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.     

Changes in sleep electroencephalogram and nocturnal hormone secretion after administration of the antidyskinetic agent sarizotan in healthy young male volunteers

Rationale Sarizotan is a 5-HT_1A agonist with high affinity to D₃ and D₄ receptors. In animal experiments, the drug shows a strong anti-cataleptic effect and suppresses effectively dyskinesias in animal models of l-dopa-induced dyskinesia and of tardive dyskinesia. Data from an open pilot study in patients with Parkinsons disease show clear indication of a treatment effect against l-dopa-induced dyskinesia.Objective CNS-active drugs are known to modulate sleep electroencephalogram (EEG) and sleep-related hormone secretion. 5-HT_1A agonists suppress rapid-eye movement (REM) sleep and enhance the secretion of ACTH, cortisol, prolactin and growth hormone (GH) at daytime. We hypothesised that sarizotan shares these effects. Furthermore, we were interested in the influence of sarizotan on leptin, which participates in the regulation of the energy balance and is enhanced after various psychoactive drugs.Methods Ten healthy male subjects were investigated twice in a double-blind, placebo-controlled crossover design. Sleep EEG and nocturnal hormone secretion of ACTH, cortisol, prolactin, GH and leptin were examined after oral administration of either placebo or 20 mg of sarizotan at night.Results After administration of sarizotan, a significant reduction of REM sleep and total sleep time in conventional sleep EEG and a significant reduction of sigma- and theta-power in spectral analysis were observed. The main effect on nocturnal hormone secretion was a significant elevation of prolactin and of ACTH in the first half of the night.Conclusions While REM sleep was suppressed, the endocrine effects of 20 mg sarizotan at night were weak. Its sleep-endocrine profile is comparable to the effects provoked by selective 5-HT reuptake inhibitors.     

Flumazenil attenuates the pituitary response to CRH in healthy males

Differential effects of flumazenil (an antagonist) and midazolam (an agonist at the benzodiazepine receptor) were studied in 8 healthy males. Adrenocorticotropic hormone (ACTH) and cortisol responses to a corticotropin-releasing hormone (CRH) challenge were measured. ACTH response was significantly lower after flumazenil administration than after saline or midazolam. No significant treatment effect was found for the CRH-induced cortisol secretion. Our results agree with previous reports that point to an agonistic effect of flumazenil on pituitary-adrenocortical system activity and, moreover, may further support the anxiolytic activity of flumazenil in stimulated stress.     

Mg2+ reduces ACTH secretion and enhances spindle power without changing delta power during sleep in men – possible therapeutic implications

Disturbances of Mg²⁺ metabolism have been reported in association with affective disorders, seizures in eclampsia, and alcohol withdrawal. Mg²⁺ has been reported to have N-methyl-D-aspartate (NMDA)-antagonistic and gamma-aminobutyric acid (GABA)-agonistic properties and modulation of GABA_A- and NMDA-dependent systems is involved in pharmacological treatment of affective disorders and seizures. We studied the effect of Mg²⁺ on sleep electroencephalogram (EEG) and nocturnal hormonal secretion in men. Ten normal controls were given MgSO₄ (3 g MgSO₄ between 2030 hours and 2100 hours, followed by 0.5 g MgSO₄ per hour until 0700 hours) or placebo IV according to a randomized schedule. The sleep EEG was recorded from 2300 hours to 0700 hours. Blood samples were taken from 2000 hours to 0700 hours for analysis of plasma corticotropin (ACTH), cortisol, growth hormone, prolactin and melatonin. The sleep-EEG power within the spindle frequency range (11.0–12.9 Hz) showed a significant increase in the third sleep cycle, but delta power was unchanged throughout the night. ACTH concentration was suppressed between 2200 hours and 0700 hours. No changes in cortisol, growth hormone prolactin or melatonin release were found. The findings are consistent with the assumption that Mg²⁺ has GABA_A-agonistic or NMDA-antagonistic effects on sleep and nocturnal hormonal secretion and hence may be useful in controlling depressive symptoms and seizures. Received: 24 June 1997/Final version: 29 October 1997     

