Biomedical subjects

M Lancel

Publications and source records attributed to M Lancel.

At least 19 recordsLinked to original sources

PubMed2001

The GABA(A) agonist gaboxadol improves the quality of post-nap sleep.

RATIONALE: Previous studies demonstrated that gaboxadol, a selective GABA(A) agonist, increases both non-REM sleep and EEG delta activity within non-REM sleep in rats and slow wave sleep (SWS) as well as low-frequency activity in the EEG within non-REM sleep in healthy humans under normal conditions. OBJECTIVE: Because the hypnotic actions of drugs may be more readily demonstrated under conditions of poor sleep quality, we investigated the influence of gaboxadol on postnap sleep. METHODS: In a randomized, placebo-controlled cross-over study using a late afternoon nap model, we assessed the effects of a single oral dose of 20 mg gaboxadol on disturbed nighttime sleep in young, healthy subjects. RESULTS: Comparisons of visually scored sleep parameters between baseline and placebo postnap nights showed that the nap prolonged sleep latency, decreased total sleep time and SWS and attenuated delta, theta and alpha activity in the EEG within non-REM sleep. Compared with the placebo postnap night, gaboxadol tended to shorten sleep latency, significantly decreased intermittent wakefulness, increased total sleep time and SWS and enhanced delta and theta activity in the non-REM EEG. Furthermore, gaboxadol increased subjective sleep quality. CONCLUSIONS: These data show that gaboxadol counteracts the disrupting effects of a nap on subsequent sleep and suggest that, in addition to promoting deep sleep and sleep maintenance, gaboxadol is able to facilitate sleep initiation and thus, exhibits significant hypnotic actions under conditions in which sleep quality is experimentally reduced.

Adult↗

PubMed2001

Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology.

Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.

Animals↗

PubMed2001

The influence of subchronic administration of the neurosteroid allopregnanolone on sleep in the rat.

The endogenous neurosteroid allopregnanolone has recently been demonstrated to have somnogenic properties that are very similar to those of other agonistic modulators of GABA(A) receptors, especially of short-acting benzodiazepines. Short-acting benzodiazepines are established to rapidly lose their hypnotic effect upon repeated administration. To investigate the tolerance potential of allopregnanolone, we assessed sleep-wake behavior in rats during subchronic treatment (once daily for five days) with placebo or 15 mg/kg allopregnanolone (n = 8 each). The sleep patterns of the placebo and allopregnanolone group did not differ significantly before and after treatment. Throughout the entire treatment period the allopregnanolone group exhibited shorter non-rapid eye movement sleep (non-REMS) latencies, prolonged REMS latencies, longer non-REMS episodes, more pre-REMS and less low-frequency, but higher spindle activity in the electroencephalogram (EEG) within non-REMS than the placebo group. The lack of tolerance effects suggests that allopregnanolone may be an efficacious modulator of sleep-wake behavior over longer time periods than most drugs targeting the benzodiazepine binding site of the GABA(A) receptor.

Animals↗

PubMed2001

Acute effects of melatonin on spontaneous and picrotoxin-evoked sleep-wake behaviour in the rat.

Various studies indicate that exogenous melatonin has hypnotic properties in humans, which may be mediated by its influence on the circadian timing system or direct sleep-promoting actions, e.g. through a modulation of GABAergic transmission. The aim of the present placebo-controlled study was to examine the effects of melatonin on sleep in rats and the contribution of gamma-aminobutyric acid (GABA)A receptors. Sleep-wake behaviour was assessed in nine rats after intraperitoneal (i.p.) administration of pharmacological doses of melatonin (5 and 10 mg kg(-1)) and after combined administration of the GABAA receptor antagonist picrotoxin (1.5 mg kg(-1)) and melatonin (10 mg kg(-1)). To prevent chronobiotic effects, melatonin was delivered in the middle of the light period. Neither doses of melatonin exerted significant effects on brain temperature, sleep architecture or sleep electroencephalogram (EEG). Moreover, melatonin failed to attenuate the picrotoxin-induced promotion of wakefulness. These observations indicate that melatonin hardly influences sleep-wake behaviour in rats.

