Effects of pemoline on spontaneous and event-related electrical activity of the brain.

The effect of pemoline on the electrical activity of the brain (electroencephalogram, EEG) was studied in relation to time since sleep and time of day in 6 healthy subjects carrying out periods of work lasting 18 h. Power of the spontaneous EEG increased with time since sleep and amplitude of the P3 event-related response decreased. The changes may be interpreted as the reduction in alertness with time awake. In contrast, pemoline decreased power of the spontaneous EEG and increased the amplitude the P3 response, effects that are consistent with improved alertness. The changes in brain activity were paralleled by effects on performance, in terms of percentage of correct responses and reaction time. Performance decreased with time awake, and was improved by pemoline compared with placebo. The drug counteracted the adverse effects of time since sleep, with the beneficial effect of the drug persisting over the 18-hour period of work. The findings emphasise that spontaneous and event-related activity of the EEG may be used both to complement measures of performance in the laboratory and to assess behaviour in occupational situations where performance testing is impractical.

Drugs and the sleep-wakefulness continuum.

The circadian cycle of sleep and wakefulness in humans is controlled by the activity of many neurotransmitters. Studies of the effects of drugs on the central nervous system have elucidated some of the mechanisms that may be involved. Some transmitters are concerned with the basic control of sleep and wakefulness, influencing both alertness during the day and the pattern of nocturnal sleep. On the other hand, there are other transmitters that appear to be concerned primarily with the manifestation of wakefulness and vigilance, without a direct role in the process of sleep.

Jet lag and motion sickness.

Jet lag. Present day aircraft operating round northern and southern latitudes cross time zones at almost the same rate as the earth rotates, and it is these rapid transmeridian transitions that lead to the syndrome commonly referred to as jet lag. On arrival at their destination, individuals find themselves out of synchrony with the social and time cues of their new environment and, until they adapt, may experience symptoms such as malaise, gastrointestinal disturbance, loss of appetite, tiredness during the day and poor sleep. The severity and exact nature of the problems vary with the direction of travel and the number of time zones crossed, and some people react more unfavourably to intercontinental travel than others. Clearly, with increasing numbers of passengers undertaking such journeys, there is considerable interest in strategies to reduce the immediate effects of jet lag or to facilitate acclimatisation. Motion sickness is a generic term which embraces seasickness, airsickness, carsickness, space sickness etc, names that identify the provocative environment or vehicle. It is a normal reaction of humans to exposure to certain motion stimuli that occur during passive transportation.

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.

Presynaptic alpha 2-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.

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.

Modulation of rapid eye movement sleep in humans by drugs that modify monoaminergic and purinergic transmission.

Modulation of rapid eye movement (REM) sleep is a well-established effect of many centrally acting drugs. However, there is uncertainty concerning the nature of the changes and their significance, and it is in this context that we have analyzed the effects of several groups of drugs that alter monoaminergic or purinergic transmission on sleep in humans. The analysis shows that drugs that modulate noradrenergic and serotonergic transmission lead to marked suppression of REM sleep, irrespective of any increase or decrease in sleep duration. There is no evidence that the timing of the ultradian cycle of REM sleep relative to sleep onset is altered by these drugs. On the other hand, reduced REM sleep with dopamimetic drugs is due solely to increased wakefulness. However, there can be more subtle effects of some drugs on REM sleep. Benzodiazepine receptor agonists and drugs that modify purinergic transmission modulate the appearance of early REM activity. There may, therefore, be two discrete systems that control entry into REM sleep, and that are responsive to drugs. The exact appearance and timing of REM periods may be modulated by a feedback mechanism involving GABAergic, or possibly purinergic, transmission, while monoaminergic and cholinergic influences exert a reciprocal and overriding control of REM sleep.

Rapid eye movement sleep and sleep continuity. Depression and antidepressants.

Abnormalities of sleep and mood occur in depressive illness, and both disturbances may respond to therapy. Antidepressant drugs of all classes bring about immediate and often pronounced changes in sleep. Some drugs reduce, whereas others increase, nocturnal wakefulness, but most, if not all, suppress rapid eye movement activity, although it is uncertain whether this is linked directly to elevation of mood. Such changes in sleep continuity are related to the individual pharmacological profile of drugs, and in some instances, such as with trimipramine, may arise from the interaction of properties which alone may not lead to marked effects on sleep. On the other hand, inhibition of REM sleep appears to be related to a nonspecific disturbance of the balance between monoaminergic and cholinergic influences. In this way, REM sleep is reduced not only with drugs which selectively modulate noradrenaline or serotonin activity, but also with drugs which have complex pharmacological profiles.

Modulation of sleep by trimipramine in man.

