Microinjection of glutamate into the pedunculopontine tegmentum induces REM sleep and wakefulness in the rat

The aim of this study was to test the hypothesis that the cells in the brain stem pedunculopontine tegmentum (PPT) are critically involved in the normal regulation of wakefulness and rapid eye movement (REM) sleep. To test this hypothesis, one of four different doses of the excitatory amino acid L-glutamate (15, 30, 60, and 90 ng) or saline (control vehicle) was microinjected unilaterally into the PPT while the effects on wakefulness and sleep were quantified in freely moving chronically instrumented rats. All microinjections were made during wakefulness and were followed by 6 h of polygraphic recording. Microinjection of 15- ng (0.08 nmol) and 30-ng (0.16 nmol) doses of L-glutamate into the PPT increased the total amount of REM sleep. Both doses of L-glutamate increased REM sleep at the expense of slow-wave sleep (SWS) but not wakefulness. Interestingly, the 60-ng (0.32 nmol) dose of L-glutamate increased both REM sleep and wakefulness. The total increase in REM sleep after the 60-ng dose of L-glutamate was significantly less than the increase from the 30-ng dose. The 90-ng (0.48 nmol) dose of L-glutamate kept animals awake for 2-3 h by eliminating both SWS and REM sleep. These results show that the L-glutamate microinjection into the PPT can increase wakefulness and/or REM sleep depending on the dosage. These findings support the hypothesis that excitation of the PPT cells is causal to the generation of wakefulness and REM sleep in the rat. In addition, the results of this study led to the identification of the PPT dosage of L-glutamate that optimally induces wakefulness and REM sleep. The knowledge of this optimal dose will be useful in future studies investigating the second messenger systems involved in the regulation of wakefulness and REM sleep.     

Slow-wave sleep in daytime and nocturnal sleep: an estimate of the time course of "Process S"

Daan et al. (1984) have proposed that sleep and wakefulness are regulated, in part, by a "Process S" that increases during wakefulness and declines during sleep. Data derived from several studies were taken to determine the time course of Process S during both wakefulness and sleep. As required by the model, slow-wave-sleep (SWS; an index of Process S) was found to increase exponentially as a function of prior wake time (equation 1) and to decline exponentially as a function of time asleep (equation 2). The equations accounted for 91% and 96% of the variance, respectively. In addition, equation 1 accurately predicted the amount the amount of SWS in the first hour of nocturnal sleep.     

Effects of thermal environment on sleep and circadian rhythm

ABSTRACT: The thermal environment is one of the most important factors that can affect human sleep. The stereotypical effects of heat or cold exposure are increased wakefulness and decreased rapid eye movement sleep and slow wave sleep. These effects of the thermal environment on sleep stages are strongly linked to thermoregulation, which affects the mechanism regulating sleep. The effects on sleep stages also differ depending on the use of bedding and/or clothing. In semi-nude subjects, sleep stages are more affected by cold exposure than heat exposure. In real-life situations where bedding and clothing are used, heat exposure increases wakefulness and decreases slow wave sleep and rapid eye movement sleep. Humid heat exposure further increases thermal load during sleep and affects sleep stages and thermoregulation. On the other hand, cold exposure does not affect sleep stages, though the use of beddings and clothing during sleep is critical in supporting thermoregulation and sleep in cold exposure. However, cold exposure affects cardiac autonomic response during sleep without affecting sleep stages and subjective sensations. These results indicate that the impact of cold exposure may be greater than that of heat exposure in real-life situations; thus, further studies are warranted that consider the effect of cold exposure on sleep and other physiological parameters.     

Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism

Background

Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with ^99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation.

Methods

Ten adult sleepwalkers and twelve controls with normal sleep were scanned using ^99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers.

Results

During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls.

Conclusions

Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness.     

