Peta A. Pascoe

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.

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.

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.

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.

Ascorbic acid and performance in man

Effects on performance of 1,2 and 4g 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.