine if aging affects the response to TSD, for the first time the combined effects of TSD on conventional and spectral sleep electroencephalographic (EEG) parameters and GH, cortisol and prolactin secretion were compared in elderly (60-80 years; n = 7) vs. younger subjects (20-30 years; n = 7). MANOVA revealed a reduction of SWS in the elderly. TSD led to an increase in SWS, a decrease in sleep onset latency, rapid eye movement (REM) density and by trend REM-latency without a global group difference. GH was reduced, whereas prolactin was enhanced in the elderly. After TSD GH was unchanged and prolactin secretion was enhanced without group difference. Thus, the plasticity of the sleep-endocrine system in response to TSD is sustained during aging. The possible involvement of the GABAergic system, that seems not to be severely impaired with age, is proposed.

When administered intravenously (i.v.) in a pulsatile mode during the first half of the night to young normal controls, growth hormone‐releasing hormone (GHRH) results in increased growth hormone (GH) plasma levels and slow wave sleep (SWS) and blunted cortisol release. In the present study we investigated whether GHRH has the same effects when administered in the early morning. Seven normal young male volunteers had 2 sessions each in the sleep laboratory (23.00 to 10.00 h) during which the secretion of GH, cortisol and corticotropin (ACTH) and polygraphic recordings were monitored. Verum (4 bolus injections of 50 μg GHRH) or placebo were injected i.v. at 04.00, 05.00, 06.00 and 07.00 h. GHRH stimulated GH plasma levels significantly whereas cortisol and ACTH were not altered. In the sleep‐electroencephalogram, only rapid‐eye‐movement density was decreased significantly during the period of active medication; all other sleep parameters were unaffected. We suggest that the physiological occurring high activity of the hypothalamic‐pituitary‐adrenocortical(HPA) system in the early morning prevents the effects of GHRH on cortisol plasma levels and SWS. Thus GHRH administered to healthy young men in the early morning hours has the same effect as GHRH administered during the first half of the night to patients with major depression who have HPA hyperactivity throughout the day.

Aging results in a more shallow sleep accompanied by a blunted growth hormone (GH) secretion. In young male normal controls repetitive administration of GH-releasing hormone (GHRH) at the beginning of the night results in an increased secretion of GH, a blunting of cortisol and a stimulation of slow-wave sleep (SWS). In healthy elderly men and women, however, GHRH exerts only weak effects on sleep-endocrine activity. In a previous report continuous treatment of healthy elderly males by repetitive administration of GHRH (during 12 days administration with 100 micrograms GHRH i.v. at 9.00 h every second day, "priming") enhanced GHRH stimulated GH secretion at daytime markedly. We tested if priming with GHRH results in a more distinct modulation of the nocturnal hormone secretion and of the sleep EEG than acute administration of the peptide. Two elderly male controls spent first three consecutive nights in the sleep laboratory, the first of which served for adaptation to laboratory conditions. During the two other nights (at days 1 and 2) sleep EEG was recorded and blood was sampled for determining the secretion of GH, cortisol and ACTH. In one of the nights the subjects received 50 micrograms GHRH hourly between 22.00 h and 1.00 h (4 x 50 micrograms) or placebo. The next examination followed after the priming period at day 14 and the last was performed two weeks after treatment at day 28. After the baseline administration of 4 x 50 micrograms GHRH before priming no clear changes of sleep EEG towards improved sleep were detectable, whereas GH secretion was increased. After priming sleep period time and SWS time were lower compared to the baseline night with GHRH administration, whereas REM time duration increased. GHRH induced GH secretion was not enhanced after priming. ACTH secretion was markedly enhanced compared to baseline stimulation. We conclude that priming with GHRH has no sleep improving effect and does not change hormone secretion in elderly normal subjects. Hence in the elderly priming with GHRH is not capable to induce a rejuvenation of sleep endocrine activity.

