Increased waking after intra-accumbens injection of m-chlorophenylbiguanide: prevention with serotonin or dopamine receptor antagonists.

Bilateral injection of the selective 5-HT3 receptor agonist m-chlorophenylbiguanide (5.0-40.0 micrograms) into the nucleus accumbens of the rat significantly increased waking and decreased slow wave sleep. Rapid eye movement (REM) sleep remained unchanged. Pretreatment with the 5-HT3 receptor antagonist MDL 72222 (1aH,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg s.c.) reversed the effects of m-chlorophenylbiguanide (10.0-20.0 micrograms) on sleep and waking. Blockade of the dopamine D1 or D2 receptor with (+)-SCH 23390 (0.25 mg/kg s.c.) or YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide) (0.5 mg/kg s.c.), respectively antagonized the increase of waking and reduction of slow wave sleep induced by m-chloro-phenylbiguanide (10.0 micrograms). Our results tend to indicate that the increase of wakefulness after injection of the selective 5-HT3 receptor agonist m-chlorophenylbiguanide into the nucleus accumbens is partly related to the release of endogenous dopamine. In addition, they suggest that concomitant stimulation of both accumbens dopamine D1 and D2 receptor-related mechanisms is a necessary prerequisite to increase wakefulness.

Effects of selective activation or blockade of the histamine H3 receptor on sleep and wakefulness.

The effects of the histamine H3 receptor agonist, (R)-alpha-methylhistamine were compared with those of the histamine H3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-alpha-Methylhistamine (1.0-4.0 micrograms) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-alpha-methylhistamine (1.0-8.0 mg/kg) was administered i.p. Thioperamide (1.0-4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-alpha-methylhistamine (2.0 micrograms) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the waking state.

Short-term sleep laboratory evaluation of midazolam in chronic insomniacs. Preliminary results.

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.

Sleep laboratory study of the effects of midazolam in insomniac patients.

The effects of midazolam, a short-acting imidazobenzodiazepine, on the sleep cycle of insomniac patients were assessed by means of polygraphic recordings. Baseline placebo nights were compared with drug (30 mg p.o.) and placebo withdrawal nights. The compound was effective in inducing and maintaining sleep on short- and intermediate-term administration. Tolerance was not observed following two weeks of drug use. Subjective reports corroborated the effectiveness of midazolam as a hypnotic. In regard to its effects on sleep stages, midazolam markedly decreased Stage 3 and abolished Stage 4 sleep, while Stage 2 was augmented. REM sleep percentage was not significantly affected. Withdrawal of midazolam was followed by rebound insomnia, in which sleep latency, total wake time and wake time after sleep onset were increased above baseline. Side-effects related to midazolam administration included headache, muscular weakness and dizziness. They were mild and wore off 1-2 hours after awakening.

The effects of the combined administration of gamma-hydroxybutyrate and diazepam on sleep parameters in the rat.

The actions of diazepam and gamma-hydroxybutyrate (GHB) were assessed on the sleep-wakefulness cycle of male Wistar rats. One and 2 mg/kg diazepam and 12.5 mg/kg GHB had no effects on the sleep variables. After 25 mg/kg GHB, slow wave sleep (SWS2) was significantly increased. Following the combined administration of non-effective doses of GHB and diazepam, significantly higher amounts of SWS2 at the expense of wakefulness were obtained. The injection of a subconvulsant dose of bicuculline (2.5 mg/kg) prior to treatments which significantly increased SWS2 prevented this effect to show up. It is suggested that the actions of GHB and diazepam on the sleep-awake cycle are related to the same neurotransmitter system.

Effects of clozapine on the activity of central dopaminergic and noradrenergic neurons.

The effects of clozapine on the spontaneous firing rate of noradrenergic (NE, locus coeruleus), dopaminergic (DA, zona compacta, ventral tegmental area) and non-dopaminergic (zona reticulata) neurons was studied in chloral hydrate anesthetized rats. Clozapine administered intraperitoneally significantly increased the spontaneous activity of NE and DA neurons. After a cumulative dose of 8 mg/kg clozapine, the increase of mean firing rate per min of zona compacta and ventral tegmental area neurons attained almost similar values. Amphetamine reversed the clozapine-induced stimulation of NE and DA neurons. Zona reticulata neurons were depressed by clozapine. Neither amphetamine nor physostigmine were effective in antagonizing the inhibition. Our results suggest that clozapine blocks central NE and DA receptors. Furthermore, they fail to reveal a smaller sensitivity of the striatum as compared to the limbic system to the effects of clozapine.

The effects of p-chlorophenylalanine, reserpine, methysergide and cyproheptadine on the dopa-induced EEG synchronization in the rat.

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) on heart and respiratory rates and skin potential fluctuations during the sleep cycle in normal volunteers and neurotic patients with insomnia.

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 actions of dihydroxyphenylalanine and dihydroxyphenylserine on the sleep-wakefulness cycle of the rat after peripheral decarboxylase inhibition.

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.