Search

1. The actions of dihydroxyphenylalanine (DOPA) and dihydroxyphenylserine (DOPS) were assessed on the sleep-wakefulness cycle of male Wistar rats. 2. In comparative studies the extracerebral decarboxylase was inhibited with serinetrihydroxybenzylhydrazide (RO 4-4602) before injection of DOPA or DOPS. 3. DOPA (80-160 mg/kg, i.p.) with or without previous inhibition of the peripheral decarboxylase gave rise to an initial significant increase of slow wave activity, which may be related to a release of 5-hydroxytryptamine. 4. During the subsequent 8 h sessions, DOPA significantly decreased slow wave sleep and rapid eye movement sleep (REM) and increased wakefulness. 5. DOPS (80-160 mg/kg, i.p.) did not significantly modify the sleep-wakefulness cycle apart from a decrease of the latency for the first REM episode after 160 mg/kg in the RO 4-4602 pretreated animals.

PGO-like spikes were described in chronically implanted cats at the cerebellar nuclei, dentatus, fastigii and interpositus, bipolarly and monopolarly recorded during natural paradoxical sleep. They showed close similarities with known PGO at occipital cortex and lateral geniculate nucleus: wave form, duration and amplitude were coincident. Moreover fast activity frequency increment in the last part of slow wave sleep also was observed at cerebellar loci. The peak-to-peak latency measurements demonstrated that the occipital cortex PGO lagged the nucleus dentatus PGO-like waves in 20-22 msec. The phasic cerebellar waves were not always related to eye movements. Acute experiments with a previous low dose of reserpine showed the PGO-like spikes when an exploring electrode penetrated a cerebellar nucleus. Chronically implanted cats, treated with reserpine, showed the phasic cerebellar waves during wakefulness and, after a few days, during the recovered paradoxical sleep. Based on electrophysiology and the reserpine experiments a common pontine generating mechanism for PGO and cerebellar PGO-like activity is proposed. It is also hypothesized that the cerebellum could participate in sleep physiology mainly related to phasic events without excluding a tonic function.

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.

1 A study was carried out in rats (prepared for chronic sleep recording) of the effects of oxolinic acid on the sleep-wakefulness cycle.2 In addition, the actions of oxolinic acid on the sleep-wake cycle were assessed after pretreatment with drugs interfering with central catecholamine mechanisms or facilitating central gamma-aminobutyric acid (GABA) activity.3 Oxolinic acid (8-32 mg/kg) induced a significant and dose-related increase of waking EEG, while slow wave and REM sleep were decreased.4 The effects of oxolinic acid on waking, slow wave and REM sleep were antagonized by alpha-methyl-p-tyrosine (50-100 mg/kg) which interferes with the synthesis of catecholamines.5 FLA-63 (25 mg/kg) which is a specific inhibitor of noradrenaline synthesis, was effective in blocking oxolinic acid-related increase of waking and decrease of slow wave sleep.6 Haloperidol (0.4-0.6 mg/kg) which blocks central dopamine and noradrenaline receptors, reversed oxolinic acid-induced actions on waking and slow wave sleep. Spiroperidol (2-4 mg/kg) which interferes with dopamine and 5-hydroxytryptamine mechanisms, only antagonized the effect of oxolinic acid on light slow wave sleep. REM sleep was further decreased by both neuroleptic agents.7 gamma-Hydroxybutyrate (25-50 mg/kg), which acts as a GABA agonist and amino-oxyacetic acid (20 mg/kg), which considerably increases central GABA levels, were ineffective in blocking oxolinic acid-related disruption of the sleep-wake cycle.8 Our results suggest that the catecholamines are involved in the arousing effect of oxolinic acid.

