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Neuropsychopharmacology (2003) 28, 694–703 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 Effect of Agomelatine in the Chronic Mild Stress Model ofDepression in the Rat Mariusz Papp*,1, Piotr Gruca1, Pierre-Alain Boyer2 and Elisabeth Mocae¨r2 Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland; 2Institut de Recherches Internationales Servier, Courbevoie Cedex, Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT2C 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 MT1/MT2 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.
Neuropsychopharmacology (2003) 28, 694–703. doi:10.1038/sj.npp.1300091 Keywords: antidepressant; agomelatine; melatonin; chronic mild stress; 5-HT2C receptors; circadian; rat binding sites in the suprachiasmatic nucleus (SCN) of thehypothalamus, the brain region involved in the mechanism Agomelatine (S 20098; N(2-(7-methoxy-1-naphthyl)ethyl) of the endogenous biological clock (Bonnefond et al, 1993).
acetamide) is a potent agonist of melatonin receptors (Yous A number of studies have demonstrated chronobiotic et al, 1992; Ying et al, 1996; Conway et al, 2000) and an activity of agomelatine. For example, this compound resets antagonist of the 5-HT2C receptor subtype (Cussac et al, the electrical activity of the SCN (Ying et al, 1996) and 2002). Agomelatine shows a high affinity for cloned human resynchronizes experimentally disrupted circadian rhythms receptors MT1 and MT2 subtypes (Ki ¼ 6.15  1011 and (Armstrong et al, 1993; Redman et al, 1995; Martinet et al, 2.68  1010 M, respectively) as well as for the 5-HT2C 1996; Van Reeth et al, 1997). After chronic administration, receptor (IC50 ¼ 2.7  107 M on human cloned 5-HT2C agomelatine dose-dependently restores the phase shifting receptors). The affinity of agomelatine at melatonin response to a dark pulse (Van Reeth et al, 2001) and accelerates by 25% resynchronization of the rhythm to the (Ki ¼ 8.52  1011 and 2.63  1010 M, respectively) and, in new light–dark cycle in old hamsters (Weibel et al, 2000).
line with this, agomelatine displaces iodomelatonin from its The re-entraining activity of agomelatine, which is relatedto a direct effect on melatonin receptors in the SCN *Correspondence: Dr M Papp, Institute of Pharmacology, Polish (Redman and Francis, 1998; Ying et al, 1998), is dose- Academy of Sciences, 12 Smetna St., 31-343 Krakow, Poland, Tel: +48 dependent, and shows a clear relation to plasma concentra- 12 662 3352, Fax: +48 12 637 4500, E-mail: nfpapp@cyf-kr.edu.pl tion of agomelatine (Martinet et al, 1996). The chronobiotic Received 17 May 2002; revised 8 October 2002; accepted 14 October properties of agomelatine are of particular interest since the 2002Online publication: 17 October 2002 at http: //www.acnp.org/citations/ disorganization of internal rhythms is believed to be involved in the pathophysiology of depression (Wehr and Antidepressant activity of agomelatine in chronic mild stressM Papp et al Wirz-Justice, 1982). Indeed, positive responses to sleep deprivation and light therapies, as well as diurnal mood Animals were first trained to consume a 1% sucrose variations, indicate a dysfunction of circadian rhythms in solution. Training consisted of ten 1-h baseline tests in depression (Healy, 1993). Moreover, depressed patients which sucrose was presented, in the home cage, following exhibit a blunting in the amplitude of their circadian 14 h of food and water deprivation. Sucrose intake was rhythms, an abnormality that is no longer observed measured by weighing preweighed bottles containing the after their recovery following antidepressant therapy sucrose solution, at the end of the test. Subsequently, (Souetre et al, 1989). Depressed patients also present a sucrose consumption was monitored, under similar condi- phase advance of their circadian rhythms of melatonin tions, at weekly intervals throughout the whole experiment.