Rapid eye movement (REM) sleep deprivation leads to an induction of galanin gene expression in the rat brain, especially in the hypothalamus. Galanin affects neuroendocrine systems that are involved in sleep regulation, i.e. the growth hormone-releasing hormone-dependent system of the hypothalamus and the locus coeruleus. In the study reported here we investigated the effects of 4×50 mg galanin (n=10) and of 4×150 mg galanin (n=8) administered hourly between 22.00 and 01.00 h as intravenous boluses on the sleep EEG and nocturnal hormone secretion in healthy young men. Galanin administration significantly increased REM sleep in the third sleep cycle with no difference between the two doses. Spectral analysis revealed a significant increase in the EEG power in the delta and theta frequency range for the total night after the lower dose of galanin, but not after the higher dose. The secretion of growth hormone, cortisol and prolactin remained unchanged during sleep in both cases. Our data are consistent with the assumption of a functional resemblance between the effect of galanin and that of REM sleep deprivation, which is known to have antidepressive efficacy.

The distribution of AMPA receptor subunit mRNAs (spliced flip and flop variants of GluR-A to GluR-D) in the human post-mortem striatum, nucleus accumbens, globus pallidus and basal nucleus of Meynert was determined by in situ hybridization histochemistry. In the striatum and nucleus accumbens, for each subunit, the mRNA for the flop variant was more enriched than that for the corresponding flip variant. The GluR-Cflop mRNA was most abundant, followed by the GluR-Aflop mRNA. Transcripts for flop forms were evenly distributed in these regions, whereas those for flip forms showed a dorsoventral increasing gradient of the hybridization signals. The signals in these areas were found to originate mainly from medium-sized neurons. In the globus pallidus, mRNAs encoding GluR-Aflop and GluR-Cflop were also abundantly expressed. The basal nucleus of Meynert was enriched for mRNAs of flop forms. In conclusion, AMPA receptors in these areas of the human basal ganglia appeared to be mainly composed of flop variants, especially GluR-Aflop and GluR-Cflop. However, the finding that flip transcripts were more abundant in the nucleus accumbens than in the striatum implies differences in functions of AMPA receptors between the two regions. © 1997 Elsevier Science B.V. All rights reserved.

Objectives: To determine if the mean sleep latency (mSL) and the presence of significant sleep onset rapid eye movement periods (SOREMPs) can be predicted from the results of the first three naps in selected patients undergoing multiple sleep latency test (MSLT).Methods: Retrospective analysis of a number of MSLTs to identify the tests in which the mSL category and the presence of ≥2 naps with SOREMPS can be accurately predicted from the sleep latencies (SLs) of and SOREMPs in the first three naps.Results: The study included 588 consecutive MSLTs performed on 552 patients during a 3-year period. (1) The mSL was normal (≥10 min) for all MSLTs (n=90, 15%) if either (a) the SL was normal in each of the first three naps, or (b) SL was 20 min for any two of the first three naps. (2) The mSL was low (<5 min) or borderline (≥5 and <10 min) for 99% MSLTs with SL in the low or borderline categories, respectively. (3) The accuracy of predicting ≥2 naps with SOREMPs was 100% (normal SL), 96% (borderline SL), and 89% (low SL). (4) The mSL category (normal or low) and the presence of ≥2 naps with SOREMPs were predicted with 100% accuracy in 23% of all MSLTs.Conclusions: The category of mSL can be predicted with >99% accuracy, if SL is normal, borderline, or low in each of the first three naps, or if the patient does not sleep in any two of the first three naps. MSLT can probably be shortened to three naps in up to 23% to reduce time, labor, discomfort, and cost of the test.

Centrally administered vasoactive intestinal polypeptide (VIP) promotes rapid eye movement (REM) sleep in rats, rabbits, and cats. We studied the effect of 4 x 10 micrograms VIP (expt 1, n = 7) and 4 x 50 micrograms VIP (expt 2, n = 10) administered hourly as intravenous boluses between 2200 and 0100 on sleep electroencephalogram and secretion of plasma adreno corticotropic hormone, cortisol, growth hormone, and prolactin in humans. In experiment 2, the sleep cycles were decelerated during the first three cycles because of increased duration of both REM and non-REM sleep periods, and there was a tendency to increased REM-to-non-REM ratios. With a low VIP dose, prolactin levels were decreased during the whole night, whereas, with a high dose, they were increased during the first half of the night. In experiment 2, the cortisol nadir was advanced, after midnight the serum cortisol levels were enhanced, and the growth hormone peak was blunted. It appears that VIP may have a phase-advancing effect on sleep cycles and cortisol secretion, possibly through actions that involve the suprachiasmatic nucleus.