Reduced Slow-Wave Rebound during Daytime Recovery Sleep in Middle-Aged Subjects

Cortical synchronization during NREM sleep, characterized by electroencephalographic slow waves (SW <4Hz and >75 μV), is strongly related to the number of hours of wakefulness prior to sleep and to the quality of the waking experience. Whether a similar increase in wakefulness length leads to a comparable enhancement in NREM sleep cortical synchronization in young and older subjects is still a matter of debate in the literature. Here we evaluated the impact of 25-hours of wakefulness on SW during a daytime recovery sleep episode in 29 young (27y ±5), and 34 middle-aged (51y ±5) subjects. We also assessed whether age-related changes in NREM sleep cortical synchronization predicts the ability to maintain sleep during daytime recovery sleep. Compared to baseline sleep, sleep efficiency was lower during daytime recovery sleep in both age-groups but the effect was more prominent in the middle-aged than in the young subjects. In both age groups, SW density, amplitude, and slope increased whereas SW positive and negative phase duration decreased during daytime recovery sleep compared to baseline sleep, particularly in anterior brain areas. Importantly, compared to young subjects, middle-aged participants showed lower SW density rebound and SW positive phase duration enhancement after sleep deprivation during daytime recovery sleep. Furthermore, middle-aged subjects showed lower SW amplitude and slope enhancements after sleep deprivation than young subjects in frontal and prefrontal derivations only. None of the SW characteristics at baseline were associated with daytime recovery sleep efficiency. Our results support the notion that anterior brain areas elicit and may necessitate more intense recovery and that aging reduces enhancement of cortical synchronization after sleep loss, particularly in these areas. Age-related changes in the quality of wake experience may underlie age-related reduction in markers of cortical synchronization enhancement after sustained wakefulness.     

Posterior cricoarytenoid muscle activity during wakefulness and sleep in normal adults

Six normal adults were studied 1) to compare respiratory-related posterior cricoarytenoid (PCA) muscle activity during wakefulness and sleep and 2) to determine the effect of upper airway occlusions during non-rapid-eye-movement (NREM) sleep on PCA activity. A new electromyographic technique was developed to implant hooked-wire electrodes into the PCA by using a nasopharyngoscope. A previously described technique was used to induce upper airway occlusions during NREM sleep (Kuna and Smickley, J. Appl. Physiol. 64: 347-353, 1988). The PCA exhibited phasic inspiratory activity during quiet breathing in wakefulness and sleep in all subjects. Discounting changes in tonic activity, peak amplitude of PCA inspiratory activity during stage 3-4 NREM sleep decreased to 77% of its value in wakefulness. Tonic activity throughout the respiratory cycle was present in all subjects during wakefulness but was absent during state 3-4 NREM sleep. In this sleep stage, PCA phasic activity abruptly terminated near the end of inspiration. During nasal airway occlusions in NREM sleep, PCA phasic activity did not increase significantly during the first or second occluded effort. The results, in combination with recent findings for vocal cord adductors in awake and sleeping adults, suggest that vocal cord position during quiet breathing in wakefulness is actively controlled by simultaneously acting antagonistic intrinsic laryngeal muscles. In contrast, the return of the vocal cords toward the midline during expiration in stage 3-4 NREM sleep appears to be a passive phenomenon.     

Geniohyoid muscle activity in normal men during wakefulness and sleep

Reduction in the activity of upper airway "dilator" muscles during sleep may allow the pharyngeal airway to collapse in some individuals. However, quantitative studies concerning the effect of sleep on specific upper airway muscles that may influence pharyngeal patency are sparse and inconclusive. We studied seven normal men (mean age 27, range 22-37 yr) during a single nocturnal sleep study and recorded sleep staging parameters, ventilation, and geniohyoid muscle electromyogram (EMGgh) during nasal breathing throughout the night. Anatomic landmarks for placement of intramuscular geniohyoid recording electrodes were determined from a cadaver study. These landmarks were used in percutaneous placement of wire electrodes, and raw and moving-time-averaged EMGgh activities were recorded. Sleep stage was determined using standard criteria. Stable periods of wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep were selected for analysis. The EMGgh exhibited phasic inspiratory activity during wakefulness and sleep in all subjects. In six of seven subjects, mean and peak inspiratory EMGgh activities were significant (P less than 0.05) reduced during stages 2 and 3/4 NREM sleep and REM sleep compared with wakefulness. This reduction of EMGgh activity was shown to result from a sleep-related decline in the level of tonic muscle activity. Phasic inspiratory EMGgh activity during all stages of sleep was not significantly different from that during wakefulness. Of interest, tonic, phasic, and peak EMGgh activities were not significantly reduced during REM sleep compared with any other sleep stage in any subject. In addition, the slope of onset of phasic EMGgh activity was not different during stage 2 NREM and REM sleep compared with wakefulness in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Compensatory sleep response to 12 h wakefulness in young and old rats

