Rapid Eye Movement Sleep Regulation Research Articles

Immunocytochemical Distribution of VIP and PACAP in the Rat Brain Stem

Recent evidence indicates that pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) might play an important role in rapid eye movement sleep (REMS) generation at the pontine level in rats. We have thus examined the immunohistochemical distribution of VIP and PACAP in the pontine and mesencephalic areas known to be involved in REMS control in rats. A dense network of VIP-immunoreactive cell bodies and fibers was found in the dorsal raphe nucleus. A large number of PACAP-positive perikarya and nerve fibers was observed in the area known as the REMS induction zone within the pontine reticular formation (PRF). The present results provide an anatomical basis to our previous functional data, and suggest that PACAPergic mechanisms within the PRF play a critical role in long-term regulation of REMS.

Role of noradrenergic and GABA-ergic inputs in pedunculopontine tegmentum for regulation of rapid eye movement sleep in rats

Rapid eye movement (REM) sleep disturbance is associated with several psycho-behavioral disorders, hence, it is important to understand its neural mechanism of regulation. Although it was known that the noradrenergic (NA-ergic) neurons from locus coeruleus (LC) project to the pedunculopontine tegmentum (PPT), the role of noradrenaline (NA) alone and in association with GABA, an inhibitory neurotransmitter, in PPT for REM sleep regulation was not known and was investigated in this study in freely moving normally behaving rats. Rats were surgically prepared for electrophysiological sleep–wake recording and simultaneous bilateral microinjections into PPT. 200 nl of prazosin (α1-antagonist) or clonidine (α2-agonist) or propranolol (β-antagonist) or combination of picrotoxin (GABA-A antagonist) and clonidine or vehicle (control) was microinjected bilaterally into PPT using a remote-controlled pump and the effects on REM sleep compared. Prazosin, clonidine and propranolol increased the total time spent in REM sleep whereas co-injection of picrotoxin and clonidine did not affect REM sleep. The results suggest that NA in PPT tonically inhibits REM sleep, possibly by acting on the cholinergic REM-ON neurons, while GABA inhibits the release of NA for REM sleep regulation. A model of neural connections explaining such regulation has been presented.

Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep

In vivo microdialysis in C57BL/6J (B6) mouse was used to test the hypothesis that activating adenosine A(2A) receptors in the pontine reticular formation (PRF) increases acetylcholine (ACh) release and rapid eye movement (REM) sleep. Eight concentrations of the adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; CGS) were delivered to the PRF and ACh in the PRF was quantified. ACh release was significantly increased by dialysis with 3 mum CGS and significantly decreased by dialysis with 10 and 100 microm CGS. Co-administration of the adenosine A(2A) receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 30 nM) blocked the CGS-induced increase in ACh release. In a second series of experiments, CGS (3 microm) was delivered by dialysis to the PRF for 2 h while recording sleep and wakefulness. CGS significantly decreased time in wakefulness (-51% in h 1; -54% in h 2), increased time in non-rapid eye movement (NREM) sleep (90% in h 1; 151% in h 2), and increased both time in REM sleep (331% in h 2) and the number of REM sleep episodes (488% in h 2). The enhancement of REM sleep is consistent with the interpretation that adenosine A(2A) receptors in the PRF of the B6 mouse contribute to REM sleep regulation, in part, by increasing ACh release in the PRF. A(2A) receptor activation may promote NREM sleep via GABAergic inhibition of arousal promoting neurons in the PRF.

Rapid Eye Movement Sleep Is Reduced in Prolactin-Deficient Mice

Prolactin (PRL) is implicated in the modulation of spontaneous rapid eye movement sleep (REMS). Previous models of hypoprolactinemic animals were characterized by changes in REMS, although associated deficits made it difficult to ascribe changes in REMS to reduced PRL. In the current studies, male PRL knock-out (KO) mice were used; these mice lack functional PRL but have no known additional deficits. Spontaneous REMS was reduced in the PRL KO mice compared with wild-type or heterozygous littermates. Infusion of PRL for 11-12 d into PRL KO mice restored their REMS to that occurring in wild-type or heterozygous controls. Six hours of sleep deprivation induced a non-REMS and a REMS rebound in both PRL KO mice and heterozygous littermates, although the REMS rebound in the KOs was substantially less. Vasoactive intestinal peptide (VIP) induced REMS responses in heterozygous mice but not in KO mice. Similarly, an ether stressor failed to enhance REMS in the PRL KOs but did in heterozygous littermates. Finally, hypothalamic mRNA levels for PRL, VIP, neural nitric oxide synthase (NOS), inducible NOS, and the interferon type I receptor were similar in KO and heterozygous mice. In contrast, tyrosine hydroxylase mRNA was lower in the PRL KO mice than in heterozygous controls and was restored to control values by infusion of PRL, suggesting a functioning short-loop negative feedback regulation in PRL KO mice. Data support the notion that PRL is involved in REMS regulation.