Animals↗

PubMed2001

Effect of the GABAA agonist gaboxadol on nocturnal sleep and hormone secretion in healthy elderly subjects.

Aging is associated with a dramatic decrease in sleep intensity and continuity. The selective GABA(A) receptor agonist gaboxadol has been shown to increase non-REM sleep and the duration of the non-REM episodes in rats and sleep efficiency in young subjects and to enhance low-frequency activity in the electroencephalogram (EEG) within non-REM sleep in both rats and humans. In this double-blind, placebo-controlled study, we investigated the influence of an oral dose of 15 mg of gaboxadol on nocturnal sleep and hormone secretion (ACTH, cortisol, prolactin, growth hormone) in 10 healthy elderly subjects (6 women). Compared with placebo, gaboxadol did not affect endocrine activity but significantly reduced perceived sleep latency, elevated self-estimated total sleep time, and increased sleep efficiency by decreasing intermittent wakefulness and powerfully augmented low-frequency activity in the EEG within non-REM sleep. These findings indicate that gaboxadol is able to increase sleep consolidation and non-REM sleep intensity, without disrupting REM sleep, in elderly individuals and that these effects are not mediated by a modulation of hormone secretion.

Aged↗

PubMed2001

Sleep changes induced by lipopolysaccharide in the rat are influenced by age.

In mammals, aging is associated with immune senescense. To examine whether the sleep changes occurring during immune challenge are affected by age, we assessed sleep alterations induced by the administration of lipopolysaccharide (LPS) in young and middle-aged rats. During vehicle, the middle-aged rats exhibited less pre-rapid eye movement sleep (pre-REMS) as well as REMS, due to a smaller number and shorter duration of REMS episodes, than young rats. LPS elevated body temperature, increased non-REMS, and suppressed both pre-REMS and REMS in the young as well as in the middle-aged rats. However, in the young animals, LPS significantly enhanced slow-wave activity in the electroencephalogram (EEG) within non-REMS, reflecting an increase in sleep intensity. In contrast, LPS attenuated EEG power in most frequency bands in the older animals. This finding indicates age-related changes in the modulation of sleep by LPS.

Aging↗

PubMed2000

Diurnal variations in lipopolysaccharide-induced sleep, sickness behavior and changes in corticosterone levels in the rat.

Inoculation of rats with microorganisms or microbial constituents that activate host defense promotes non-rapid eye movement sleep (non-REMS) and suppresses REMS. In this study, we evaluated circadian influences on the effects of lipopolysaccharide (LPS) on sleep, sickness behavior and plasma corticosterone levels in the rat. Three sets of experiments were performed. In each, the animals were intraperitoneally injected with vehicle for LPS (30 microg/kg) during 2 consecutive days, at the beginning of either the circadian rest or the activity phase. In experiment 1, sleep-wake behavior and brain temperature were recorded, and in experiment 2, core body temperature, locomotor activity as well as food and water intake. In experiment 3, corticosterone blood levels were measured. The results show that LPS-evoked changes in temperature, sleep and other behavioral parameters depend markedly on the time of day LPS is administered. However, a direct comparison of the LPS data demonstrates that, except for sleep parameters, the absolute time course of the assessed parameters was rather similar between the rest and activity phases. These findings suggest that LPS evokes a state characterized by high temperature and low vigilance, which is reached independently of the circadian phase.

Animals↗

PubMed2000

gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats.

Many hypnotics, such as benzodiazepines, are agonistic modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. Such compounds increase the ability to fall and stay asleep, but inhibit rapid-eye movement (REM) sleep and deep non-REM sleep. However, tolerance to their hypnotic action may develop rapidly. Previous findings in rats and humans demonstrate that the gamma-aminobutyric acid(A) agonist 4, 5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) promotes deep non-REM sleep and increases non-REM sleep continuity. To investigate the effects of repeated administration, we assessed sleep in rats before, during, and after chronic dosing of THIP (3 mg/kg, once daily for 5 days; n = 9) or of placebo (n = 8). The substances were administered i.p. at the onset of darkness. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 h after injection. During baseline recording, the placebo and the THIP group exhibited similar sleep patterns. After the first THIP injection, rats displayed more non-REM sleep, longer non-REM episodes, and higher levels of slow wave activity in the EEG within non-REM sleep than the placebo group rats. The effects were sustained during all treatment days. REM sleep was not affected. After drug withdrawal, the sleep patterns of the THIP and the placebo group were practically identical again. These observations suggest that THIP does not rapidly produce tolerance toward its sleep effects and abrupt drug withdrawal may not be associated with sleep disturbances. These findings confirm and extend the existing information suggesting that THIP may be promising for treatment of insomnia.