relative to their sleep (Lewy et al, 1987; Sack et al, 1990; On the basis of their sucrose intake in the final baseline test, Dahl et al, 1993), along with cortisol and temperature animals were divided into two matched groups. One group of animals was subjected to the chronic stress procedure for In the present study, antidepressant-like activity of a period of 9 consecutive weeks. Each week of the stress agomelatine was tested in the chronic mild stress (CMS) regime consisted of: two periods of food or water model, a chronic procedure based on the evaluation of deprivation; two periods of 451 cage tilt; two periods of anhedonia, that is, inability to experience pleasure, which is intermittent illumination (lights on and off every 2 h); two a core symptom of the human depressive disorder (see periods of soiled cage (250 ml water in sawdust bedding); Willner, 1997). The CMS model appears to be particularly two periods of paired housing; two periods of low intensity appropriate for studying antidepressant-like activity of stroboscopic illumination (150 flashes/min); and two compounds with chronobiotic properties since, apart from periods of no stress. All stressors were 10–14 h of duration a deficit in their responsiveness to reward, animals exposed and were applied individually and continuously, day and to the CMS procedure show advanced phase shift of diurnal night. Control animals were housed in separate rooms and rhythms (Gorka et al, 1996), diurnal variation with had no contact with the stressed animals. They were symptoms worst at the start of the dark (ie active) phase deprived of food and water for 14 h preceding each sucrose (D'Aquila et al, 1997), and a variety of sleep disorders test, but otherwise food and water were freely available in characteristic of depression, including decreased rapid eye the home cage.
movement (REM) sleep latency, increased number of REMsleep episodes, and more fragmented sleep patterns(Moreau et al, 1995; Cheeta et al, 1997). All these findings Drug Administration indicate that the CMS procedure causes a generalized On the basis of their sucrose intake following initial 2 weeks disorganization of internal rhythms, which are postulated to of stress, both stressed and control animals were each play an important role in the pathophysiology of depression further divided into matched subgroups (n ¼ 8 rats per (Wehr and Wirz-Justice, 1982).
group), and for subsequent 5 or 7 weeks (see below) they In order to determine the involvement of circadian received daily intraperitoneal injections, either in the rhythms resynchronization in the action of agomelatine in evening or in the morning.
the CMS model, this compound was administered at twotime points: 2 h before (evening treatment) and 2 h after(morning treatment) the dark phase of the 12-h light/dark Evening Administration. Vehicle (1% hydroxy ethyl cycle, that is, when agomelatine is devoid of chronobiotic cellulose suspension in distilled water, 1 ml/kg), agomela- effect (Van Reeth et al, 1997). The effects of these tine (10 and 50 mg/kg), melatonin (10 and 50 mg/kg), treatments were compared with the results of similar imipramine (10 mg/kg), or fluoxetine (10 mg/kg) were administration of melatonin and traditional antidepres- administered at 06.00 pm (ie 2 h before the dark phase of sants, imipramine, and fluoxetine. Finally, the effect of an the 12-h light/dark cycle) for 7 weeks. At Week 6, all acute dose of S 22153, a melatonin receptor antagonist animals received an acute dose of the melatonin antagonist, (Weibel et al, 1999), on the effects of all the above S 22153 (20 mg/kg, i.p.), 30 min before the sucrose test. After treatments was studied.
this test, treatments were continued and a final sucrose testwas carried out at Week 7.
Morning Administration. Vehicle (1% hydroxy ethyl MATERIAL AND METHODS cellulose suspension in distilled water, 1 ml/kg) and agomelatine (10 and 50 mg/kg) were administered at10.00 am (ie 2 h after the dark phase of the 12-h light/dark Male Wistar rats (n ¼ 336, Gorzkowska, Warsaw) were cycle). After 5 weeks, all treatments were terminated and brought into the laboratory 2 months before the start of the one additional sucrose test was carried out following 1 week experiment. Except as described below, the animals were of withdrawal. Other groups of animals received a similar singly housed with food and water freely available, and were administration of vehicle, agomelatine (50 mg/kg), melato- maintained on a 12-h light/dark cycle (lights on at 08.00) at nin (50 mg/kg), or imipramine (10 mg/kg) for 7 weeks. At a temperature of 22 7 21C. The study was conducted in Week 6, these animals were injected (30 min before the compliance with the Animal Protection Bill of 21 August sucrose test) with an acute dose of the melatonin antagonist, 1997, and has been approved by the Bioethical Committee at S 22153 (20 mg/kg, i.p.). After this test, treatments the Institute of Pharmacology, Polish Academy of Sciences, were continued and a final sucrose test was carried out at Krakow, Poland.