1 A study was carried out in rats (prepared for chronic sleep recording) of the effects of pretreatment with neuroleptics differing in their relative antinoradrenaline and antidopamine receptor potencies, on the L-DOPA and (+)-amphetamine-induced increase in waking EEG. 2 Haloperidol (0.6 mg/kg), which blocks central dopamine and noradrenaline (NA) receptors, reversed the EEG desynchronizing actions of L-DOPA and (+)-amphetamine. 3 Low doses of pimozide (0.4 to 0.8 mg/kg) which block dopamine receptors exclusively, were not able to modify the pharmacologically induced disruption of the sleep-awake cycle. However, at 1 mg/kg, a dose which also produces blockade of NA receptors, pimozide counteracted the increase in waking elicited by (+)-amphetamine. 4 Spiroperidol (1 to 4 mg/kg) which is devoided of NA receptor blocking properties, failed to reverse the L-DOPA or (+)-amphetamine-induced arousal. 5 Our results suggest that the increased waking time observed after the catecholamine agonists is related to an increased availability of NA rather than dopamine.

The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats. During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.

The effects of furosemide and xipamide on guinea pig cochlear potentials were studied under acute conditions. Auditory nerve action potentials (AP) and cochlear microphonics (CM) were depressed by both diuretics in a dose-related manner. Furosemide was more effective on AP than on CM. In contrast, the xipamide-induced reductions of AP and CM were similar. Our results suggest that the depressive effects of furosemide or xipamide may be related to a direct action on cochlear mechanisms.

The effects of clonidine were assessed on conditioned avoidance responses (CAR) in control, 6-hydroxy-dopamine (6-OHDA)- and vehicle-treated rats, using a shuttle box device. Clonidine (100--400 micrograms/kg) produced a significant decrease of CAR in control and vehicle-treated animals. On the other hand, avoidance responding was only slightly inhibited in the 6-OHDA-lesioned rats. Pretreatment with the alpha-adrenergic blocking drugs yohimbine or phentolamine (1--8 mg/kg) prevented the CAR disrupting effects of clonidine. When animals were pretreated with the beta-adrenergic blocking agent propranolol (1--8 mg/kg) the ensuing injection of clonidine caused a greater CAR depression. Our results further support the hypothesis relating the conditioned performance depression observed after clonidine to the activation of a presynaptic negative feedback mechanism mediated by alpha-adrenoceptors. It is also suggested that propranolol increases the clonidine inhibition through the blockade of a positive feedback mechanism dependent on the activation of presynaptic beta-receptors.

The effects of midazolam (15 and 30 mg p.o.) on the sleep of insomniac patients were assessed by means of polysomnographic recordings. As compared with placebo, 15 mg midazolam significantly increased non-REM sleep while other objective measures of insomnia were only slightly modified. At the 30 mg dose, midazolam significantly decreased total wake time and wake time after sleep onset. On the other hand, total sleep and non-REM sleep time were increased. No development of tolerance was observed following 2 weeks of drug use.

The influence of prior catecholamine depletion was studied on the behavioral depressant effects of haloperidol using a conditioned avoidance response. The butyrophenone disrupting effects on the avoidance behavior were significantly increased by 6-hydroxydopamine pretreatment.

The number of scratching episodes and average frequency with which they started during each sleep stage as well as the effects of nighttime pruritus on objective sleep parameters in nine children with atopic dermatitis were assessed in the sleep laboratory. Scratching episodes occurred during rapid eye movement (REM) sleep and non-REM (NREM) sleep. The largest average frequency corresponded to stage 1, followed by stage 2, REM sleep, stage 4, and stage 3. Sleep maintenance was markedly altered. Total sleep time decrease was related mainly to smaller amounts of stage 4 NREM sleep. REM sleep percentage of total sleep time was increased as compared with normal children of the same age. Furthermore, in six of nine patients REM sleep latency was found to be decreased.

