Sleep impairment by diethyldithiocarbamate in rat. Protective effects of pre-conditioning and antioxidants

Dithiocarbamates, a class of compounds widely used in medicine and agriculture, have been reported to impair sleep structure. These effects have been attributed to the decrease in norepinephrine levels induced by these drugs. However, it has also been recently demonstrated that most of the mechanisms by which dithiocarbamates damage cell function involve changes in oxidative environment. To verify the potential relevance of the latter mechanism in the sleep impairment, we examined the sleep response of adult rats to an acute administration of diethyldithiocarbamate (DDTC). At the dose of 0.6 g/kg, DDTC induced fragmentation and a decrease in slow wave sleep (SWS), and a dramatic loss of paradoxical sleep (PS). These changes occurred soon after the treatment (day 0), persisted the following day (day 1), partially recovered on day 3, and regained near basal values on day 6. No sleep anomalies were observed with a lower dose of DDTC (0.06 mg/kg). On the other hand, when the higher dose of DDTC was given in association with either one of two antioxidants, a-tocopherol or melatonin, the amounts of SWS and PS significantly improved even on day 1, suggesting that the DDTC effects on sleep involved an impairment of the brain oxidative balance. Likewise, administration of the lower dose of DDTC 5 days before the higher dose induced a much earlier recovery of normal sleep, presumably due to the development of a tolerance to DDTC. On the whole, the data suggest that the brain oxidative environment may play a role in the mechanisms subserving sleep regulation. (C) 2002 Elsevier Science B.V. All rights reserved.