Differential Effects of the Muscarinic M1 Receptor Agonist RS-86 and the Acetylcholine-Esterase Inhibitor Donepezil on REM Sleep Regulation in Healthy Volunteers

Broad evidence from preclinical and clinical research indicates that cholinergic neurotransmission contributes significantly to the generation of rapid eye movement (REM) sleep. However, a potential role of different acetylcholine receptor (AChR) subtypes for the regulation of three main aspects of REM sleep, (1) REM onset, (2) REM maintenance, and (3) generation of REMs, are not clear. In the present double-blind, randomized and placebo-controlled study, we investigated the differential effects of the M1 muscarinic AChR (mAChR) agonist RS-86 and the ACh-esterase inhibitor donepezil to further specify the AChR subtype function on REM sleep regulation in n = 20 healthy volunteers. We found that RS-86 selectively shortened REM latency (multivariate analysis of variance post hoc contrast p = 0.024 compared to placebo, not significant for donepezil) and that donepezil specifically enhanced the duration of REM sleep (% sleep period time, p = 0.000 compared to placebo; p = 0.003 compared to RS-86) and the number of REMs (p = 0.000 compared to placebo; p = 0.000 compared to RS-86). These results provide evidence that the onset of REM sleep is, in part, mediated by M1 mAChR activity, whereas the maintenance of REM sleep and the number of REMs are mediated by non-M1, but presumably M2 mAChR activity. These findings are of interest for the understanding of sleep regulation and of neuropsychiatric disorders, such as Alzheimer's dementia and depressive disorders, whose etiopathology may involve alterations in cholinergic neurotransmission.

Short-Term Homeostasis of REM Sleep Throughout a 12:12 Light:Dark Schedule in the Rat

Intervals extending from the end of a rapid eye movement (REM) sleep episode until the triggering of the next tend to be longer when they follow a longer REM sleep episode. A short-term REM sleep homeostatic process has been hypothesized to explain this effect. The present study assessed and modeled the REM sleep episode-interval relationship and compared its expression at different phases of a 12:12 light: dark schedule. Chronically implanted rats were continuously recorded for 3 consecutive days. Automated state scoring in 15-second epochs determined lengths of REM sleep episodes and intervals and non-rapid eye movement sleep and wakefulness content of intervals. Individual sound-attenuated temperature-regulated boxes. 16 Sprague-Dawley rats. Scheduled 12:12 light:dark cycle. The effect of REM sleep episode length is evidenced by a rising trend in the means and robust means of intervals and non-rapid eye movement content that follow REM sleep episodes of a given length. The relationship of robust means of intervals and REM sleep episode length was best fitted by a Gompertz sigmoid function. The parameters of the Gompertz equation were modulated throughout the 24 hours, presenting the highest amplitude and earliest rise in hours 1 to 4 after lights on and the lowest amplitude at the start of lights off. The modulation was also evident when only intervals with less than 3 minutes of wakefulness were considered. Short-term REM sleep homeostasis is modulated throughout the 24 hours under a 12:12 light:dark regime. Its assessment may provide a useful measure of REM sleep propensity, regulation, and recurrence.

Urotensin II Modulates Rapid Eye Movement Sleep through Activation of Brainstem Cholinergic Neurons

Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast synaptic transmission because it persisted in the presence of TTX and antagonists of ionotropic glutamate, GABA, and glycine receptors. Collectively, these results suggest that UII plays a role in the regulation of REM sleep independently of its cerebrovascular actions by directly activating cholinergic brainstem neurons.