Antidepressant activity of agomelatine in chronic mild stress tion (imipramine: F(4,112) ¼ 3.971; po0.01, fluoxetine:F(4,112) ¼ 3.452; po0.01). As compared to Week 0 scores, The weekly sucrose tests were carried out 16 h (evening the increases in sucrose intake in stressed animals administration) or 24 h (morning administration) following administered with imipramine and fluoxetine reached the last drug injection. Stress was continued throughout the statistical significance after 3 weeks of treatment. This entire period of treatment and withdrawal.
effect was maintained and further enhanced thereafter, andat Week 5 the amount of sucrose solution drunk by these animals was comparable to that of vehicle-treated controls Changes in sucrose consumption during 5 weeks of vehicle (imipramine: p ¼ 0.067, fluoxetine: p ¼ 0.329) and signifi- and drug treatment in control and stressed animals were cantly higher than that of vehicle-treated stressed animals analyzed separately for morning and evening administra- (imipramine: p ¼ 0.0005, fluoxetine: p ¼ 0.006). The sucrose tion by multiple analysis of variance with group (stress/ consumption in control and stressed animals receiving control) and treatment (vehicle/drug) as the between- imipramine and fluoxetine was not affected by acute subject factors and successive sucrose measurements injection of the melatonin antagonist, S 22153, as evidenced (Weeks 0–5) as the within-subject factor. Effects of by nonsignificant Group  Weeks interaction effects for melatonin antagonist, S 22153, were analyzed by comparing imipramine and fluoxetine (F(2,28) ¼ 0.214 and 0.229, sucrose consumption measured during three consecutive respectively; see Figure 1, upper panel).
tests; that is, at Weeks 5, 6 (injection of S 22153), and 7.
Similarly, separate analyses were performed for Weeks 5–6 Effects of agomelatine. As shown in Figure 2 (upper panel), to evaluate effects of withdrawal from agomelatine admin- evening administration of agomelatine did not affect the istration. The Fisher's LSD test was used for post hoc consumption of sucrose solution in control animals comparisons of means. P values lower than 0.05 were (F(2,21) ¼ 0.158; NS) but in stressed animals agomelatine considered statistically significant.
caused a significant Treatment effect (F(2,21) ¼ 4.809;po0.05). In consequence, when compared to vehicleinjections, the overall effect of 5 weeks of agomelatine treatment led to significant effects of Group (F(1,42) ¼ Agomelatine (S 20098), S 22153 (N-[2-(5-ethylbenzo[b]thio- 12.855; po0.001), Weeks (F(5,210) ¼ 4.414; po0.001) and phen-3yl)ethyl] acetamide, melatonin, and fluoxetine were interaction (F(10,210) ¼ 3.585; po0.01). The increase in provided by Servier (France), and imipramine was pur- sucrose consumption was apparent during the first 3 weeks chased from RBI (USA). All drugs were injected in a volume of treatment, and reached statistical significance at Week 4 of 1 ml/kg body weight.
in stressed animals receiving the higher dose of 50 mg/kg(po0.05) and at Week 5 in animals treated with the lowerdose of 10 mg/kg (po0.01).
Acute injection of the melatonin antagonist, S 22153, was without any effect in control animals treated with both Evening Administration doses of agomelatine, but it completely reversed recovery of CMS caused a gradual decrease in the consumption of 1% sucrose drinking in stressed animals (Weeks effect: sucrose solution. Thus, in the final baseline test, all animals F(2,56) ¼ 4.413; po0.001 and Weeks  Group interaction: drank approximately 12–14 g of sucrose solution (data not F(2,28) ¼ 4.726; po0.05) (see Table 1). In stressed animals shown) and following initial 2 weeks of stress (ie at Week 0), treated with 50 mg/kg of agomelatine, this inhibition the intakes remained at the same level (approx. 13.5 g) in disappeared in the following week (Week 7) and their controls but fell to 8–8.5 g in stressed animals, resulting in a intakes were again comparable to that of vehicle-treated significant Group effect (F(1,104) ¼ 71.769; po0.001). Such controls (p ¼ 0.839) and significantly higher than that of a difference between control and stressed animals treated vehicle-treated stressed animals (p ¼ 0.001). Animals receiv- with vehicle, persisted at similar level for the remainder of ing a lower dose of 10 mg/kg also drank more sucrose the 5-week treatment period, and was reflected in a solution on the following test, but this effect was not significant Group effect (F(1,14) ¼ 8.844; p ¼ 0.01), and in significant (p ¼ 0.171) and the intakes in these animals at the nonsignificant effects of Weeks and Group  Weeks Week 7 were just above that seen in the vehicle-treated interaction (F(5,70) ¼ 1.761 and 1.395, respectively) (see stressed group (see Table 1).