There is a pronounced decline in sleep with age. Diminished output from the circadian oscillator, the suprachiasmatic nucleus, might play a role, because there is a decrease in the amplitude of the day-night sleep rhythm in the elderly. However, sleep is also regulated by homeostatic mechanisms that build sleep drive during wakefulness, and a decline in these mechanisms could also decrease sleep. Because this question has never been addressed in old animals, the present study examined the effects of 12 h wakefulness on compensatory sleep response in young (3.5 mo) and old (21.5 mo) Sprague-Dawley and F344 rats. Old rats in both strains had a diminished compensatory increase in slow-wave sleep (SWS) after 12 h of wakefulness (0700-1900, light-on period) compared with the young rats. In contrast, compensatory REM sleep rebound was unaffected by age. To assess whether the reduced SWS rebound in old rats might result from loss of neurons implicated in sleep generation, we counted the number of c-Fos immunoreactive (c-Fos-ir) cells in the ventral lateral preoptic (VLPO) area and found no differences between young and old rats. These findings indicate that old rats, similar to elderly humans, demonstrate less sleep after prolonged wakefulness. The findings also indicate that although old rats have a decline in sleep, this cannot be attributed to loss of VLPO neurons implicated in sleep.     

Selected Contribution: Regulation of sleep-wake states in response to intermittent hypoxic stimuli applied only in sleep.

Recurrent sleep-related hypoxia occurs in common disorders such as obstructive sleep apnea (OSA). The marked changes in sleep after treatment suggest that stimuli associated with OSA (e.g., intermittent hypoxia) may significantly modulate sleep regulation. However, no studies have investigated the independent effects of intermittent sleep-related hypoxia on sleep regulation and recovery sleep after removal of intermittent hypoxia. Ten rats were implanted with telemetry units to record the electroencephalogram (EEG), neck electromyogram, and body temperature. After >7 days recovery, a computer algorithm detected sleep-wake states and triggered hypoxic stimuli (10% O2) or room air stimuli only during sleep for a 3-h period. Sleep-wake states were also recorded for a 3-h recovery period after the stimuli. Each rat received an average of 69.0 +/- 6.9 hypoxic stimuli during sleep. The non-rapid eye movement (non-REM) and rapid-eye-movement (REM) sleep episodes averaged 50.1 +/- 3.2 and 58.9 +/- 6.6 s, respectively, with the hypoxic stimuli, with 32.3 +/- 3.2 and 58.6 +/- 4.8 s of these periods being spent in hypoxia. Compared with results for room air controls, hypoxic stimuli led to increased wakefulness (P < 0.005), nonsignificant changes in non-REM sleep, and reduced REM sleep (P < 0.001). With hypoxic stimuli, wakefulness episodes were longer and more frequent, non-REM periods were shorter and more frequent, and REM episodes were shorter and less frequent (P < 0.015). Hypoxic stimuli also increased faster frequencies in the EEG (P < 0.005). These effects of hypoxic stimuli were reversed on return to room air. There was a rebound increase in REM sleep, increased slower non-REM EEG frequencies, and decreased wakefulness (P < 0.001). The results show that sleep-specific hypoxia leads to significant modulation of sleep-wake regulation both during and after application of the intermittent hypoxic stimuli. This study is the first to determine the independent effects of sleep-related hypoxia on sleep regulation that approximates OSA before and after treatment.     

Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep.