Novel Role of Brain Stem Pedunculopontine Tegmental Adenylyl Cyclase in the Regulation of Spontaneous REM Sleep in the Freely Moving Rat

Physiological activation of kainate receptors and GABA(B) receptors within the pedunculopontine tegmentum (PPT) is involved in regulation of rapid-eye-movement (REM) sleep. Because these two types of receptors may also directly and/or indirectly activate the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway, we hypothesized that this signaling pathway may be involved in the PPT to regulate spontaneous REM sleep. To test this hypothesis, four different doses (0.25, 0.50, 0.75, and 1.0 nmol) of a specific adenylyl cyclase (AC) inhibitor, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536), were microinjected bilaterally (100 nl/site) into the PPT, and the effects on REM sleep in freely moving chronically instrumented rats were quantified. By comparing alterations in the patterns of REM sleep after control injections of vehicle or one of the four different doses of SQ22536, the contributions made by each dose of SQ22536 to REM sleep were evaluated. The results demonstrated that the local microinjection of AC inhibitor SQ22536 into the PPT decreased the total amount of REM sleep for 3 h and increased slow-wave sleep (SWS) for 2 h in a dose-dependent manner. This reduction in REM sleep was due to increased latency and decreased frequency of REM sleep episodes. These results provide evidence that inhibition of AC within the PPT can successfully reduce REM sleep. These findings suggest that activation of the cAMP-signaling pathway within the cholinergic cell compartment of the PPT is an intracellular biochemical/molecular step for generating REM sleep in the freely moving rat.

REM sleep latency and neurocognitive dysfunction in schizophrenia.

Background:Cognitive deficits—the hallmark of schizophrenic deterioration—still remain elusive as far as their pathophysiology is concerned. Various neurotransmitter systems have been implicated to explain these deficits. Abnormalities in cholinergic neurotransmission in the brain are one of the postulations; acetylcholine has also been postulated to regulate rapid eye movement (REM) sleep, especially REM latency. Thus, REM latency in patients with schizophrenia might provide a non-invasive window to look into the cholinergic functions of the brain.Aim:To study REM sleep measures and neurocognitive function in schizophrenia, and the changes occurring in these parameters following pharmacological treatment.Methods:Thirty subjects (15 with schizophrenia and 15 normal non-relative controls) were evaluated in this study. Most patients with schizophrenia had prominent negative symptoms and deficits in the performance in neurocognitive tests battery. They were treated with antipsychotics for a variable period of time and post-treatment evaluation was done using the same battery of neurocognitive tests and polysomnography. Patients were either drug-naïve or kept drug-free for at least two weeks both at baseline as well as at the post-treatment stage.Results:A positive correlation between the severity of negative symptoms and neurocognitive deficits (especially on the Wisconsin Card Sorting), and a negative correlation between these two parameters and REM latency was observed.Conclusion:It can be hypothesized that the acetylcholine deficit model of dementia cannot be applied to schizophrenic dementia, rather a hypercholinergic state results. This state warrants anticholinergic medication as a treatment option for negative symptoms of schizophrenia.

GABAA receptors inhibit acetylcholine release in cat pontine reticular formation: implications for REM sleep regulation.

This study used in vivo microdialysis in cat (n=12) to test the hypothesis that gamma aminobutyric acid A (GABAA) receptors in the pontine reticular formation (PRF) inhibit acetylcholine (ACh) release. Animals were anesthetized with halothane to hold arousal state constant. Six concentrations of the GABAA receptor antagonist bicuculline (0.03, 0.1, 0.3, 1, 3, and 10 mM) were delivered to a dialysis probe in the PRF, and endogenously released ACh was collected simultaneously. Bicuculline caused a concentration dependent increase in ACh release (maximal increase=345%; EC50=1.3 mM; r2=0.997). Co-administration of the GABAA receptor agonist muscimol prevented the bicuculline-induced increase in ACh release. In a second series of experiments, the effects of bicuculline (0.1, 0.3, 1, and 3 mM) on ACh release were examined without the use of general anesthesia. States of wakefulness, rapid-eye-movement (REM) sleep, and non-REM sleep were identified polygraphically before and during dialysis delivery of bicuculline. Higher concentrations of bicuculline (1 and 3 mM) significantly increased ACh release during wakefulness (36%), completely suppressed non-REM sleep, and increased ACh release during REM sleep (143%). The finding that ACh release in the PRF is modulated by GABAA receptors is consistent with the interpretation that inhibition of GABAergic transmission in the PRF contributes to the generation of REM sleep, in part, by increasing pontine ACh release.

Adrenergic signaling plays a critical role in the maintenance of waking and in the regulation of REM sleep.

