Reversal of Diazepam Tolerance and Withdrawal-induced Hyper Locomotor Activity and Anxiety by Melatonin in Mice

Abstract

Background & Objectives: Earlier studies from our laboratory have confirmed the role of melatonin in the reversal of morphine tolerance and dependence in mice. The present study was performed to explore the possible involvement of melatonin in the reversal of diazepam tolerance and dependence in mice. Methods: Diazepam (20 mg/kg/day, i.p.) was administered chronically on days 1–21. Mirrored-chamber was used to evaluate the anxiogenic reaction in mice due to withdrawal. Melatonin (2.5 or 5mg/kg; i.p.) was administered daily prior to diazepam administration for 21 days. Results: Chronic administration of diazepam (20 mg/kg/day, i.p.) on days 1–21 and its withdrawal produced anxiogenic reaction in mice as assessed in the mirrored-chamber test. Daily administration of melatonin (2.5 or 5 mg/kg, i.p.) prior to diazepam for 21 days prevented withdrawal-induced anxiety in mice. However, acute administration of a single dose of melatonin (2.5 or 5 mg/kg), to animals withdrawn from diazepam, i.e. on the 22nd day, did not prevent withdrawal-induced anxiety. Diazepam withdrawal also induced a significant increase in the locomotor activity of mice indicating an anxiogenic response. Daily administration of melatonin (2.5 or 5 mg/kg) prior to diazepam for 21 days also prevented withdrawal- induced increased locomotor activity. Both acute and chronic administration of melatonin (2.5 and 5 mg/kg) exhibited a significant protection against diazepam withdrawal-induced anxiety and hyper locomotor activity in mice. Conclusions: The result suggests the protective effect of this safe drug, melatonin, in the management of diazepam withdrawal reactions. doi: 10.5214/ans.0972.7531.2006.130202