We tested the hypothesis that, following exposure to high altitude, cerebrovascular reactivity to CO2 and cerebral autoregulation would be attenuated. Such alterations may predispose to central sleep apnea at high altitude by promoting changes in brain PCO2 and thus breathing stability. We measured middle cerebral artery blood flow velocity (MCAv; transcranial Doppler ultrasound) and arterial blood pressure during wakefulness in conditions of eucapnia (room air), hypocapnia (voluntary hyperventilation), and hypercapnia (isooxic rebeathing), and also during non-rapid eye movement (stage 2) sleep at low altitude (1,400 m) and at high altitude (3,840 m) in five individuals. At each altitude, sleep was studied using full polysomnography, and resting arterial blood gases were obtained. During wakefulness and polysomnographic-monitored sleep, dynamic cerebral autoregulation and steady-state changes in MCAv in relation to changes in blood pressure were evaluated using transfer function analysis. High altitude was associated with an increase in central sleep apnea index (0.2 +/- 0.4 to 20.7 +/- 23.2 per hour) and an increase in mean blood pressure and cerebrovascular resistance during wakefulness and sleep. MCAv was unchanged during wakefulness, whereas there was a greater decrease during sleep at high altitude compared with low altitude (-9.1 +/- 1.7 vs. -4.8 +/- 0.7 cm/s; P < 0.05). At high altitude, compared with low altitude, the cerebrovascular reactivity to CO2 in the hypercapnic range was unchanged (5.5 +/- 0.7 vs. 5.3 +/- 0.7%/mmHg; P = 0.06), while it was lowered in the hypocapnic range (3.1 +/- 0.7 vs. 1.9 +/- 0.6%/mmHg; P < 0.05). Dynamic cerebral autoregulation was further reduced during sleep (P < 0.05 vs. low altitude). Lowered cerebrovascular reactivity to CO2 and reduction in both dynamic cerebral autoregulation and MCAv during sleep at high altitude may be factors in the pathogenesis of breathing instability.     

Sleep and wakefulness in the green iguanid lizard (Iguana iguana)

The reptile Iguana iguana exhibits four states of vigilance: active wakefulness (AW), quiet wakefulness (QW), quiet sleep (QS) and active sleep (AS). Cerebral activity decreases in amplitude and frequency when passing from wakefulness to QS. Both parameters show a slight increase during AS. Heart rate is at a maximum during AW (43.8+/-7.9 beats/min), decreases to a minimum in QS (25.3+/-3.2 beats/min) and increases in AS (36.1+/-5.7 beats/min). Tonical and phasical muscular activity is present in wakefulness, decreases or disappears in QS and reappears in AS. Single or conjugate ocular movements are observed during wakefulness, then disappear in QS and abruptly reappear in AS. Although these reptiles are polyphasic, their sleep shows a tendency to concentrate between 20:00 and 8:00 h. Quiet sleep occupies the greater percentage of the total sleep time. Active sleep episodes are of very short duration, showing an average of 21.5+/-4.9 (mean+/-SD). Compensatory increment of sleep following its total deprivation was significant only for QS. Reaction to stimuli decreased significantly when passing from wakefulness to sleep. It is suggested that the lizard I. iguana displays two sleep phases behaviorally and somatovegetatively similar to slow wave sleep and paradoxical sleep in birds and mammals.     

Dynamics of neuronal activity in the posterior hypothalamus during alternating phases of the sleep-wake cycle

The dynamics of neuronal activity in the posterior hypothalamus in different phases of the sleep-wake cycle were investigated during experiments on free-ranging cats. The highest frequency discharges were found to occur in 89.3% of neurons belonging to this region during the stages of active wakefulness and emotionally influenced paradoxical sleep. These neurons become less active during restful wakefulness and the unemotional stage of paradoxical sleep; this reduced activity can be most clearly observed in the context of slow-wave sleep. It was found that 7.1% of test neurons discharged at the highest rate during the stage of active wakefulness. They did not achieve an activity level characteristic of active wakefulness during the period of paradoxical sleep, although activity level was higher than during other states. Only 3.6% of neurons followed the opposite pattern, with discharges succeeding more frequently in slow-wave sleep and activity reduced to an equal degree during wakefulness and paradoxical sleep. The neurophysiological mechanisms governing the sleep-wake cycle and how the posterior hypothalamus contributes to these mechanisms are discussed.I. S. Beritashvili Institute of Physiology, Academy of Sciences of Georgian SSR, Tbilisi. Translated from Neirofiziologiya, Vol. 20, No. 2, pp. 160–167, March–April, 1988.     