Many experiments have suggested that the adrenergic system is important for arousal and the regulation of sleep/wake states. Electrophysiological studies have found strong correlations between the firing of adrenergic neurons and arousal state. Lesions of adrenergic neurons have been reported to cause changes in sleep/wake regulation, although findings have been variable and sometimes transient. To more specifically address the role of adrenergic signaling in sleep/wake regulation, we performed electroencephalographic and electromyographic recordings in mice with a targeted disruption of the gene for dopamine beta-hydroxylase, the enzyme that converts dopamine to norepinephrine. These mice are unable to synthesize the endogenous adrenergic ligands norepinephrine and epinephrine. The mutant mice sleep approximately 2 h more each day. The decrease in waking is due to a considerable decrease in the duration of waking bouts in spite of an increase in the number of waking bouts and transitions from sleep to waking. In contrast, the amount of rapid-eye-movement (REM) sleep is only half that in control mice due to a decrease in the number and duration of REM sleep bouts. Delta power is selectively increased in the mutant mice, and there is much less variation in non-REM sleep delta power over 24 h. After 6 h of total sleep deprivation during the first half of the light period, there is no rebound recovery of sleep time in the mutant mice. These results provide genetic evidence that adrenergic signaling acts to maintain waking and is important for the regulation of REM sleep and possibly sleep homeostasis.

Trouble du comportement en sommeil paradoxal

Rapid eye movement (REM) sleep behavior disorder is a parasomnia which occurs only during REM sleep characterized by the loss of skeletal muscle atonia, characteristic of paradoxical sleep and by excessive motor activity more or less develop during dreaming. A polysomnographic study is necessary to assess the diagnosis showing the absence of REM sleep atonia and related abnormal behavior. This parasomnia, rare, is more frequent in aged patients, of masculine gender and in a context of neurological disease. It is frequently associated with neurodegenerative disease with parkinsonism. Furthemore, the REM sleep behavior disorder can be the revealing symptom of the underlying disease. The idiopathic form represents fewer than half of cases. In the case of acute emergence, a medication and/or toxic cause should be considered and withdrawn if possible.The ethiopathogenics of this affection is still uncertain in human. A functional anomaly of REM sleep pontic generators – principally pedunculopontine nucleus - is nonetheless probable. Disorders in balance of major neurotransmitter systems (monoaminergic and cholinergic substance) implied in the regulation of REM sleep could therefore be responsible for this parasomnia. Clonazepam is very effective in reducing the symptoms and is generally well tolerated.

Spontaneous REM Sleep Is Modulated By the Activation of the Pedunculopontine Tegmental GABAB Receptors in the Freely Moving Rat

Considerable evidence suggests that the neurotransmitter gamma-aminobutyric acid (GABA)-ergic system and pedunculopontine tegmentum (PPT) in the brain stem are critically involved in the regulation of rapid-eye-movement (REM) sleep. GABA and its various receptors are normally present in the PPT cholinergic cell compartment. The aim of this study was to identify the role of GABA and its receptors in the regulation of REM sleep. To achieve this aim, specific receptors were activated differentially by local microinjection of selective GABA receptor agonists into the PPT while quantifying its effects on REM sleep in freely moving chronically instrumented rats (n = 21). The results demonstrated that when GABAB receptors were activated by local microinjection of a GABAB receptor selective agonist, baclofen, spontaneous REM sleep was suppressed in a dose-dependent manner. The optimum dose for REM sleep reduction was 1.5 nmol. In contrast, when GABAA and GABAC receptors were activated by microinjecting their receptor selective agonists, isoguvacine (ISGV) and cis-4-aminocrotonic acid (CACA), respectively, the total percentages of REM sleep did not change compared with the control values. In another eight freely moving rats, effects of baclofen application was tested on firing rates of REM-on cells (n = 12). Of those 12 neurons, 11 stopped firing immediately after application of baclofen [latency: 50 +/- 14 s (SD)] and remained almost silent for 130 +/- 12 min. Findings of the present study provide direct evidence that the PPT GABAB receptors and REM-on cells are involved in the regulation of REM sleep.