Figure 1). Acute injection of the melatonin antagonist, S22153, at Week 6 had no significant effect on sucrose intake Effects of melatonin. As shown in Figure 2 (lower panel), in either control or stressed animals receiving vehicle evening treatment with melatonin did not significantly (Group  Weeks interaction, F(2,28) ¼ 1.176; NS) (see affect the consumption of sucrose solution in controls, but Figure 1 and Table 1).
gradually increased sucrose drinking in stressed animals,resulting in significant effects of Group (F(1,42) ¼ 18.474; Effects of imipramine and fluoxetine are presented in po0.001), Weeks (F(5,210) ¼ 11.063; po0.001), and inter- Figure 1 (upper panel). Chronic treatment with both drugs action (F(10,210) ¼ 3.291; po0.01). When compared to had no significant effect on sucrose intake in control Week 0 values, the increase of sucrose drinking in animals animals and increased sucrose consumption in stressed receiving the highest dose of 50 mg/kg reached statistical animals, resulting in significant effects of Treatment significance after 3 weeks of treatment (p ¼ 0.001). This (imipramine: F(1,28) ¼ 7.499; po0.01, fluoxetine: F(1,28) ¼ effect was further enhanced and, after 5 weeks of treatment, 4.859; po0.05) and Treatment  Group  Weeks interac- the intakes in these animals did not differ from those


Antidepressant activity of agomelatine in chronic mild stressM Papp et al Sucrose intake (g) Sucrose intake (g) Weeks of treatment Consumption of 1% sucrose solution, in controls (Con, open symbols) and in animals exposed to CMS (Str, closed symbols). Upper panel shows effects of vehicle (1 ml/kg), imipramine, and fluoxetine (both at 10 mg/kg) administered at 06.00 pm, that is, 2 h before the dark phase of the 12-h light/dark cycle (evening administration). Lower panel shows effects of vehicle (1 ml/kg) and imipramine (10 mg/kg) administered at 10.00 am, that is, 2 h after thedark phase of the 12-h light/dark cycle (morning administration). At Week 6, all animals were injected with 20 mg/kg of melatonin antagonist, S 22153 (seetext for details). Values are means 7 SEM. **po0.01, ***po0.001; relative to vehicle- or drug-treated control animals. #po0.05, ##po0.01, ###po0.001;relative to drug-treated stressed animals at Week 0.
measured in vehicle-treated controls (p ¼ 0.223) and were treated stressed animals (Weeks effect: F(2,56) ¼ 6.348; significantly higher than those of vehicle-treated stressed po0.01) (see Table 1). This inhibitory action of S 22153 animals (po0.005). The action of the lower dose of 10 mg/ was short lasting; in the following test at Week 7, full kg was slower; the increase of sucrose consumption was recovery of sucrose drinking was again apparent in animals significant only after 5 weeks of treatment (po0.05) and, at receiving a higher dose of 50 mg/kg of melatonin. Animals this point, the intakes in stressed animals receiving 10 mg/ administered 10 mg/kg also increased their intakes, relative kg of melatonin were midway between those seen in both to Week 6, but this effect was not significant (p ¼ 0.243).