The effects of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) in oral formulation of 15 and 30 mg on the sleep cycle of patients suffering from insomnia were assessed by means of polysomnographic recordings using a double-blind cross-over design. Both doses of midazolam were effective in improving sleep on short-term administration. In addition, significantly larger decrements of non-REM (NREM) sleep latency and of wake time through the 3rd third of night and nonsignificant trends toward smaller number of awakenings as well as shorter total wake time and longer NREM sleep time were induced by the 30 mg dose. Irrespective of the dosage sleep was almost exclusively increased at the expense of NREM sleep. Following 3 days treatment there was no rebound insomnia. These preliminary results suggest that the 15 mg dose could be appropriate in patients with difficulties in falling asleep, while the 30 mg dose would be more appropriate for patients who also experience difficulties in staying asleep.

The effects of delta sleep-inducing peptide (DSIP), on the sleep cycle of insomniac patients were assessed by means of polysomnographic recordings. DSIP in a dose of 25 nmol/kg or a placebo was administered i.v. during four nights using a double-blind crossover design. The number of nocturnal awakenings, non-rapid-eye-movement (NREM) sleep latency, total waking time and waking time after sleep onset were decreased under DSIP treatment, but no significant differences were found in comparison to baseline or to double-blind placebo nights. Total sleep time and NREM sleep time were increased by the peptide. Their increase was related to increases in stage 2, while stage 1, slow wave sleep (stages 3 and 4) and rapid-eye-movement sleep were not modified. For NREM sleep time and stage 2 sleep differences between DSIP and a placebo were significant, but the same differences existed already for the baseline values. It can be concluded that sleep improvement under DSIP treatment is of little clinical significance.

Polysomnographic recordings allow the recognition of three normal sleep stages: wakefulness, NREM and REM sleep. There are quantitative changes in these stages from childhood to old age. Most characteristic are progressive decreases in total sleep time, stage 4 NREM sleep and REM sleep. Insomnia can be defined as an alteration of both the quantity and quality of sleep. It can be associated with psychophysiological factors, psychiatric disorders, use of drugs and alcohol, sleep apnea, sleep-related myoclonus and restless legs, medical, toxic and environmental conditions, or REM sleep interruptions. At present, the benzodiazepines are the most frequently prescribed hypnotics. Their efficacy has been evaluated in the sleep laboratory and by means of sleep questionnaires (clinical studies). Their derivatives are grouped according to their pharmacokinetic profiles as short acting (triazolam), intermediate acting (flunitrazepam) and long acting (flurazepam). At the EEG level these compounds induce an increase in fast frequencies and in the number of sleep spindles. Slow wave activity is markedly decreased. All of the derivatives effectively and significantly induce and maintain sleep. Total sleep time increase is related to an imcrement of stage 2 sleep while REM sleep and stages 3 + 4 sleep are consistently reduced. Triazolam withdrawal is followed by a rebound insomnia. In contrast, under the same circumstances, flurazepam has a carry-over effect.

A study was carried out on the effects of methoxamine, prazosin, and yohimbine on the sleep-wake cycle in rats prepared for chronic sleep recordings. Methoxamine (4-8 mg/kg), an alpha 1-adrenoceptor agonist, induced a dose-related increase in wakefulness (W) and a decrease in slow-wave sleep (SWS) and REM sleep (REMS). Prazosin (0.125-1 mg/kg), which selectively blocks alpha 1-adrenoceptors, modified only slightly the amount of time spent in W and SWS, and consistently decreased REMS values. Prazosin (0.5 mg/kg) reversed the effects of methoxamine, decreasing W and increasing sleep. Yohimbine (3 mg/kg), which blocks alpha 2-adrenoceptors, augmented W and diminished sleep. Methoxamine (4 mg/kg) in animals pretreated with yohimbine (3 mg/kg) induced a further decrease of SWS and REMS and an increase of W. Thus, pharmacological activation of alpha 1- or blocking of alpha 2-adrenoceptors appears to decrease sleep and increase W. Further, blocking of alpha 1-adrenoceptors decreases REMS. Rapid eye movement sleep depression by the alpha 1-agonist or the alpha 1-antagonist is tentatively ascribed to a critical change in noradrenergic transmission in the brain.