Characteristics of the hippocampal formation functioning during wakefulness and paradoxical sleep

In view of the available published data concerning various concentration of neuromodulators in the brain during paradoxical sleep and wakefulness and the evidence for the influences of neuromodulators on efficiency of synaptic inputs to hippocampal neurons it is concluded that during paradoxical sleep, increase in concentrations of acetylcholine, cortisol, and dopamine and simultaneous decrease in serotonin and noradrenaline levels could synergistically lead to essential depression of efficacy of synaptic transmission in the polysynaptic pathway through the hippocampus (i.e. in the perforant path to dentate gyrus, from the dentate gyrus to CA3 area, from CA3 to CA1 area and from CA1 to the subiculum) but potentiation of the efficacy of the perforant input to pyramids of CA1 and CA3 areas and increase in efficacy of associative connections between CA3 neurones. The specified changes in functioning of the hippocampal loop can underlie differences in storing and extraction of information from memory during paradoxical sleep as compared to wakefulness.     

Sleep duration varies as a function of glutamate and GABA in rat pontine reticular formation

The oral part of the pontine reticular formation (PnO) is a component of the ascending reticular activating system and plays a role in the regulation of sleep and wakefulness. The PnO receives glutamatergic and GABAergic projections from many brain regions that regulate behavioral state. Indirect, pharmacological evidence has suggested that glutamatergic and GABAergic signaling within the PnO alters traits that characterize wakefulness and sleep. No previous studies have simultaneously measured endogenous glutamate and GABA from rat PnO in relation to sleep and wakefulness. The present study utilized in vivo microdialysis coupled on-line to capillary electrophoresis with laser-induced fluorescence to test the hypothesis that concentrations of glutamate and GABA in the PnO vary across the sleep/wake cycle. Concentrations of glutamate and GABA were significantly higher during wakefulness than during non-rapid eye movement sleep and rapid eye movement sleep. Regression analysis revealed that decreases in glutamate and GABA accounted for a significant portion of the variance in the duration of non-rapid eye movement sleep and rapid eye movement sleep episodes. These data provide novel support for the hypothesis that endogenous glutamate and GABA in the PnO contribute to the regulation of sleep duration.     

Collapsibility of the human upper airway during normal sleep

Upper airway resistance (UAR) increases in normal subjects during the transition from wakefulness to sleep. To examine the influence of sleep on upper airway collapsibility, inspiratory UAR (epiglottis to nares) and genioglossus electromyogram (EMG) were measured in six healthy men before and during inspiratory resistive loading. UAR increased significantly (P less than 0.05) from wakefulness to non-rapid-eye-movement (NREM) sleep [3.1 +/- 0.4 to 11.7 +/- 3.5 (SE) cmH2O.1-1.s]. Resistive load application during wakefulness produced small increments in UAR. However, during NREM sleep, UAR increased dramatically with loading in four subjects although two subjects demonstrated little change. This increment in UAR from wakefulness to sleep correlated closely with the rise in UAR during loading while asleep (e.g., load 12: r = 0.90, P less than 0.05), indicating consistent upper airway behavior during sleep. On the other hand, no measurement of upper airway behavior during wakefulness was predictive of events during sleep. Although the influence of sleep on the EMG was difficult to assess, peak inspiratory genioglossus EMG clearly increased (P less than 0.05) after load application during NREM sleep. Finally, minute ventilation fell significantly from wakefulness values during NREM sleep, with the largest decrement in sleeping minute ventilation occurring in those subjects having the greatest awake-to-sleep increment in UAR (r = -0.88, P less than 0.05). We conclude that there is marked variability among normal men in upper airway collapsibility during sleep.     