the drug- and vehicle-treated control and stressed groups Table 2 shows that at the end of the treatment period the (see Figure 2, lower panel). Melatonin antagonist, S 22153, vehicle-treated control animals were smaller than the administered acutely prior to the sucrose test at Week 6, stressed animals but this difference was not significant completely reversed the effects of melatonin in the CMS (Group effect: F(1,14) ¼ 1.238; NS). As compared to vehicle- modelFthe sucrose consumption in both melatonin- treated groups, body weights of control and stressed treated stressed groups returned to the level of vehicle- animals were not significantly affected by imipramine Antidepressant activity of agomelatine in chronic mild stress Sucrose Consumption in Control (Con) and Stressed sucrose intake in stressed animals receiving morning (Str) Animals in Three Consecutive Tests administration of imipramine reached statistical signifi-cance after 3 weeks of treatment (po0.01) and this effect was further enhanced and maintained thereafter. The sucrose consumption in control and stressed animals Evening administration treated with imipramine was not affected by S 22153(Group  Weeks interaction: F(2,28) ¼ 0.162; NS) (see Figure 1, lower panel).
Con/agomelatine, 10 mg Str/agomelatine, 10 mg Effects of agomelatine are shown in Figure 3. Morning Con/agomelatine, 50 mg administration of agomelatine had no significant effect on Str/agomelatine, 50 mg sucrose intake in control animals (F(2,21) ¼ 0.204; NS) Con/melatonin, 10 mg while in stressed animals it caused a highly significant Str/melatonin, 10 mg Treatment effect (F(2,21) ¼ 12.133; p Con/melatonin, 50 mg o0.001, Figure 3, Str/melatonin, 50 mg upper panel). In consequence, when compared to vehicleinjections, the overall effect of 5 weeks of agomelatine Morning administration (F(1,42) ¼ 22.404; o0.001), Weeks (F(5,210) ¼ 3.856; po0.01) and interaction (F(10,210) ¼ 2.512; po0.01). The Con/agomelatine, 50 mg action of agomelatine was dose-dependent; increases in Str/agomelatine, 50 mg sucrose intake reached first statistical significance after 3 Con/melatonin, 50 mg weeks of treatment with the lower dose of 10 mg/kg Str/melatonin, 50 mg (po0.05) and already after the first week of treatment with At Week 6 all animals received an acute injection of the melatonin antagonist, a higher dose of 50 mg/kg (po0.05). This effect was S 22153 (20 mg/kg, see text for details). Values are means 7 SEM. *po0.001, maintained or enhanced thereafter and at Week 5 the relative to Week 5 values; **po0.001, relative to Week 6 values.
sucrose intakes in stressed animals receiving the two dosesof agomelatine were comparable to those measured in the (controls: F(1,14) ¼ 0.055; stressed: F(1,14) ¼ 0.099; NS) drug- and vehicle-treated control groups (see Figure 3, while fluoxetine caused significant effect in control upper panel). At 1 week after cessation of treatment, the (F(1,14) ¼ 8.947; po0.01), but not in stressed animals intakes remained at similar levels in both control and (F(1,14) ¼ 0.030; NS). Chronic treatment with melatonin stressed animals (Week 5 vs Withdrawal: Group, Weeks, had no significant effect on body weights of both control and interaction effects (F(1,28) ¼ 0.63, 1.041, and 1.502, (F(2,21) ¼ 1.064; NS) and stressed (F(2,21) ¼ 0.174; NS) respectively; all nonsignificant, see Figure 3, upper panel).
animals. The effect of chronic administration of agomela-tine on body weights was also not significant (controls: Effects of melatonin. As shown in the lower panel of Figure F(2,21) ¼ 0.899; NS, stressed: F(2,21) ¼ 0.747).
3, morning administration of melatonin for 5 weeks did notchange sucrose intake in either control or stressed animals, Morning Administration resulting in a significant Group effect (F(1,28) ¼ 86.406;po0.001) In the final baseline test, all animals drank approximately (F(1,28) ¼ 0.077), Weeks (F(5,140) ¼ 2.139), and interaction 14–16 g of the solution (data not shown) and following (F(5,140) ¼ 0.250). Acute injection of S 22153 at Week 6 was initial 2 weeks of stress (ie at Week 0), intakes remained at without any effect on the sucrose consumption in both similar level in controls but fell to approximately 7–9 g in control and stressed animals treated with melatonin stressed animals (Group effect: F(1,56) ¼ 79.646; po0.001).