We have studied the acute effect of trimipramine (25, 50 and 75 mg) on nocturnal sleep in 6 young men. Fluoxetine (60 mg) and diazepam (10 mg) were included as controls for the potential changes in sleep measures. Trimipramine reduced awake activity, Stage 1 (drowsy) sleep, and the duration of rapid eye movement (REM) sleep. Non-REM (Stage 2) sleep was increased. Residual effects of trimipramine were present the next morning (9 h after ingestion) with impaired coding ability. The effects of trimipramine on sleep and daytime alertness are consistent with its complex pharmacological profile. Reduced wakefulness and sedation are most likely due to synergism between histamine H1, alpha 1-adrenoceptor, and dopamine receptor antagonism. Anticholinergic activity and possibly blockade of alpha 1-adrenoceptors would disturb the balance of transmitter activities which facilitates the optimal appearance of REM sleep. In this way the effects of trimipramine on nocturnal wakefulness and REM sleep are similar to drugs which inhibit the uptake of noradrenaline.

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.

Nocturnal sleep and daytime alertness of aircrew after transmeridian flights.

The nocturnal sleep and daytime alertness of aircrew were studied by electroencephalography and the multiple sleep latency test. After a transmeridian flight from London to San Francisco, sleep onset was faster and, although there was increased wakefulness during the second half of the night, sleep duration and efficiency over the whole night were not changed. The progressive decrease in sleep latencies observed normally in the multiple sleep latency test during the morning continued throughout the day after arrival. Of the 13 subjects, 12 took a nap of around 1-h duration in the afternoon preceding the return flight. These naps would have been encouraged by the drowsiness at this time and facilitated by the departure of the aircraft being scheduled during the early evening. An early evening departure had the further advantage that the circadian increase in vigilance expected during the early part of the day would occur during the latter part of the return flight.

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.

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.

Modulation of catecholamine transmission and sleep in man.

The effect of modulation of catecholamine transmission on sleep in man was studied using mianserin (20 and 40 mg) and nomifensine (50 and 100 mg). It is suggested that reduced wakefulness induced by mianserin during sleep is primarily related to postsynaptic antagonism of alpha adrenoceptors, though a possible synergistic effect with antagonism of histamine H1 receptors cannot be excluded, while increased wakefulness with nomifensine is related to inhibition of the uptake of catecholamines and/or direct or indirect dopaminergic activity. The reduction in rapid eye movement (REM) sleep with both drugs is believed to be a non-specific effect which arises from a disturbance of the balance between monoaminergic and cholinergic influences.

Performance overnight in shiftworkers operating a day-night schedule.

Performance was measured during the day (0800-1700 hours) and during the night (1700-0800 hours) of a day-night schedule, and the effect of caffeine (300 mg) was studied during the overnight periods of work. The sleep electroencephalogram was recorded together with oral temperature and urinary electrolyte excretion. Impairment of performance within 9 h after the beginning of the daytime work period was minimal, and was limited to a test of continuous performance, but impairment of performance within 9 h after the beginning of the overnight work period was more pronounced and included lowered vigilance. Impaired performance overnight was related to time on task and circadian rhythmicity, and was alleviated to some extent by the use of caffeine.

Hypnotic activity of an imidazo-pyridine (zolpidem).

Effects of an imidazo-pyridine (zolpidem: 10, 20 and 30 mg) on overnight sleep and on performance the next day were studied in young adults and in middle aged individuals. The young adults were used particularly as an homogenous group to establish any possible adverse effects of the drug on sleep and on performance the next day, and the middle aged subjects with their less restful sleep were used to study efficacy. In the young adults zolpidem led to a marked increase in slow wave sleep with a reduction in stage 2 sleep. There were no significant changes in REM sleep, though there was a tendency for REM sleep to be delayed. In the middle aged there was a reduction in awake activity and drowsy sleep with an increase in stage 2 sleep. The latency to REM sleep was increased but the duration of REM sleep over the whole night was not reduced. Digit symbol substitution and a complex reaction time task were used to study performance, but there were no residual effects with zolpidem (9 h after ingestion). Zolpidem is likely to prove useful in the management of transient and short-term insomnia in healthy middle aged individuals when impaired performance the next day is to be avoided.

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.

Sustained performance with short evening and morning sleeps.

The effect which early evening sleep may have on overnight and subsequent daytime performance, and the effect which morning sleep may have on daytime performance after overnight sleep deprivation has been studied in six healthy male volunteers. It would appear that relatively short periods of natural and drug induced (brotizolam 0.125 mg) sleep have a beneficial effect on subsequent performance even in the absence of preceding sleep debt. In the event of disturbed sleep in shiftwork an hypnotic may be helpful, and in this context, one which is rapidly eliminated and sustains sleep is appropriate.

Ascorbic acid and performance in man.

Effects on performance of 1, 2 and 4 g ascorbic acid were studied from 0.5-5.5 h after ingestion in six healthy females. Diazepam (5 mg) was included as an active control, and it impaired digit symbol substitution, visuomotor coordination and complex reaction time. There were no effects of any dose of ascorbic acid on performance.