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.