Long term blocking of GABA-A receptor in locus coeruleus by bilateral microinfusion of picrotoxin reduced rapid eye movement sleep and increased brain Na–K ATPase activity in freely moving normally behaving rats

Isolated studies showed that norepinephrinergic REM-OFF neurons are active throughout except during rapid eye movement (REM) sleep when they are inhibited possibly by GABA. Similarly, independent studies have also reported that during REM sleep deprivation those REM-OFF neurons continue firing, that there is increased norepinephrine (NE) in the brain and that increased levels of NE increases the Na–K ATPase activity in the brain. However, it was not known if all those changes were directly related to REM sleep deprivation, what could be the mechanism for such changes and their patho-physiological significance. To confirm the same, based on the reports, mostly from our group, it was hypothesised that GABA antagonist in the locus coeruleus (LC) should at least significantly reduce REM sleep and simultaneously increase Na–K ATPase activity in the brain. To confirm the proposed hypothesis, picrotoxin, a GABA-A receptor antagonist, was bilaterally microinjected every 6 h for 36 h into the LC of freely moving normally behaving rats and the effects on electrophysiological signals signifying sleep-wakefulness and on brain synaptosome Na–K ATPase activity were estimated. The microinjection was done with the help of a remote control pump without handling or disturbing the rats. The findings that REM sleep was significantly reduced and there was associated increase in Na–K ATPase activity confirmed our hypothesis. The results also support our modified (GABA-mediated) model of neural connections in the LC for the regulation of REM sleep. Also, this is probably the first report to simulate REM sleep deprivation using receptor antagonist.

Regulation of rapid eye movement sleep in the freely moving rat: local microinjection of serotonin, norepinephrine, and adenosine into the brainstem.

Considerable evidence suggests that rapid eye movement (REM) sleep is induced by glutamatergic activation of cholinergic cells within the pedunculopontine tegmentum (PPT). The aim of this study is to test a popular hypothesis that serotonin, norepinephrine, and adenosine act on PPT cells to regulate REM sleep. This study also tests an alternate hypothesis that serotonin may inhibit REM sleep signs by direct action on the individual REM sleep sign generators. Serotonin, norepinephrine, and adenosine were locally microinjected into the PPT and serotonin was microinjected into the pontine-wave (P-wave) generator (dorsal part of the locus subcoeruleus nucleus) while quantifying the effects on REM sleep and P-wave activity in freely moving rats. N/A. N/A. N/A. Local microinjections of serotonin, norepinephrine, and adenosine into the PPT did not change REM sleep. Microinjection of serotonin into the P-wave generator suppressed P-wave activity but not REM sleep. The present findings provide direct evidence that serotonin, norepinephrine, and adenosine-induced REM sleep suppression in the behaving rat are not mediated by the PPT. The results also provide direct evidence, for the first time, that serotonin suppresses P-wave activity by acting directly on the P-wave generator. These results suggest that the serotonin-induced inhibition of REM sleep in the freely moving rat is probably not mediated through the mesopontine cholinergic cell compartment but, rather, through individual REM sleep sign generators.

Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genes

Nitric oxide (NO) affects almost every physiological process, including the regulation of sleep. There is strong evidence that NO plays an important role in rapid eye movement sleep (REMS) regulation. To further investigate the role of NO in sleep, we characterized spontaneous sleep in mice with targeted disruptions (knockout; KO) in the neuronal nitric oxide synthase (nNOS) or inducible (i)NOS genes. REMS in nNOS KO mice was substantially lower than that of their control mice. In contrast, the iNOS KO mice had significantly more REMS than their controls. Inducible NOS KO mice also had less non-REMS (NREMS) during the dark period. Results suggest that nNOS and iNOS play opposite roles in REMS regulation.

A two-state stochastic model of REM sleep architecture in the rat.

Rapid eye movement (REM) sleep is a recurring state throughout the sleeping period. Based on the examination of 45 sleep records of 3-mo-old male rats during the middle of the light phase, a stochastic model is proposed for the sequence X(1),Y(2), X(2),Y(2),. of REM sleep durations X and inter-REM sleep waiting times Y experienced by a rat during a sleeping period. In our model the probability distribution of any variable in the sequence, given the past, is allowed to depend on only the immediately previous variable. The conditional distributions f(y(i) | x(i)) and g(x(i+1) | y(i)) do not depend on the index i. It is shown that the marginal distributions tend to stationarity. Aggregations of the data on a discrete time scale suggest that the conditional distributions be formulated as two-component mixtures. These component distributions are modeled as Poisson and their means are called the means of short and long waiting time and the means of short and long REM sleep duration. Associated with each mean is a probability weight. Parametric forms are given to the means and probability weights. The model estimated by maximum likelihood shows a good fit to data of the 3-mo-old rats. The model fit to a smaller data set obtained from rats aged 15-22 mo shows a significant shortening of the means for both short and long REM sleep bout durations compared with the means of the 3-mo-old rats. Neuronal correlates for the behavior of the model are discussed in the context of the reciprocal interaction model of REM sleep regulation.