DHEA wird als Präkursor zu Sexualhormonen im großen Umfang in der Nebennierenrinde synthetisiert und liegt in der Blutzirkulation hauptsächlich als sulfatiertes Ester (DHEAS) vor. Die Frage nach der biologischen Funktion von DHEA ist bisher nicht geklärt und gewinnt zusätzlich durch die Tatsache an Bedeutung, daß auch Gliazellen des zentralen Nervensystems in großer Menge DHEA und Pregnenolon als sog. „Neurosteroide“ synthetisieren (Corpéchot et al. 1981, Mathur et al. 1993). In elektrophy-siologischen Experimenten wurde gezeigt, daß Metaboliten von DHEA und Pregnenolon am GABA-Benzodiazepinrezeptorkomplex (GBR) binden und dabei 5α,3α-reduzierte Steroide stereoselektiv GABA-agonistisch, dagegen die sulfatierten Ester von Pregnenolon und DHEA (DHEAS) GABA-antagonistisch wirken (Gee et al. 1988, Demirgören et al. 1991). Im Tierexperiment wurde für 5α,3α-reduzierte Metaboliten von Pregnenolon eine anxiolytische und auch hypnotische Wirkung nachgewiesen (Crawley et al. 1986, Mendelson et al. 1987). Die systemische Gabe von Pregnenolon bewirkte im Tier- und Humanexperiment Schlaf-EEG-Veränderungen im Sinne eines invers GABA-agonistischen Effekts (Steiger et al., in diesem Band, Lancel et al. 1994). Die vorliegende Untersuchung sollte prüfen, ob sich die Schlafarchitektur beim Menschen, die durch Liganden des GBR beeinflußt wird, auch nach Gabe von DHEA verändert.

Intracerebroventrikuläre Applikation von VIP führte zu einer signifikanten Steigerung von REM-Schlaf in Ratten [6, 9], Kaninchen [7] und Katzen [3]. VIP stimuliert daneben die Wachstumshormon-Sekretion bei der Ratte [2] sowie der Prolaktinsekretion sowohl bei der Ratte [4] als auch beim Menschen [5, 8]. Außerdem gibt es Hinweise, daß VIP eine Rolle bei der Regulation des circadianen Rhythmus über einen Einfluß auf den Nucleus suprachiasmaticus ausübt [1]. Wir untersuchten den Effekt von stündlichen pulsatilen peripheren Applikationen zwischen 22.00 und 1.00 Uhr von 4 × 10 µg VIP (n = 7) und 4 × 50 µg VIP (n = 10) auf den Schlaf und auf die nächtliche endokrine Aktivität bei männlichen Kontrollpersonen (20–30 Jahre alt) gegenüber Placebo. Nach Applikation von 4 × 10 µg VIP sank die Prolaktinkonzentration signifikant (Area under the curve AUC: 4651 ± 542 ng/ml x min nach VIP vs. 6293 + 856 ng/ml x min nach Placebo, im Zeitraum von 22.00 bis 7.00 Uhr, p < 0,05), wohingegen das Schlaf-EEG keine Veränderungen aufwies. Nach Gabe von 4 × 50 µg VIP wurde ein signifikanter Anstieg von Prolaktin beobachtet (22.00 bis 3.00 Uhr: 3526 ± 325 ng /ml x min vs. 2766 ± 313 ng/ml x min, p < 0, 01). Nach 4 × 50 µg VIP war der Cortisolnadir signifikant vorverlagert (62 ± 27 min unter VIP vs. 146 ± 19 min unter Placebo, p < 0,01, Zeit nach „Licht aus“). Zwischen 0.20 und 4.40 Uhr fand sich in Folge davon eine signifikante Erhöhung der Cortisolkonzentration (11965 ± 1939 ng/ml x min vs. 7747 ± 1136 ng/ml x min, p < 0, 05).