The actions of drugs interfering with central indolaminergic mechanisms were assessed on the Dopa-induced EEG synchronization in the rat. The increased slow wave activity observed during the first 30 min following Dopa (100 mg/kg) was significantly decreased by p-chlorophenylalanine (400 mg/kg), reserpine (4 and 8 mg/kg) and methysergide (16 mg/kg). Cyproheptadine was ineffective in this respect. Our findings lend support to the hypothesis that the initial synchronization after Dopa is related to the release of 5-hydroxytryptamine.

The actions of flunitrazepam (Rohypnol) were assessed on the sleep cycle, heart and respiratory rates and skin potential fluctuations of normal volunteers and neurotic patients with insomnia by means of all night recordings. The most conspicuous effect of flunitrazepam (2 mg p.o.) in the healthy subject's sleep cycle was an increase of the latency for the appearance of the first REM period. In the insomniacs the compounds was effective in inducing and maintaining sleep. Flunitrazepam diminished heart rates during the REM phases and significantly decreased the variability indices, this effect being more prominent in the normal subjects. Skin potential fluctuations during stages 2 and REM sleep were also decreased although tolerance developed rapidly in this connection.

The correlation between marihuana-induced aggressive behavior and changes in the sleep-wakefulness cycle was studied in chronically implanted rats. Marihuana injection in non-REM deprived rats did not induce aggressiveness irrespective of the animals being caged in isolation or paired. During this procedure quantization of the sleep-awake cycle revealed that wakefulness was increased while slow wave and REM sleep were decreased, mainly in the paired animals. REM deprived-marihuana injected animals recorded in isolation behaved like the control solution-injected rats. They showed a large rebound of REM and were not aggressive at the end of the 8 hr sessions. Conversely, when these animals were paired during the recording periods, they remained continuously awake and showed numerous episodes of aggressiveness. These results suggest that the aggressiveness inducing properties of marihuana are related to the REM deprivation and to the increased environmental stimulation achieved by pairing the animals.

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025-2.0 mg/kg) and bromocriptine (0.25-6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05-0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects. The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhibitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.

The exact role of catecholamines (CA) on the sleep-wake cycle is still controversial. Critical analysis of lesion studies tends to suggest a neuromodulatory role for both dopamine (DA) and norepinephrine (NE) on EEG and behavioral arousal. Support for this view is provided by pharmacological studies in which catecholaminergic systems are activated or inhibited. Taken together they show that disturbances in the dynamic balance between neurochemical systems may alter the conditions for wake-triggering mechanisms to express at optimal levels. Large electrolytic or neurotoxic lesions which affect noradrenergic and dopaminergic structures are associated with marked and prolonged EEG changes and decreased behavioral arousal, respectively. In contrast, specific and circumscribed damage restricted to these systems is followed by a transient decrease in waking activity. Thus, results observed after large central lesions are most probably related to destruction of non-catecholaminergic neurons. Inhibition of brain CA synthesis causes behavioral sedation and a decrease in waking activity. Selective pharmacological stimulation of presynaptic alpha-adrenergic (alpha 2) receptors tends to decrease waking, while opposite effects result from alpha 2-receptor blockade. Drugs with agonistic activity at postsynaptic alpha-adrenergic (alpha 1) sites increase EEG desynchronization, but specific blockade of alpha 1-receptor does not result in marked decreases of waking EEG. In contrast, treatments which simultaneously block NE and DA receptors significantly affect waking. Beta-adrenergic receptor blockers show no conclusive effects on waking or sleep. Selective DA-receptor agonists induce biphasic effects, with low doses decreasing and large doses increasing cortical desynchronization and motility. Opposite effects are observed in laboratory animals after injection of specific DA-receptor blockers.

The intraventricular injection of 6-hydroxydopamine (200 mug) blocked a previously learned conditioned avoidance response (CAR) in rats. The administration of NE, DOPA, amphetamine, phenelzine, desipramine and clonidine induced the reappearance of the CAR. These results are in agreement with current hypotheses on the mechanism of action of 6-hydroxydopamine on the central nervous system.