Clozapine Alters Sleep-Wake Behavior in Rats

Abstract

Clozapine is an atypical antipsychotic agent showing therapeutic efficacy superior to that of classical neuroleptics. Clozapine has strong sedative effects, but detailed studies on the drug influencing sleep in rodents are lacking. We studied the effects of clozapine on sleep and body temperature in rats. Clozapine (0, 2.5, and 7.5 mg/kg) was given i.p. to male Wistar rats at the beginning of the rest period. After administration of 7.5 mg/kg clozapine, animals were significantly more awake during the first 2 h postinjection. In parallel, the slow-wave activity (SWA) was suppressed. In the following 2 h non-REM sleep was markedly increased, whereas the SWA returned to baseline. At both doses clozapine decreased overall wakefulness and increased non-REM sleep on the first treatment day, which was associated with prolonged non-REM sleep episodes. These effects were transiently present even after subchronic treatment (7 days). After acute treatment, 7.5 mg/kg clozapine significantly reduced REM sleep and pre-REM sleep due to an increase in REM sleep latency and a reduction in the number of REM sleep episodes. Furthermore, clozapine produced a transient decrease in brain temperature that was followed by a moderate, but long-lasting elevation. To conclude, clozapine affected sleep-wake behavior in a way comparable to its effects in humans, suggesting that the rat is a suitable model for further studies on the underlying mechanisms.

Sleep Homeostatic and Waking Behavioral Phenotypes inEgr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

“…27 Our data demonstrate that clozapine not only suppresses AW and slows the waking EEG, as reported in humans 28 and rodents, 24 but additionally induces marked alterations in their waking EEG/EMG lasting up to 2 h following treatment. We defined this state as dissociated state (DS) because it was a mixture of extremely low amplitude EEG (typically associated with wake) and low muscle tone (typically associated with sleep).…”

“…The effect was not explained by sex, previous exposure to clozapine or distinct litters. Inconsistent EEG responses to clozapine treatment have also been reported in rats, 24 and systematic differences between responding and non-responding rats were not described.…”

“…Only WT mice showed typical 24 clozapine-induced changes in time spent in SWS (genotype × time: F5,315 > 2.6, P < 0.027), see Figure 3B. WT mice spent more time in SWS when receiving high-dose compared to vehicle treatment.…”

“…These findings are in line with prior studies in Egr3-deficient mice showing resistance to locomotor suppression to similar pharmacological treatment. 11,16 In WT mice, clozapine caused sedation as reported in rats 24 and blockade of the 5-HT2 receptors produced a prolonged inhibition of AW and low-frequency activity. These effects were not detected in Egr3-/-mice.…”

A Versatile Wireless Portable Monitoring System for Brain–Behavior Approaches

“…A single channel of EEG recordings at the left-side frontal cortex (Cortex-L) and recordings of the three acceleration (ACC) channels (axis-X, axis-Y, and axis-Z) were combined to classify each 10-s epoch as either a wake or a sleep epoch [26]. Fig.…”