Shift Work and Inter‐Individual Differences in Sleep and Sleepiness

Inter‐individual differences in tolerance for shift work have been studied primarily in terms of external factors affecting alertness on the job or the ability to rest and sleep while at home. However, there is increasing evidence that neurobiological factors play a role as well, particularly the major processes involved in the regulation of sleep and wakefulness. These include a sleep homeostatic process seeking to balance wakefulness and sleep and a circadian process seeking to promote wakefulness during the day and sleep during the night. Shift work is associated with a temporal misalignment of these two endogenous processes. During nightwork, this misalignment makes it difficult to stay awake during the nightshift and sleep during the day. However, inter‐individual variability in the processes involved in sleep/wake regulation is substantial. Recent studies have demonstrated the existence of inter‐individual differences in vulnerability to cognitive deficits from sleep loss. Moreover, these inter‐individual differences were shown to constitute a trait. Interestingly, self‐evaluations of sleepiness did not correspond well with the trait inter‐individual variability in objective levels of performance impairment during sleep deprivation. Perhaps because of this discrepancy, in operational settings, the inter‐individual differences in vulnerability to sleep loss do not appear to be limited due to self‐selection mechanisms. Indeed, even among a highly select group of active‐duty jet fighter pilots flying a series of simulated night missions, systematic inter‐individual differences in performance impairment from sleep loss were still observed. There are significant personal and economic consequences to human error and accidents caused by performance deficits due to sleep loss. It is important, therefore, to study the inter‐individual differences in the regulation of sleep and wakefulness in the work environment so that cognitive impairment during shift work may be better anticipated and prevented.     

Shift work and inter-individual differences in sleep and sleepiness

Inter-individual differences in tolerance for shift work have been studied primarily in terms of external factors affecting alertness on the job or the ability to rest and sleep while at home. However, there is increasing evidence that neurobiological factors play a role as well, particularly the major processes involved in the regulation of sleep and wakefulness. These include a sleep homeostatic process seeking to balance wakefulness and sleep and a circadian process seeking to promote wakefulness during the day and sleep during the night. Shift work is associated with a temporal misalignment of these two endogenous processes. During nightwork, this misalignment makes it difficult to stay awake during the nightshift and sleep during the day. However, inter-individual variability in the processes involved in sleep/wake regulation is substantial. Recent studies have demonstrated the existence of inter-individual differences in vulnerability to cognitive deficits from sleep loss. Moreover, these inter-individual differences were shown to constitute a trait. Interestingly, self-evaluations of sleepiness did not correspond well with the trait inter-individual variability in objective levels of performance impairment during sleep deprivation. Perhaps because of this discrepancy, in operational settings, the inter-individual differences in vulnerability to sleep loss do not appear to be limited due to self-selection mechanisms. Indeed, even among a highly select group of active-duty jet fighter pilots flying a series of simulated night missions, systematic inter-individual differences in performance impairment from sleep loss were still observed. There are significant personal and economic consequences to human error and accidents caused by performance deficits due to sleep loss. It is important, therefore, to study the inter-individual differences in the regulation of sleep and wakefulness in the work environment so that cognitive impairment during shift work may be better anticipated and prevented.     

The influence of prior wakefulness on REM sleep

Data from studies of naps and of shifted sleep were used to determine the relationship between two measures of rapid eye movement (REM) sleep (percentage of REM in the first 2 hr of sleep and REM latency) and prior wakefulness. For each sample, we calculated the difference between the observed value and that predicted by a cosine function that estimated the circadian rhythm of REM sleep propensity. The difference values were found to correlate reliably with hours and log hours of prior wakefulness. We conclude that while REM sleep is regulated in part by an endogenous circadian oscillator, it is also influenced by the duration of prior wakefulness.     

Disturbances of sleep and wakefulness associated with the use of antihypertensive agents

Sleep disturbances are frequently associated with the use of antihypertensive drugs. They are observed mainly during the administration of drugs that affect central adrenergic mechanisms. Beta-adrenoceptor antagonists which readily penetrate into the brain (propranolol, pindolol) increase wakefulness and/or decrease REM sleep. Alpha 2-adrenoceptor agonists (clonidine, guanfacine) markedly reduce the duration of REM sleep. The catecholamine depleting agent reserpine increases REM sleep during single or repeated-dose administration, while the MAOI phenelzine shows opposite effects. The 5-HT2 antagonist ritanserin, which is chemically related to the antihypertensive agent ketanserin, increases slow wave sleep while REM sleep is decreased. Sleep disturbances have not been reported during the administration of calcium entry antagonists. However, they seem to modify the effects of hypnotics and CNS stimulants. There are no formal studies on the effects of angiotensin converting enzyme inhibitors and vasodilators on sleep in man.