A. N. Nicholson

Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.

1 The effects of 10 mg (+)‐ and (−)‐chlorpheniramine and 5 mg (+)‐ and (−)‐dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well‐being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2 Daytime sleep latencies were reduced with triprolidine, (+)‐chlorpheniramine and (−)‐dimethindene, and subjects also reported that they felt more sleepy after (+)‐chlorpheniramine and (−)‐dimethindene. Performance on digit symbol substitution was impaired with (+)‐chlorpheniramine. 3 Changes in measures with (−)‐chlorpheniramine and (+)‐dimethindene were not different from changes with placebo. 4 In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1‐receptor. These findings strongly suggest that sedation can arise from H1‐receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Histaminergic systems and sleep. Studies in man with H1 and H2 antagonists.

Effects of H1 (mepyramine, mequitazine, triprolidine and brompheniramine) and H2 (cimetidine and ranitidine) antagonists on sleep were studied in healthy man. There were no effects of mepyramine (50 and 100 mg), and the only effect of mequitazine (5 and 10 mg) was a reduction in the number of awakenings. Triprolidine (10 and 20 mg) and brompheniramine (4 and 8 mg) did not alter wakefulness during sleep or the total sleep time, but rapid eye movement sleep was reduced. There were no effects of ranitidine (150 and 300 mg), but slow wave sleep was increased by cimetidine (200 and 400 mg). It is tentatively suggested that the histaminergic system is concerned with the mechanisms which favour vigilance during the wakeful state, and the balance between wakefulness and slow wave activity during sleep. Effects of some H1 antihistamines on rapid eye movement sleep are believed to be due to their monoaminergic rather than their histaminergic activity.

Studies on the modulation of the sleep-wakefulness continuum in man by fluoxetine, a 5-HT uptake inhibitor

The effects of an inhibitor of the uptake of 5-hydroxytryptamine (5-HT) fluoxetine (20, 40 and 60 mg), on nocturnal sleep and on alertness during the day, were studied in healthy adults. Fluoxetine reduced the total sleep time and the duration of rapid eye movement (REM) sleep and increased awake activity and stage 1 (drowsy) sleep during the night. Daytime sleep latencies were longer after fluoxetine but, paradoxically, the subjects felt more drowsy and coding ability was impaired. It is considered that the alerting effect of fluoxetine in man is most likely related to modulation of 5-HT-mediated transmission, whereas suppression of REM sleep is a nonspecific effect which arises when the balance of monoaminergic and cholinergic influences is disturbed. It is suggested that the serotonergic system has a pervasive influence throughout the sleep-wakefulness continuum, in contrast with some other neurotransmitter systems, which may be more concerned with the subtle manifestations of vigilance.

The influence of a 1 h nap on performance overnight

The effect on performance overnight of a 1 h nap taken at 0200 h was studied in six young female subjects. The subjects completed three schedules, including one with a nap and two without a nap, during which either a placebo or 300 mg caffeine was ingested at 2315 h. Performance was measured from 1700 h in the evening until 1030 h the next morning. Caffeine improved performance overnight on almost all tasks compared with placebo. The nap had some limited beneficial effect compared with placebo, but most tasks remained impaired.

Dopaminergic transmission and the sleep-wakefulness continuum in man

Modulation of dopaminergic transmission on daytime alertness and performance and on nocturnal sleep were studied in man using 30, 60 and 90 mg pemoline, a dopamimetic drug, and 2, 4 and 6 mg pimozide, a dopamine receptor antagonist. Pemoline lengthened daytime sleep latencies and improved attention, and increased wakefulness during nocturnal sleep. Rapid eye movement (REM) sleep was reduced with 90 mg pemoline, but this was due entirely to increased wakefulness. Pimozide had little effect on overnight sleep, but increased the tendency to fall asleep and impaired performance during the day. These studies suggest that the effects of certain drugs which modulate the activity of neurotransmitters, involved in the control of sleep and wakefulness, may be related to the inherent level of activity of the central nervous system. Modulation of the dopaminergic system can have a profound influence on the manifestation of wakefulness and vigilance, but is unlikely to modify directly the elaboration of REM sleep in man.

