Effect of Agomelatine in the Chronic Mild Stress Model of Depression in the Rat

Abstract

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT 2C antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose 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 of agomelatine and melatonin was completely inhibited by an acute injection of the MT 1 /MT 2 antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT 2C antagonist properties.

Enhanced sensitivity to naltrexone-induced drinking suppression of fluid intake and sucrose consumption in maternally separated rats

“…Sometimes in these latter studies, sucrose solution consumption is used to assess not reward per se, but anhedonia, a condition associated with depression and characterized by inability to experience pleasure from normally pleasurable stimuli. In many of these studies, consumption of sucrose solution (or sucrose) was reduced, an outcome similar to that resulting from chronic mild stress, another procedure used to model depressive phenotypes (Grippo et al, 2003;Matthews et al, 1995;Papp et al, 2003). The results of our study are in contrast to the findings of those studies.…”

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…Agomelatine is a novel antidepressant possessing melatonergic receptor agonist (MT1 and MT2) (Audinot et al, 2003) and 5-HT 2C receptor antagonist properties (Millan et al, 2003), which displays robust antidepressant and anxiolytic-like actions in preclinical models (Papp et al, 2003;Millan et al, 2005) and alleviates various symptoms of major depression in humans (Loo et al, 2002;Kennedy and Emsley, 2006;Olié and Kasper, 2007;Dubocovich, 2006). Interestingly, both under basal and stressful conditions, agomelatine enhances hippocampal neurogenesis in rats (Maccari S, unpublished data;Banasr et al, 2006), with a distinctive profile in that it (1) selectively increases cell proliferation and neurogenesis in the ventral hippocampus (VH), a region connected with limbic structures, such as the amygdala, the prefrontal cortex and the nucleus accumbens, and strongly implicated in the response to stress (Bannerman et al, 2004), and (2) enhances the survival of newly generated cells throughout the entire hippocampus.…”

Comment déveloper un antidépresseur au mécanisme d’action innovant : l’exemple de l’agomélatine

“…Dans le cadre du développement d'un agoniste mélatoninergique, le test de résignation acquise, le stress chronique modéré et le modèle des souris transgé-niques avec un déficit des récepteurs des glucocorticoïdes sont des modèles plus particulièrement intéressants, car des perturbations des rythmes circadiens et du sommeil ont été clairement démontrées chez ces animaux « résignés » [27] et en « anhédonie » [15]. De fait, la mélatonine est active dans le modèle de stress léger chronique chez des souris C3H/He [28] et, dans une moindre mesure, chez des rats soumis à ce test [29]. L'agomélatine a été testée dans ces differents modèles, avec la méla-tonine et des antidépresseurs de référence comme comparateurs.…”

“…Enfin, ce test permet d'observer si la molécule testée provoque un phénomène de sevrage après l'arrêt du traitement. Une série d'expérimentations réalisées par le groupe de Papp, en Pologne, a montré l'efficacité de l'agomélatine (10 et 50 mg/kg, en injection intrapéritonéale) dans ce modèle : la molécule s'oppose à l'anhédonie provoquée par le stress chronique, et ce de façon rapide (un délai de 2-3 semaines suffit) et robuste, aucun phénomène de sevrage n'apparaissant même après une semaine d'arrêt de traitement (Figure 1) [29]. L'efficacité de l'agomélatine a été testée en fonction du moment de son administration, le matin ou le soir.…”

“…Il est important de signaler que l'agomélatine est dépourvue des effets sérotonergiques observés avec les SSRI ou les imipraminiques : une administration aiguë Administration matinale d'agomélatine à la dose de 50 mg/kg en injection intrapéritonéale (voir commentaires dans le texte). ** p < 0,01, *** p < 0,001 par rapport aux animaux témoins traités avec le véhicule ou le médicament à la semaine 0 ; # p < 0,05, ## p < 0,01, ### p < 0,001 par rapport aux animaux stressés traités avec le médicament à la semaine 0 (d'après [29]). …”