(F(2,28) ¼ 0.059; NS, see Table 1). Importantly, this experi- Such a difference between control and stressed animals ment also included control and stressed animals adminis- treated with vehicle persisted at a similar level until the end tered 50 mg/kg of agomelatine and the results were of the 5-week treatment period, resulting in a significant comparable to those described in previous paragraphFno Group effect (F(1,14) ¼ 26.459; po0.001) and nonsignificant effect in control animals and fast (ie following first 2 weeks of treatment) recovery from the CMS-induced deficit in (F(5,70) ¼ 1.159 and 0.383, respectively; see Figure 1). Acute sucrose consumption (see Figure 3, lower panel). As shown injection of melatonin antagonist, S 22153, at Week 6 did in Table 1, sucrose drinking in both control and stressed not affect sucrose intake in both control and stressed animals receiving 50 mg/kg of agomelatine in the morning animals receiving vehicle (Group  Weeks interaction: was not affected by acute injection of the melatonin F(2,28) ¼ 0.354; NS) (see Figure 1 and Table 1).
antagonist, S 22153 (Weeks effects: F(2,28) ¼ 2.068; NS,Weeks  Group interaction: F(2,28) ¼ 2.119; NS).
Effects of imipramine. As shown in Figure 1 (lower panel), At the end of the treatment period, vehicle-treated chronic treatment with imipramine had no significant effect stressed animals were smaller than controls, but this on sucrose intake in control animals and increased sucrose difference did not reach statistical significance (Group consumption in stressed animals, resulting in a significant effect: F(1,14) ¼ 1.127; NS). As compared to vehicle-treated Treatment effect (F(128) ¼ 4.301; po0.05) and Treat- groups, the body weights of control and stressed animals ment  Group  Weeks (F(5,140) ¼ 4.677; were not significantly affected by imipramine (controls: po0.001). As compared to Week 0 scores, the increases in F(1,14) ¼ 0.197; NS, stressed: F(1,14) ¼ 0.1.172; NS), melatonin


Antidepressant activity of agomelatine in chronic mild stressM Papp et al Evening administration Sucrose intake (g) Con/Agomelatine-10 mg Str/Agomelatine-10 mg Con/Agomelatine-50 mg Str/Agomelatine-50 mg Sucrose intake (g) Weeks of treatment Effects of evening administration of vehicle (1 ml/kg), agomelatine, and melatonin (both at 10 and 50 mg/kg, i.p.) on the consumption of 1% sucrose solution, in controls (Con, open symbols) and in animals exposed to CMS (Str, closed symbols). All drugs were administered at 06.00 pm, that is, 2 hbefore the dark phase of the 12-h light/dark cycle. Values are means 7 SEM. *po0.05, **po0.01, ***po0.001; relative to vehicle- or drug-treated controlanimals. #po0.05, ##po0.01, ###po0.001; relative to drug-treated stressed animals at Week 0.
(control: F(1,14) ¼ 1.595; NS, stressed: F(1,14) ¼ 0.014; NS), substantial decrease in the consumption of 1% sucrose or agomelatine (controls: F(1,14) ¼ 0.504; NS, stressed: solution, and that this deficit can be effectively reversed by F(1,14) ¼ 0.002; NS, data not shown).
chronic treatment with traditional antidepressant drugs,imipramine, and fluoxetine (Muscat et al, 1992). Moreover,as in most of the previous studies with the CMS model (seeWillner, 1997), also in this study the action of both antidepressants had several parallels with that of their The results of this study confirm earlier reports that chronic clinical activity, both in terms of their efficacy (full recovery sequential exposure to a variety of mild stressors causes a at the end treatment period), specificity (lack of significant


Antidepressant activity of agomelatine in chronic mild stress Body Weights (g) Measured at the End of Drugs effects in control animals), and time course (4–5 weeks of treatment required to reverse the deficit in sucroseconsumption).