Animals↗

PubMed1999

Sleep and Its Modulation by Drugs That Affect GABA(A) Receptor Function.

Most sleeping pills are made up of chemical compounds that are ligands for allosteric modulatory binding sites on the GABA(A) receptor. Polysomnographic studies demonstrate that these hypnotics effectively increase the ability to fall and to stay asleep, but disrupt the physiological sleep profile (typical electroencephalograms (EEG) for the awake state and the different states of sleep are shown). Hence, there is an urgent need for sleep-promoting substances with a different mechanism of action. GABA analogues are one class of promising molecules.

Journal Article↗

PubMed1999

Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists.

This paper reviews the sleep effects of systemically administered agonistic modulators of GABAA receptors, including barbiturates, benzodiazepines, zolpidem, zopiclone and neuroactive steroids, and the selective GABAA agonists muscimol and THIP. To assess the involvement of GABAA receptors in the physiologic regulation of sleep, the article emphasizes the hypnotic properties shared by agonistic modulators and by the selective agonists of the GABAA receptor complex. In both rats and normal sleeping individuals, agonistic modulators are able to reduce sleep latency, increase sleep continuity, and promote non-rapid-eye-movement (NREM) sleep as well as the occurrence of spindles. Furthermore, nearly all of these compounds have been shown to attenuate slow-wave activity (SWA) and to suppress the occurrence of REM sleep. In the same species, GABAA agonist(s) do not seem to affect sleep latency or REM sleep time, but may increase sleep continuity and NREM sleep and augment SWA while depressing spindle activity in humans. The distinct sleep effects of GABAA agonists may be due to their unspecific stimulation of GABAA receptors throughout the brain, and to the fact that they are poor substrates for uptake and probably exert more tonic effects than liberated GABA. If so, the involvement of GABAA receptors in the various aspects of sleep can be inferred more accurately from the hypnotic effects of agonistic modulators. This implies that an activation of GABAA receptors plays a crucial role in the initiation and maintenance of NREM sleep and in the generation of sleep spindles, but disrupts the processes underlying slow EEG components and the triggering of REM sleep.

Animals↗

PubMed1999

The GABA(A) receptor antagonist picrotoxin attenuates most sleep changes induced by progesterone.

Progesterone has been shown to exert benzodiazepine-like effects on sleep, which suggests that they are mediated by an agonistic modulation of GABA(A) receptor functioning. To assess the involvement of GABA(A) receptors, we investigated the sleep responses to one dose of the GABA(A) antagonist picrotoxin (1.5 mg/kg) and progesterone (90 mg/kg), administered IP to eight rats alone and in combination, during the first 4 post-injection hours. Compared with vehicle, picrotoxin significantly delayed the latency to non-rapid eye movement sleep (non-REMS) and thereby decreased all sleep states, but barely affected the EEG activity within non-REMS. Progesterone significantly shortened non-REMS latency, increased pre-REMS, depressed low-frequency EEG activity (< or = 8 Hz) and augmented EEG activity in the higher frequencies within non-REMS. Except for the changes in high-frequency EEG activity, picrotoxin attenuated all effects of progesterone. These findings support the notion that GABA(A) receptors play an important role in the sleep effects of progesterone.

Animals↗

PubMed1999

Assessment of neuroleptic-like properties of progesterone.