The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects

RATIONALE: Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin but acts as an antagonist at presynaptic alpha(2) receptors, at postsynaptic 5-HT(2) and 5-HT(3) receptors, and at histaminergic H(1) receptors. This special mechanism of action may be characterized by a distinct pharmacoendocrinological profile. OBJECTIVES: In the present investigation the influence of acute oral administration of 15 mg mirtazapine on the cortisol (COR), corticotropin (ACTH), growth hormone (GH), and prolactin (PRL) secretion was examined in six healthy male subjects, compared to placebo. METHODS: After insertion of an intravenous catheter, both the mean arterial blood pressure (MAP) and the heart rate were recorded and blood samples were drawn 1 h prior to the administration of mirtazapine or placebo (7:00 a.m.), at time of application (8:00 a.m.), and thereafter every hour up to 8:00 p.m. Concentrations of COR, ACTH, GH, and PRL were measured in each blood sample by double-antibody radioimmunoassay and chemiluminescence immunoassay methods. The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. Furthermore, the urinary free cortisol excretion (UFC) was determined beginning at 8:00 a.m. (time of application of placebo or mirtazapine) up to 8:00 a.m. the day after. RESULTS: Multivariate analyses of variance revealed significantly lower COR AUC, ACTH AUC, and UFC values after 15 mg mirtazapine compared to placebo, whereas no differences were found with respect to GH and PRL stimulation, MAP, and heart rate. CONCLUSIONS: Since the acute inhibition of COR secretion in the healthy volunteers was paralleled by a simultaneous decrease of ACTH release, central mechanisms (for example, inhibition of hypothalamic CRH output) are suggested to be responsible for the inhibitory effects of mirtazapine on COR secretion. Our results are of particular interest in the light of the hypercortisolism observed in depressed patients and new pharmacological approaches such as CRH(1) receptor antagonists.     

Flumazenil and saccadic eye movements in patients with panic disorder and normal controls

The effects of the benzodiazepine receptor antagonist flumazenil on saccadic eye movements were studied in patients with panic disorder and in controls. Compared with vehicle, flumazenil displayed slight partial agonist effects in that it significantly reduced peak deceleration of eye movements, with a similar but non-significant trend for peak velocity, in both groups. In controls flumazenil had little in the way of subjective effects whereas in panic patients it produced marked anxiety. The paradoxical responses to flumazenil in panic disorder (partial agonist effects on saccadic eye movements but partial inverse agonist effects on mood) may be due to different receptor subtypes controlling these variables.     

Effects of promethazine on nocturnal sleep in normal man

The effects of a phenothiazine, promethazine, on sleep in ten healthy volunteers were investigated in two double blind polygraphic studies. The first part consisted of a single dose study with promethazine 50, 100, and 200 mg, using pentobarbital 100 mg as a reference substance. In the second part, four subjects spent 20 consecutive nights with nine drug nights (promethazine 100 mg), followed by a placebo withdrawal period of six nights, in the sleep laboratory.Promethazine showed a dose related REM-depressing effect with a greater decrease, the higher the dose. The placebo value was 20.7% REM of total sleep time and gave 16.3, 13.5 and 11.4 respectively, for promethazine 50, 100 and 200 mg. Pentobarbital gave 16.2% REM. There was also an increase of stage II and with the highest dose an increase of stage III + IV. An increase of REM-latency together with a decrease of REM-periods was also seen, and while pentobarbital gave a decrease in REM-density, promethazine did not cause any changes in the phasic REM-component. A REM-rebound was seen in the first night of withdrawal with an increase of per cent REM from 19.9–25.1%. The mean for the whole withdrawal period was 23.1%. Promethazine in the highest dose, 200 mg, gave drowsiness and hangover effects in 14 nights out of 20. The REM-depressing effect of promethazine together with its relatively weak REM-rebound effect may explain its value in the treatment of withdrawal symptoms following abuse of alcohol and barbiturates.     

癫痫与睡眠关系的脑电图分析

目的探讨癫痫与睡眠时相的关系及癫痫对睡眠结构的影响。方法对20例确诊为颞叶癫痫患者和20名与之相匹配的健康者进行多导睡眠仪监测,并对结果进行分析。结果癫痫组与健康组相比,睡眠潜伏期明显延长,差异有统计学意义（P〈0．05）;癫痫患者睡眠中每小时唤醒次数增加,差异有统计学意义（P〈0．05）;癫痫患者的睡眠结构明显发生了变化,以浅睡期[非快速眼动（NREM）Ⅰ、Ⅱ期]所占时间比例比健康对照组明显延长（P〈0．01）,深睡期（NREMⅢ、Ⅳ期）时间（P〈0．01）和快速眼动（REM期）时间均缩短（P=0．01）;癫痫患者的睡眠纺锤波密度要明显低于健康者（P〈0．01）。结论癫痫患者存在明显的睡眠结构改变,睡眠期间的癫痫发作,可加重睡眠障碍。     