Spontaneous sleep interruptions during extended nights. Relationships with NREM and REM sleep phases and effects on REM sleep regulation.

There is no agreement in the literature as to whether sleep interruption causes rapid eye movement (REM) pressure to increase, and if so, whether this increase is expressed as shortened REM latency, increased REM density, or increased duration of REM sleep. The purpose of the present study was to examine the effect of different durations of spontaneous sleep interruptions on the regulation of REM sleep that occurs after return to sleep. The occurrence of spontaneous periods of wakefulness and their effects on subsequent REM sleep periods were analysed in a total sample of 1189 sleep interruptions which occurred across 364 extended nights in 13 normal subjects. Compared with sleep interruptions that last less than 10 min, sleep interruptions that last longer than 10 min occur preferentially out of REM sleep. In both the short and long types of sleep interruptions, the duration of REM periods that ended in wakefulness were shorter than the duration of those that were not interrupted by wakefulness. REM densities of the REM periods that terminated in periods of wakefulness were higher than those of uninterrupted REM periods. The proportion of episodes of wakefulness following REM sleep that were long-lasting progressively increased over the course of the extended night period. The sleep episodes that followed the periods of wakefulness were characterised by a short REM latency. REM duration was increased in episodes that followed long sleep interruptions compared to those that followed short sleep interruptions. REM density did not appear to change significantly in the episodes that followed sleep interruption. REM sleep mechanisms appear to be the main force controlling sleep after a spontaneous sleep interruption, presumably because during the second half of the night, where more sleep interruptions occur, the pressure for non-rapid eye movement sleep is reduced and the circadian rhythm in REM sleep propensity reaches its peak. Processes promoting REM sleep at the end of the night are consistent with the Pittendrigh and Daan dual oscillator model of the circadian pacemaker.

Effects of the selective activation of 5-HT 3 receptors on sleep: a polysomnographic study in healthy volunteers

The respective role of various classes of central serotonin (5-HT) receptors in the regulation of sleep–wakefulness cycles has been the subject of many studies. Notably, it has been reported that 5-HT 1A/B receptors are involved in the regulation of rapid eye movement sleep (REMS) and that 5-HT 2A/C receptors participate in the control of slow wave sleep (SWS), but the role of 5-HT 3 receptors is less well characterised. In this study we investigated the effects of SR 57227A, a potent and selective 5-HT 3 agonist, on the sleep EEG of normal young male volunteers. SR 57227A (2.5, 5, 10, 20, 40 mg o.d. and 20 mg b.i.d.) or placebo were administered during 7 consecutive days in seven groups of ten subjects using a parallel group design. Sleep EEG recordings were performed on days 6 and 7 after an habituation session. SR 57227A produced a dose-dependent shift of REMS toward the end of the night without changing REMS and SWS duration nor altering sleep continuity. It suggests a role for the 5-HT 3 receptor in the human sleep–wakefulness cycle and particularly in REMS regulation.

Role of wake inducing brain stem area on rapid eye movement sleep regulation in freely moving cats

Some of the characteristic symptoms associated with rapid eye movement (REM) sleep are opposite to, while some apparently resemble, those of wakefulness. Therefore, it was hypothesised that the neurons present in the wakefulness inducing area(s) in the brain are likely to communicate with the REM sleep related neurons. Brain stem neurons were classified based on their firing rates in relation to electrophysiological correlates associated with spontaneous sleep and wakefulness recorded from freely moving, normally behaving cats. Thereafter, the responses of those classified neurons to stimulation of brain stem reticular wakefulness inducing area were studied. Results from 63 neurons showed that the wake inducing area affected 62% of the neurons. Fifty-eight percent of the neurons which increased firing during wakefulness, including the REM-OFF neurons, were excited, while 70% of the neurons which decreased firing during wakefulness, including the REM-ON neurons, were inhibited. These observations support our hypothesis and, along with their physiological significance, are discussed.