5-Hydroxytryptamine and noradrenaline uptake inhibition: studies on sleep in man

Effects of an inhibitor of the uptake of noradrenaline (maprotiline, 75 and 150 mg) and two inhibitors of the uptake of 5-hydroxytryptamine (zimelidine, 100 and 200 mg; indalpine, 25 and 50 mg) on sleep were studied in healthy man. Maprotiline reduced the duration of rapid eye movement (REM) sleep and increased the duration of stage 2 sleep, and there was evidence of sedation the next day. Zimelidine and indalpine reduced the duration of REM sleep, but also reduced the total sleep time and increased wakefulness and stage 1 (drowsy) sleep. It is suggested that in acute studies, the effects of inhibition of uptake on sleep are likely to arise from presynaptic inhibition of release of transmitter, although other mechanisms cannot be excluded. Suppression of REM sleep is believed to be due to the balance between cholinergic and monoaminergic influences being disturbed rather than a specific effect arising from the modulation of a particular transmitter.

l-Tryptophan and sleep in healthy man

The effect of L-tryptophan on night-time and day-time sleep (from 14.00 h) sleep was studied in six healthy males aged between 20 and 30 years. The doses used in the night-time studies were 2, 4 and 6 g, and in the day-time studies 1, 2 and 4 g. It was not possible to establish an effect of L-tryptophan compared with placebo on night-time sleep, but analysis of the sleep measures with 4 g compared with placebo and the other doses of L-tryptophan considered together suggested reduced awakenings, increased stage 3 and an increased percentage of REM sleep. With 4 g L-tryptophan there was an increase in the duration of stage 3 of day-time sleep compared with placebo. The studies provide marginal evidence that REM sleep may be modified by L-tryptophan in man, though the evidence is somewhat stronger that SWS may be increased. The effect on REM sleep may involve circadian mechanisms. The hypnotic activity of L-tryptophan per se is limited and uncertain.

Sleep after transmeridian flights.

Nocturnal sleep and daytime sleep latencies, recorded electroencephalographically after westward and eastward flights across the North Atlantic involving time zone shifts of 5 h, were influenced by the time of the flight and by subsequent displacement of the rest period. After the westward flight there was sleep disturbance during the latter part of the first night. However, there was persistent disturbance of sleep after the eastward flight. A rapidly eliminated hypnotic may be useful for the first night or two after a westward flight and for a few nights after an overnight eastward flight.

Presynaptic alpha2-adrenoceptor function and sleep in man: Studies with clonidine and idazoxan

The effects of an alpha 2-adrenoceptor agonist, clonidine and an antagonist, idazoxan, were studied on nocturnal sleep in man. Clonidine increased non-rapid eye movement sleep and idazoxan reduced slow wave sleep and increased awake activity. Changes in the continuity of sleep with clonidine were similar to, and those with idazoxan opposite to, the effects of maprotiline, an inhibitor of the uptake of noradrenaline, used as an active control. These findings support the previous conclusion that raised levels of noradrenaline in the synapse, after inhibition of uptake, lead to increased presynaptic inhibition of release of transmitter in man. However, all three drugs decreased rapid eye movement (REM) sleep and the ratio of REM to nonREM sleep and this is believed to be due to a non-specific upset of the balance of influences which control the appearance of REM sleep.

Influence of back angle on the quality of sleep in seats

Nocturnal sleep was assessed electroencephalographically in 9 males aged between 29 and 48 (mean 36·5) years in bed and in three seats with back angles to the vertical of 49·5° (sleeperette), 37·0° (reclining seat) and 17·5° (armchair). Sleep in the sleeperette did not differ from that in bed, but in the reclining seat the duration of sleep was reduced and the amount of awake activity was increased. Sleep in the armchair was markedly worse than in any of the other three conditions. Total sleep time was shorter and awake activity was increased with more awakenings. Sleep efficiency was also reduced. It would appear that adequate sleep may be obtained in seats as long as the back angle with the vertical approaches 40°.