Effect of zolpidem on sleep and sleep EEG spectra in healthy young men

A single 10 mg dose of zolpidem, an imidazopyridine hypnotic, was administered to young, healthy male volunteers prior to bedtime. The drug reduced REM sleep but did not significantly affect other sleep stages and subjective sleep parameters. All-night spectral analysis of the EEG revealed that power density in nonREM sleep was reduced in the low-frequency range (1.25–2.5 Hz; 5.25–10.0 Hz) and increased in the spindle frequency range (12.25–13.0 Hz). Significant changes in the EEG spectrum were present in the first 4 h of sleep. The pattern of the spectral changes was similar to those induced by other hypnotics that bind to the GABA_A/benzodiazepine receptor complex. There were no residual effects of zolpidem on psychomotor performance in the morning, on the self-rated state in the morning and at noon, and on sleep and EEG parameters in the subsequent drug-free night.     

Effects of brofaremine (CGP 11 305A), a short-acting,reversible, and selective inhibitor of MAO-A on sleep,nocturnal penile tumescence and nocturnal hormonal secretion in three healthy volunteers

The effects of brofaremine (CGP 11 305A), a short-acting, reversible and selective inhibitor of MAO-A, on sleep, nocturnal penile tumescence (NPT) and hormonal secretion during the night were studied during a long-term trial. Three healthy males underwent sleep-EEG and NPT recordings during consecutive nights (1) under placebo, (2) under stepwise increasing dosages of brofaremine and (3) under placebo after withdrawal. Hormone profiles were sampled during selected nights to analyze the plasma concentration of cortisol, HGH, prolactin, testosterone, LH and FSH. REM sleep was suppressed markedly under 150 mg brofaremine, while stages 1 and 2 increased. In comparison to the effect of irreversible MAOIs the REM suppression was shorter and did not persist after withdrawal. A decrease of the plasma concentration of the drug coincided with a return of sleep variables to baseline values. A REM rebound occurred after withdrawal of brofaremine. REM sleep and NPT showed a dissociation; NPT variables did not follow the decrease of REM sleep. The effects of REM parameters are correlated with the dosage and the plasma concentration of the substance. Intraindividually, a decrease in secretion of HGH was observed throughout the trial. No marked changes were found in the other endocrinological variables.     

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.     

Effects of trazodone on EEG sleep and clinical state in major depression

The effects of the antidepressant trazodone on clinical state and on EEG sleep in eight outpatients with a major depressive disorder were investigated in a single blind study. A medication period of 5 weeks was preceded and followed by one week placebo treatment. Five subjects showed a positive treatment response. Trazodone did not influence sleep continuity and slow wave sleep, but did suppress REM sleep significantly. A significant increase of REM sleep latency was also found. These results are in contrast with earlier reports on trazodone's effects on EEG sleep but are in accordance with the general finding that antidepressants influence REM sleep characteristics without necessarily affecting sleep continuity.     

Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice

Modafinil is a wakefulness-promoting substance whose profile differs from that of the classical psychostimulants. It is still unknown whether waking induced by modafinil and wakefulness induced by sleep deprivation differ in terms of their effect on subsequent sleep. To investigate this problem sleep was recorded in two groups of OF1 mice. One group received modafinil (200 mg/kg, i.p.) at light onset which induced a period of wakefulness of approx. 5 h, while animals of the subsequent control group were injected with vehicle and kept awake for an equivalent duration. The effect of the two treatments on sleep was similar. REM sleep was initially reduced and slow-wave activity (SWA; EEG power in the 0.75-4.0 Hz range) in nonREM sleep was enhanced for several hours. The SWA increase was more prominent over the frontal cortex than over the occipital cortex after both treatments. A minor difference was seen at the occipital site where the initial rise of power in the low-frequency range was larger after vehicle combined with enforced waking than after modafinil. The study shows that the homeostatic sleep response following the modafinil-induced wakefulness corresponds largely to the response following a non-pharmacologically induced extended waking episode.     

