Effect of agomelatine in the chronic mild stress model of depression in the rat

Abstract

Chronic mild stress (CMS), a well-validated modelof depression, was used to study the effects of the melatonin agonist and selective 5-HT2 cantagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. Alldrugs were administered either2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) eveningtreatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction insucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine(both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration ofagomelatine and melatonin was completely inhibited by an acute injection of the MT1/MT2 antagonist, S 22153 (20 mg/kg i.p.), while theantagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatinecaused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin wasineffective. Moreover, melatonin antagonist, S 22153, did not modifythe intakes in stressed animals receiving morning administration ofagomelatine and in any other controland stressed groups tested in this study. These data demonstrate antidepressant-like activity ofagomelatine in the rat CMS modelof depression, which was independent ofthe time of drug administration. The efficacy of agomelatineis comparable to that of imipramine and fluoxetine, but greaterthan that of melatonin, which had no antidepressant-like activity aftermorning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, itsmorning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufflcientto sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on somecombination of its melatonin agonist and 5-HT2Cantagonist properties. © 2003 American College of Neuropsychopharmacology.