Lorenz Trachsel

Dynamics of slow-wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone.

Electroencephalographic slow-wave activity (SWA; power density in the 0.75 to 4.5 Hz band) and spindle frequency activity (SFA; 11.25 to 15.0 Hz) exhibit a typical time course and a distinct mutual relationship during sleep. Because benzodiazepines (BDZ) suppress SWA and enhance SFA, we investigated the effect of two BDZ-receptor agonists on the dynamics of these EEG parameters. A single dose of midazolam (15 mg), zopiclone (7.5 mg), or placebo was administered before bedtime to healthy young men. Although the two drugs reduced SWA and enhanced SFA, their time course across and within sleep cycles as well as their mutual relationship were little affected. The results constitute further evidence that hypnotics acting as BDZ-receptor agonists do not substantially interfere with the homeostatic aspect of sleep regulation.

Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation.

The steroid pregnenolone (P) and its sulfate (PS) can accumulate in the central nervous system independent of peripheral sources. Pharmacologically, the sulphated form of P interacts with the GABAA receptor complex, and functional assays show that this steroid behaves as an allosteric GABAA receptor antagonist. The present study explored the effect of a single dose of P upon the sleep-EEG and concurrent secretion of growth hormone and cortisol in male volunteers. P increased the amount of time spent in slow wave sleep and depressed EEG sigma power. Sleep-associated nocturnal cortisol and growth hormone secretion remained unchanged, ruling out the possibility that P exerted its effect via altered regulation of these hormones. Furthermore, results from in vitro studies on the potency of P to activate gene transcription via corticosteroid receptors made a genomic action of P via hormone receptor-sensitive DNA sequences unlikely. We conclude that P acts in a non-genomic fashion at or in the vicinity of the benzodiazepine binding site, modulating allosterically the GABAA receptor like a partial inverse.

The 5-HT1A agonist ipsapirone enhances EEG slow wave activity in human sleep and produces a power spectrum similar to 5-HT2 blockade ☆

The REM sleep-suppressing effect of postsynaptic 5-HT1A stimulation has been well established. Here we investigate the effects of the 5-HT1A agonist ipsapirone (10 and 20 mg) on sleep EEG power spectra during non-REM sleep in nine healthy humans. At the lower dose, slow wave activity (SWA; EEG power in the delta (1-4.5 Hz) range) was significantly enhanced. At the higher dose, where side-effects occurred, the enhancement in SWA was not significant. The spectral profile was characterized by a bimodal increase of power in the lower delta and in the theta (5-8 Hz) frequencies, and by troughs at 4 Hz and at 11 Hz, a pattern compellingly similar to that reported for a 5-HT2 antagonist (seganserin). We propose that the spectral data following the lower ipsapirone dose reflect a net decrease of neuronal activity at 5-HT2 receptors, mediated through stimulation of somatodendritic autoreceptors in the raphe nuclei (presynaptic) and/or through stimulation of postsynaptic 5-HT1A receptors colocalized with 5-HT2 receptors. The spectral non-REM sleep EEG profile might be used to investigate central 5-HT function in humans.

Acute cortisol administration promotes sleep intensity in man

The neuronal mechanisms of sleep generation, in particular synchronization of brain activity in the process of non-rapid-eye movement (non-REM) sleep, has been elucidated in the past decade. A previous study of our group showed that acute administration of cortisol is known to increase slow-wave sleep and suppress rapid-eye movement (REM) sleep in man. To further elucidate the non-REM sleep-promoting effects of cortisol with respect to the synchronization of cortical activity, it is important to establish a sleep-state-specific quantitative EEG analysis. We therefore investigated the effects of repetitive injections of hydrocortisone on spectral composition of sleep EEG in 10 healthy male young volunteers. In addition, we performed high-frequency blood samplings to assess the relation between changes in the sleep EEG and sleep-associated secretion of growth hormone (GH). Cortisol administration resulted in a significant increase in highly synchronized EEG activity including delta and theta frequencies, according to a higher amount of slow-wave sleep. This effect predominated in the first few hours of night sleep. REM sleep was decreased, which appeared to be secondary to the lengthened first sleep cycle. The cortisol-induced stimulation of GH release did not occur in correspondence with the increased slow-wave activity. In view of the sleep impairing properties of corticotropin-releasing hormone (CRH) and the sleep-promoting function of GH-releasing hormone, it appears likely that a negative feedback inhibition of endogenous CRH was the key mechanism mediating the observed results. The cortisol-induced effects on sleep intensity and sleep-associated GH secretion appeared to be driven by different mechanisms.

Effects of flumazenil on recovery sleep and hormonal secretion after sleep deprivation in male controls

The effects of flumazenil, a benzodiazepine antagonist, on the sleep electroencephalogram (EEG) and neuroendocrine secretion in early morning recovery sleep (0500–0800 hours) following sleep deprivation (SD; 2300–0500 hours) were studied in seven healthy men. SD induced an increase in slow wave sleep (SWS), a decrease in sleep onset latency (SOL), an enhancement of EEG delta and theta power in non-rapid-eye-movement sleep, an increase in plasma human growth hormone (GH) concentration, and a decrease in plasma cortisol levels in recovery sleep (0500–0800 hours). Plasma GH, but neither plasma cortisol nor adrenocorticotrophic hormone (ACTH) concentration was attenuated during SD as compared to sleep (2300–0445 hours). The administration of flumazenil (3×1 mg intravenously) during recovery sleep resulted in an inhibition in SWS, an increase in stage 2 sleep, a selective reduction in delta and theta power, and a tendency to prolongation of SOL. Plasma GH concentration was decreased but plasma cortisol and ACTH remained unaffected. Since the SD-induced changes in sleep EEG and plasma GH secretion were antagonized by flumazenil, it is suggested that electrophysiological and hormonal effects of SD are mediated at least in part through GABAergic mechanisms.