The GABAA receptor agonist THIP alters the EEG in waking and sleep of mice

THIP is a GABA(A) agonist with hypnotic properties consisting in reducing sleep latency and prolonging and consolidating sleep. THIP has been reported to increase EEG slow-wave activity (SWA; EEG power in the 0.75-4 Hz band) in non-REM (NREM) sleep in both rats and humans. We investigated the effects of THIP on sleep in C57BL/6 mice. EEG recordings were performed after 2, 4 and 6 mg/kg THIP and saline control. The results were compared with analyses of recordings obtained after 6 h of sleep deprivation (SD) in the same strain of mice. The two higher doses of THIP induced an abnormal EEG pattern both in waking and NREM sleep. The EEG was characterized by sporadic asymmetric high-voltage potentials recurring at a low-frequency (<1 Hz) on the background of a low-amplitude EEG pattern. In contrast, after SD the typical regular synchronous high amplitude delta waves predominated. THIP at 4 and 6 mg/kg led to a prominent enhancement of spectral power in the low-frequency range of the waking and sleep EEG which was much higher than the increase attained after 6 h SD. This effect was particularly prominent in the waking EEG. In NREM sleep the increase of spectral power after THIP reflected the frequency of recurrence of the high-voltage potentials, and was restricted to a narrower frequency band than after SD. The EEG changes after 2mg/kg differed little from saline control. Sleep latency was not affected by the two lower doses of THIP, and was prolonged after 6 mg/kg. REM sleep was suppressed after the two higher doses. In contrast to previous results reported in other species, THIP did not have a hypnotic action in mice. The changes induced by THIP in the waking and sleep EEG differed from those caused by enhanced physiological sleep pressure encountered after SD. Considering the abnormal EEG pattern and the similarity of the spectral changes in the sleep and waking EEG, THIP does not seem to exert a specific effect on mechanisms involved in sleep regulation.     

The effects of sub-chronic administration of hydrocortisone on hormonal and psychological responses to L-tryptophan in normal male volunteers

RATIONALE: 5-Hydroxytryptamine(1A) (5-HT(1A)) receptor function has been shown to be attenuated by corticosteroid hormones in a variety of animal experimental paradigms. It has been suggested that this effect may be central to the pathophysiology of severe depressive illness in humans, a condition in which 5-HT(1A) receptor function is reduced and corticosteroid hormone levels are elevated. Evidence suggests that the hormonal response to L-tryptophan ( L-TRP) is mediated by 5-HT(1A) receptors. This response has been shown to be reduced following acute administration of hydrocortisone, and we hypothesised that sub-chronic administration of hydrocortisone would also blunt it. OBJECTIVES: To examine the effects of sub-chronic administration of hydrocortisone on hormonal and psychological responses to L-TRP infusion in healthy male subjects. To ascertain whether cortisol was exerting effects on prolactin release directly at the pituitary rather than via hypothalamic 5-HT(1A) receptors, a thyroid-releasing hormone (TRH) challenge test was performed. METHODS: Fourteen healthy male volunteers took part in a random-order, double-blind, placebo-controlled study, in which 20 mg hydrocortisone or placebo was administered twice daily for 7 days before infusion of L-TRP. A TRH challenge was administered to eight of the subjects following the L-TRP infusion. RESULTS: Pre-treatment with hydrocortisone significantly reduced the growth hormone (GH) and cortisol responses, but not the prolactin (PRL) response to the infusion. TRH administration caused a robust increase in PRL, but this response was not attenuated by hydrocortisone pre-treatment. The TSH response to TRH was blunted. There was no effect of pre-treatment on psychological responses to L-TRP. CONCLUSIONS: The attenuation in GH response following hydrocortisone pre-treatment could indicate a reduction in 5-HT(1A) receptor function, although it is probable that it is attributable to the action of hydrocortisone at the pituitary level. More precise, non-neuroendocrine models of 5-HT(1A) receptor function are necessary to clarify this.     

The effect of acute and repeated electroconvulsive treatment on plasma β-endorphin,growth hormone,prolactin and cortisol secretion in depressed patients

The effects of single and repeated electroconvulsive treatment (ECT) on β-endorphin (β-EP), cortisol, growth hormone (GH) and prolactin (Prl) plasma levels were investigated in nine depressed patients. Blood samples were monitored a day before ECT, the day of the first and sixth ECT (0, 30, 60 and 90 min after seizures), the day afterwards and 4 weeks after termination of the ECT course. A significant elevation of β-EP levels was achieved immediately with and 24 h after the first and the sixth ECT. A transient increase in basal β-EP was observed 1 day following the sixth ECT in comparison with pre-treatment level. Peak and 30 min levels of cortisol were increased compared with baseline by the first ECT. The former (peak) but not the latter (30 min) were increased also at the sixth treatment. GH levels were decreased the day after the first ECT in comparison with the pre-treatment levels and immediately following each ECT in comparison with baseline. A trend toward elevation of Prl was observed immediately after the first and sixth ECT, although the rise did not reach significant levels. ECT administration stimulated β-EP and cortisol secretion and suppressed human GH release, possibly by activation of endorphinergic and/or serotonergic systems. These mechanisms might be involved in the beneficial effect of ECT in depression.     