Die Ergebnisse aus Untersuchungen mit gesunden Kontrollpersonen [1] bzw. aus Tierexperimenten mit Ratten [2, 3] und Kaninchen [3] weisen darauf hin, daß Wachstumshormon freisetzendes Hormon (GHRH) eine zentrale Rolle in der gemeinsamen Steuerung von hormoneller Sekretion und Schlaf spielt. So führen pulsatile, während der ersten Nachthälfte erfolgende, intravenöse GHRH-Injektionen bei gesunden jungen Männern zu einer Steigerung von Tiefschlaf und Wachstumshormonausschüttung, während die Cortisolausschüttung sinkt [1]. Möglicherweise trägt eine Hemmung der GHRH-Ausschüttung zu den für Patienten mit Depression charakteristischen schlafendokrinologischen Auffälligkeiten bei. Gestörte Schlafkontinuität, verminderter Tiefschlaf, verringerte Wachstumshormonsekretion und Hypercortisolismus sind häufige Symptome der Depression.

The synthetic hexapeptide growth hormone-releasing peptide (GHRP-6) stimulates growth hormone (GH) release in animals and man. GH-releasing hormone (GHRH) has the same effect. In addition, pulsatile administration of GHRH in normal men results in increased slow-wave sleep (SWS) and blunted cortisol levels. The effect of GHRP on nocturnal hormone secretion and on the sleep electroencephalogram (EEG) is still unknown. We compared the effect of repetitive i.v. boluses (4 x 50 micrograms) of GHRP and placebo (PL) on the sleep EEG (23.00 to 07.00 h) and on the secretion profiles of GH, ACTH and cortisol (20.00 to 07.00 h) in normal male controls. After GHRP, the GH concentration (22.00 to 03.00 h) increased (15.4 +/- 9.6 ng/ml after GHRP vs. 5.5 +/- 4.0 ng/ml after PL, p < 0.02), as did the ACTH level (22.00 to 02.00 h: 21.0 +/- 5.3 pg/ml after GHRP vs. 16.6 +/- 3.1 pg/ml after PL, p < 0.02). During the total night, and particularly during the first half of the night, cortisol secretion was enhanced (22.00 to 03.00 h: 56.0 +/- 31.0 ng/ml after GHRP vs. 25.2 +/- 9.0 ng/ml after PL, p < 0.02). Stage 2 sleep increased (270.1 +/- 25.3 min after GHRP vs. 245.4 +/- 25.8 min after PL, p < 0.02), whereas other sleep-EEG variables including SWS remained unchanged. Our data demonstrate that GHRP stimulates not only GH release but also hypothalamic-pituitary-adrenocortical hormone secretion. The latter effect is opposite to the blunting of cortisol after GHRH. Both GHRP and GHRH promote sleep. However, GHRP enhances stage 2 sleep and does not affect SWS.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuropeptides growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) play a key role in sleep endocrine regulation. After pulsatile application of GHRH during the first few hours of the night in young normal controls SWS and GH increase, whereas cortisol is blunted. CRH however prompts inverse effects. The balance between these peptides is changed in favour of CRH physiologically during the second time of the night, during the acute episode of depression (due to overactivity of GRH) and in the elderly (due to reduced activity of CHRH). These changes explain the aberrances of sleep endocrine activity in these states, as shallow sleep, low GH and enhanced cortisol.

Dehydroepi-androsterone (DHEA) exhibits various behavioral effects in mammals, at least one of which is enhancement of memory that appears to be mediated by an interaction with the gamma-aminobutyric acidA (GABAA) receptor complex. We investigated the effects of a single oral dose of DHEA (500 mg) on sleep stages, sleep stage-specific electroencephalogram (EEG) power spectra, and concurrent hormone secretion in 10 healthy young men. DHEA administration induced a significant (P < 0.05) increase in rapid eye movement (REM) sleep, whereas all other sleep variables remained unchanged compared with the placebo condition. Spectral analysis of five selected EEG bands revealed significantly (P < 0.05) enhanced EEG activity in the sigma frequency range during REM sleep in the first 2-h sleep period after DHEA administration. In contrast, the EEG power spectra of non-REM sleep were not affected, nor were the nocturnal time course curves of plasma cortisol, growth hormone, or testosterone concentration. The results suggest that DHEA administration has a mixed GABAA-agonistic/antagonistic effect, exerted either directly or through DHEA-induced changes in steroid metabolism. Because REM sleep has been implicated in memory storage, its augmentation in the present study suggests the potential clinical usefulness of DHEA in age-related dementia.