The intrinsic optical signal evoked by chiasm stimulation in the rat suprachiasmatic nuclei exhibits GABAergic day-night variation

Infrared light transmittance imaging was used in rat hypothalamic slices to record an intrinsic optical signal (IOS) of the cell ensemble in the suprachiasmatic nuclei (SCN), the locus of the endogenous circadian clock. Upon optic chiasm stimulation, a transient IOS was observed in an area conforming to the known retinohypothalamic tract innervation in the ventral SCN. An increase in extracellular Mg2+ concentration to 10 mM reduced the IOS, suggesting that the elicited IOS is dependent on synaptic transmission. D‐2‐Amino‐5‐phosphonopentanoic acid and muscimol suppressed the elicited IOS, indicating that NMDA and GABAA receptor‐mediated mechanisms were involved in cell ensemble activity reflected in the IOS. The extracellularly recorded spiking of SCN neurons located outside the IOS area remained largely unaffected by the afferent stimulus. Neurons located within the IOS area responded with a depressed electrical discharge, manifesting an inverse relationship between single‐unit discharge and the optical measure. The influence of the endogenous circadian rhythm on the elicited IOS was assessed by carrying out daytime‐dependent concentration‐response experiments. NMDA and non‐NMDA receptor specific compounds did not exhibit significant day‐night differences, whereas GABA‐specific ligands showed a significant day‐night variation in activity. The competitive GABAA receptor antagonist bicuculline enhanced the IOS exclusively in the daytime SCN. 5α‐Pregnane‐3α, 21‐diol‐20‐one (allotetrahydrodeoxy‐corticosterone), a neuroactive steroid that potentiates GABAergic inhibition, suppressed the IOS in the night‐time SCN more than in the daytime SCN. This suggests that in the rat the level of extracellular GABA is higher in the night‐time SCN compared to the daytime SCN.

Temporal EEG dynamics of non-REM sleep episodes in humans

The process of the human non-rapid eye movement (non-REM) sleep period has not been clarified. Time-based analysis on sleep EEG may provide an explanation. We focused on chronological aspects of initiation and termination of non-REM episodes, using spectral analysis of sleep EEG. The subjects were healthy male volunteers (n14 Hz) and longer in lower frequency ranges (<14 Hz). There were significant differences in the rise and decay latencies between low and high sigma ranges, indicating that the whole frequency ranges were clearly separated at the middle of the sigma range (14 Hz). The rise and decay latencies were significantly different in lower frequency ranges. The clock time of the night significantly affected only the rise latencies of the delta (0.78-3.9 Hz), alpha (8.2-11.7 Hz) and low sigma (12.1-13.7 Hz) ranges. In conclusion, initiation and termination of non-REM sleep was represented by higher frequency ranges, whereas further evolution and devolution of non-REM sleep was represented by lower frequency ranges, and only the evolution process was affected by the clock time of the night.

Bretazenil modulates sleep EEG and nocturnal hormone secretion in normal men

Preclinical data suggest that the imidazo-diazepinone derivative bretazenil (Ro 16-6028) has anxiolytic and anticonvulsant properties with only weak sedative effects. We examined the influence of oral administration of 1 mg bretazenil on the sleep EEG and the concomitant nocturnal secretion of cortisol, growth hormone and prolactin in ten healthy young men. After bretazenil we found a significant increase in stage 2 sleep and a significant reduction in stage 3 sleep. REM latency was prolonged. Spectral analysis of sleep-EEG power revealed a decrease in delta and in theta power and an increase in sigma power. We found no significant influence on sleep onset latency or on intermittent wakefulness. Bretazenil prompted a significant decrease in cortisol secretion and a significant increase in prolactin release. It had no major influence on growth hormone secretion.

Human plasma DSIP decreases at the initiation of sleep at different circadian times

Nocturnal plasma delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) was determined serially in seven healthy male subjects. Time courses during nocturnal sleep (2300-0800 h), nocturnal sleep deprivation (2300-0500 h), and morning recovery sleep (0500-0800 h) after sleep deprivation were compared. A significant decrease in plasma DSIP-LI was found at the transition from wakefulness to sleep in both evening sleep (2300 h) and morning recovery sleep (0500 h). Time courses were accompanied by physiological changes in sleep electroencephalographic slow-wave activity, and in plasma concentrations of cortisol and human growth hormone. No sleep stage specificity was found. It is concluded that DSIP is influenced by the initiation of sleep.

Die Gabe von Dehydroepiandrosteron (DHEA) verlängert den Rapid-Eye-Movement (REM)-Schlaf und erhöht die EEG-Aktivität im Sigma-Frequenzbereich

DHEA wird als Prakursor zu Sexualhormonen im grosen Umfang in der Nebennierenrinde synthetisiert und liegt in der Blutzirkulation hauptsachlich als sulfatiertes Ester (DHEAS) vor. Die Frage nach der biologischen Funktion von DHEA ist bisher nicht geklart und gewinnt zusatzlich durch die Tatsache an Bedeutung, das auch Gliazellen des zentralen Nervensystems in groser Menge DHEA und Pregnenolon als sog. „Neurosteroide“ synthetisieren (Corpechot et al. 1981, Mathur et al. 1993). In elektrophy-siologischen Experimenten wurde gezeigt, das 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, Demirgoren et al. 1991). Im Tierexperiment wurde fur 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-Veranderungen im Sinne eines invers GABA-agonistischen Effekts (Steiger et al., in diesem Band, Lancel et al. 1994). Die vorliegende Untersuchung sollte prufen, ob sich die Schlafarchitektur beim Menschen, die durch Liganden des GBR beeinflust wird, auch nach Gabe von DHEA verandert.