Cerebral ventricular infusion of excess calcium in the rat: effects on sleep states, behavior and cortical EEG.

Sleep and behavior of the rat were recorded during cerebroventricular infusion of artificial cerebrospinal fluid (aCSF) containing regular or excess concentrations of calcium. Three different types of aCSF were used for control infusions. Depending on the ionic composition, paradoxical sleep (PS) was reduced by 6--52% during a 1-h aCSF infusion period, whereas the total amount of sleep was not altered. The depression of PS by aCSF could be prevented by increasing the concentration of Ca in the infusate by a factor of 2--5 (2.6--9.1 mM). Infusions of high concentrations of Ca (9.1--54.6 mM) caused feeding and wet-dog shakes. A slow-wave cortical EEG pattern prevailed during feeding elicited by either infusion of excess Ca or systemic administration of a small dose of pentobarbital. It is concluded (a) that the ionic composition of the CSF may selectively influence the occurrence of a sleep state, and (b) that Ca-induced feeding may be related to a covert sedative action of this cation.     

Effect of clomipramine on sleep and EEG power spectra in the diurnal rodentEutamias sibiricus

Sleep was recorded in the diurnal rodentEutamias sibiricus, chronically implanted with EEG and EMG electrodes. The tricyclic antidepressant drug clomipramine suppressed the duration of REM sleep and EEG power density in the frequencies between 1.5 and 13.5 Hz in nonREM sleep. During the administration of clomipramine, 24 h of sleep deprivation by forced locomotion significantly reduced the duration of waking and increased the duration of nonREM sleep. During the first 2 h of recovery sleep, EEG power density of the frequencies between 2.5 and 6 Hz was enhanced. These effects of sleep deprivation were to a large extent similar to those of sleep deprivation under drug free conditions. It is concluded that clomipramine affects the EEG in nonREM sleep but does not interfere substantially with nonREM sleep regulatory processes, which are activated by sleep deprivation.     

Analysis of sleep EEG microstructure in subchronic paroxetine treatment of healthy subjects

Paroxetine is a selective and potent serotonin reuptake inhibitor and its efficacy for the treatment of depression has been proven. Under acute and subchronical treatment regimens, disturbances of the regular sleep pattern are a reported side effect of the drug. The present study was therefore performed to investigate the impact of subchronic treatment with the selective serotonin reuptake inhibitor paroxetine on the microstructure of the sleep EEG. The study especially addressed the question of subchronic effects of paroxetine medication (30 mg/day) in eight healthy male volunteers in a double blind, placebo-controlled crossover design. Conventional sleep EEG parameters and a spectral power analysis for different sleep stages after 4 weeks of treatment were computed. Additionally, the correlation of certain EEG rhythms across the night was calculated in order to detect subtle dynamical EEG alterations, not necessarily obvious when regarding conventional EEG analysis. Although we could not detect any alterations of the spectral power values in certain frequency bands either during NREM nor during REM sleep following subchronic paroxetine medication, the dynamical EEG attributes across the night revealed a significant enhancement of the correlation between certain EEG rhythms mainly during NREM sleep. Received: 18 July 1996 /Final version: 19 February 1997     

Effect of dexfenfluramine on sleep in healthy subjects

The acute effects of dexfenfluramine on nocturnal sleep were studied in ten healthy male subjects by means of sleep EEG recordings and ratings of subjective sleep quality. Four different dosages (3 mg, 7 mg, 15 mg, and 30 mg) were tested, administered over a period of 3 days each. Under 15 mg and 30 mg dexfenfluramine, only slight effects on sleep were observed: 15 mg led to decreased sleep efficiency in the first night of medication, and to reduced percentage of slow wave sleep in the first and third night. A significant lengthening of REM latency was present in the third night under 30 mg dexfenfluramine, without changes in other REM sleep parameters. Daily doses of 3 mg and 7 mg dexfenfluramine did not influence sleep, except for a significant REM latency reduction observed in the first night under 3 mg. Apart from a transient slight impairment under 30 mg, ratings of subjective sleep quality did not mirror any impact of dexfenfluramine. The data suggest that therapeutic dosages of dexfenfluramine only slightly influence nocturnal sleep, which contrasts with the known impact of other anti-obesity agents like the amphetamines. Unlike classical antidepressants, dexfenfluramine does not reduce REM sleep; in light of a hypothetical link between REM sleep reduction and antidepressant action of a drug, dexfenfluramine is not expected to have a pronounced antidepressant effect.