There is considerable evidence from epidemiological studies that the onset of psychiatric disorders may be related to changes in the secretion of gonadal hormones. For example, the postpartum period appears to be a vulnerable phase for the occurrence of psychiatric disturbances such as dysphoric mood and even severe psychotic disturbances. It has been suggested that a sudden drop in progesterone concentrations may contribute to the development of such disorders. Because the administration of this steroid might be of therapeutic value in psychiatric disturbances, we investigated the behavioral properties of progesterone in the rat to assess putative neuroleptic-like properties of this steroid. Progesterone administration dose-dependently increased the EEG activity during wakefulness in the 10- to 30-Hz frequency bands and decreased locomotor activity. While no anxiolytic activity could be detected in the plus maze, the highest dose of progesterone (90 mg/kg) exerted an inhibitory effect on the conditioned avoidance response. In contrast to haloperidol (0.5 mg/kg), progesterone neither produced catalepsy nor antagonized amphetamine-induced stereotypy. However, both progesterone (10, 30 and 90 mg/kg) and haloperidol (0.1 mg/kg) effectively restored the disruption of the prepulse inhibition (PPI) of the acoustic startle response (ASR) that was evoked by apomorphine (2 mg/kg). In contrast, allopregnanolone (10 mg/kg), one of the main metabolites of progesterone, did not significantly antagonize the effect of apomorphine on the PPI. This behavioral profile of progesterone is compatible with the sedative properties of its metabolite allopregnanolone via the GABAA receptor, but also with the possibility that progesterone itself shares some properties with atypical antipsychotics, which may be relevant for the development and treatment of psychotic disturbances.

Animals↗

PubMed1998

Effect of the GABA uptake inhibitor tiagabine on sleep and EEG power spectra in the rat.

1. The sleep profiles induced by agonists and agonistic modulators of gamma-aminobutyric acidA (GABA[A]) receptors differ markedly. With regard to GABA(A) agonists, the effects may be due to the fact that these agents are poor substrates for uptake and are therefore likely to activate GABA(A) receptors tonically. To investigate this possibility, we assessed the sleep effects of two doses (2 and 10 mg kg[-1]) of the GABA re-uptake inhibitor tiagabine, administered intraperitoneally at light onset in 8 rats. Electroencephalogram (EEG) and electromyogram were recorded during the first 8 h after the injection. 2. Compared with vehicle, tiagabine had minimal effects on the temporal pattern of non-rapid eye movement sleep (non-REMS) and on the total time spent therein. However, tiagabine dose-dependently elevated EEG activity during non-REMs, most prominently in the lower frequencies (1-8 Hz) and least pronounced in the frequencies between 11 and 16 Hz. During the first 2 h after the injection, 10 mg kg(-1) tiagabine elicited repetitive episodes of hypersynchronous EEG waves during wakefulness and slightly suppressed REMS. Except for these effects, tiagabine hardly influenced the time spent in and EEG activity during wakefulness and REMS. 3. The effects of tiagabine on state-specific EEG activity were qualitatively very similar to those elicited by GABA(A) agonists. These findings support the hypothesis that the influence of GABA(A) agonists on EEG signals may be caused by tonic stimulation of GABA(A) receptors.

Animals↗

PubMed1997

Soluble tumor necrosis factor receptor (p75) does not attenuate the sleep changes induced by lipopolysaccharide in the rat during the dark period.

Sleep is generally enhanced during the early phase of infection. The cytokine tumor necrosis factor (TNF) has been postulated to play an important role in the acute phase sleep response. After demonstrating the ability of a soluble p75 TNF receptor (TNFR) to inhibit TNF activity in vitro, we assessed the influence of TNFR on the sleep changes evoked by lipopolysaccharide (LPS). In this vehicle-controlled experiment, 24 rats received either an intracerebroventricular injection of 10 micrograms TNFR, an intraperitoneal injection of 30 micrograms/kg LPS, or both, at the beginning of the dark period. EEG, EMG and brain temperature (Tbr) were recorded during the first 12 h post injection. Compared with vehicle, LPS had minimal effects on Tbr, but promoted non-rapid eye movement sleep (non-REMS), suppressed REMS, shortened the sleep episodes and decreased high-frequency (> or = 8 Hz) EEG activity during non-REMS. TNFR alone had no significant effects and did not attenuate any of the LPS-induced sleep changes. These results may either indicate that TNF is not critically involved in the sleep response to a low level LPS challenge during the activity phase or that the soluble p75 TNFR does not effectively antagonize the sleep changes evoked by TNF.

Animals↗

PubMed1997

The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans.

Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABAA receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sleep. In this placebo-controlled study, we assessed the influence of an oral dose of 20 mg THIP on nocturnal sleep in young healthy humans. Compared to placebo, THIP increased slow wave sleep by about 25 min. Spectral analysis of the EEG within NREM sleep revealed significant elevations in the lower frequencies (< 8 Hz) and reductions in the spindle frequency range (approximately 10-16 Hz). In accordance with previous findings in the rat, these data imply that GABAA agonists promote deep NREM sleep, without suppressing REM sleep. These effects are opposite to those induced by agonistic modulators of GABAA receptors such as benzodiazepines and are at variance with established mechanisms according to which GABAA agonists and modulatory agonists would have similar effects. The sleep response to GABAA agonists is highly similar to that evoked by sustained wakefulness, suggesting that GABAA receptors may be implicated in the homeostatic regulation of sleep.

Adult↗

PubMed1997

The GABA(A) agonist THIP increases non-REM sleep and enhances non-REM sleep-specific delta activity in the rat during the dark period.

Peripheral administration of the selective gamma-aminobutyric acid (GABA[A]) receptor agonists muscimol and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) to rats has recently been found to increase non-rapid eye movement sleep (non-REMS) duration and to enhance delta activity (0.5-4.0 Hz) within non-REMS during the light period, i.e. the circadian rest phase. In this vehicle-controlled study, we investigated the sleep response to two doses of THIP (2 and 4 mg/kg) administered intraperitoneally to eight rats at the beginning of the dark period. Electroencephalogram and electromyogram recordings were made continuously during the first 6-hours postinjection. The 4-mg/kg THIP dose significantly increased the time in non-REMS, lengthened the non-REMS episodes, and elevated delta activity within non-REMS. Quantitatively similar, but smaller effects were induced by 2 mg/kg THIP. Neither dose of THIP affected the time in REMS. These effects are very similar to those evoked by THIP and muscimol during the light period. This indicates that GABA(A) agonists dose-dependently promote non-REMS, by increasing non-REMS maintenance, and increase the intensity of non-REMS, and that these effects are independent of the light-dark and circadian cycle.

Animals↗

PubMed1997

Muscimol and midazolam do not potentiate each other's effects on sleep EEG in the rat.

The interaction of a gamma-aminobutyric acid-A (GABAA) receptor agonist and a benzodiazepine-type modulator of GABAA receptors on sleep was investigated. Low doses of muscimol (0.3 mg/kg) and the benzodiazepine midazolam (1.5 mg/kg) were administered alone and in combination, in random order, to eight rats. All injections were given intraperitoneally at light onset. Electroencephalogram (EEG) and electromyogram were recorded during the first 6 h post injection. Compared with vehicle, muscimol hardly affected the time spent in non-rapid eye movement sleep (non-REMS) and REMS, but significantly enhanced EEG activity in the frequency range between 2 and 6 Hz during non-REMS. Midazolam significantly increased the time spent in non-REMS, reduced EEG activity at frequencies < 12 Hz, and elevated EEG activity in most higher frequencies during this state. The combined administration of muscimol and midazolam affected non-REMS-specific EEG activity in an unexpected fashion: the effects were intermediate between those of muscimol and midazolam. These results indicate that muscimol and midazolam have dissimilar effects on EEG within non-REMS and demonstrate that midazolam does not augment but attenuates the muscimol-induced changes in sleep EEG. Our data are at variance with established mechanisms, according to which agonistic modulators would have similar effects and should potentiate the effects of GABAA agonists. The present data suggest that application of agonists and agonistic modulators of GABAA receptors causes differential net effects on sleep parameters.

Animals↗

PubMed1997

Allopregnanolone affects sleep in a benzodiazepine-like fashion.

Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-rapid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone significantly increased the time spent in pre-REMS, an intermediate state between non-REMS and REMS. Furthermore, allopregnanolone dose-dependently influenced EEG activity during non-REMS and REMS. In non-REMS, EEG activity was decreased in the lower frequencies (< or =7 Hz) and enhanced in the frequencies of > or =13 Hz. In REMS, allopregnanolone enhanced high-frequency EEG activity (> or =17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep.

Analysis of Variance↗