However, the main finding of the present study is that the CMS-induced reduction in the intake of sweet solution can be normalized by chronic administration of agomelatine (S 20098), a potent agonist of melatonin MT1 and MT2 receptors (Yous et al, 1992; Ying et al, 1996; Conway et al, 2000) and an antagonist of the 5-HT2C receptors (Cussac et As mentioned earlier (see Introduction), among other biochemical, physiological and behavioral impairments, theCMS procedure causes generalized disorganization of *po0.05; relative to vehicle-treated control animals.
Morning administration Sucrose intake (g) Con/Agomelatine-10 mg Str/Agomelatine-10 mg Con/Agomelatine-50 mg Str/Agomelatine-50 mg 0 1 2 3 4 5 Withdrawal Sucrose intake (g) Con/Agomelatine-50 mg Str/Agomelatine-50 mg Weeks of treatment Effects of morning administration of vehicle (1 ml/kg), agomelatine (10 and 50 mg/kg), and melatonin (50 mg/kg) on the consumption of 1% sucrose solution in controls (Con, open symbols) and in animals exposed to CMS (Str, closed symbols). All drugs were administered at 10.00 am, that is, 2 hafter the dark phase of the 12-h light/dark cycle. Values are means 7 SEM. **po0.01, ***po0.001; relative to vehicle- or drug-treated control animals.
#po0.05, ##po0.01, ###po0.001; relative to drug-treated stressed animals at Week 0.
Antidepressant activity of agomelatine in chronic mild stressM Papp et al circadian rhythms, and agomelatine can resynchronize antidepressant-like effect of agomelatine depends, at least experimentally disrupted circadian rhythms. Therefore, in partially, on its chronobiotic properties exerted by an order to verify the hypothesis that antidepressant-like interaction with melatonin receptors. This conclusion is action of agomelatine in the CMS model involves its consistent with other reports showing that agomelatine can chronobiotic properties, the chronic injection of this resynchronize circadian rhythms in animals (Armstrong et compound was performed either in the evening, that is, al, 1993; Redman et al, 1995; Martinet et al, 1996; Van Reeth when it shows most potent chronobiotic activity, or in the et al, 1997, 2001; Weibel et al, 2000) and with known clinical morning, that is, when agomelatine is clearly devoid of such observations that disorganization of internal rhythms is one an activity (Van Reeth et al, 1997). The results obtained in of the most characteristic feature of various depressive this study demonstrate that similar efficacy of agomelatine disorders and diurnal mood variations (Souetre et al, 1989; in the CMS model can be observed independent of the time Wehr and Wirz-Justice, 1982; Healy, 1993).
of administration. In other words, both morning and Similar action of agomelatine and melatonin in the CMS evening administration of agomelatine resulted in a full model and inhibition of this effect by the melatonin and dose-dependent reversal of the CMS-induced deficit in antagonist, S 22153 (inactive in the CMS model when given sucrose consumption, without any significant effects in aloneFdata not shown), strongly indicate the involvement nonstressed control animals. The magnitude of this action of melatonin receptors in antidepressant-like action of of agomelatine was comparable to that of fluoxetine and evening administration of agomelatine and confirms other imipramine but the onset of action, in particular when the preclinical reports that melatonin can be effective as an compound was administered in the morning, was faster antidepressant. For example, melatonin can prevent some of than that usually observed following chronic administration the behavioral disturbances produced by the CMS proce- of traditional antidepressants as the intakes in stressed dure in C3H/He mice, but with lower efficacy than animals receiving agomelatine was apparent within the first fluoxetine (Kopp et al, 1999). Antidepressant-like effects 2 weeks of treatment, compared to 4 weeks required by of melatonin have also been reported in the forced swim test imipramine. Although in this study fluoxetine was not (Overstreet et al, 1998; Shaji and Kulkarni, 1998; Raghaven- included in the ‘morning' experiment, in many of our dra et al, 2000). The clinical studies with melatonin and previous studies this drug was administered at similar time depression are less clear as, for example, both decreases and the onset of its action was comparable (ie 3–4 weeks (Beck-Friis et al, 1985; Brown et al, 1985; Zetin et al, 1987) delay) to that reported here for imipramine (Papp and as well as increases (Claustrat et al, 1984; Thompson et al, Sa´nchez, 2002; Papp, unpublished data).
1988; Sekula et al, 1997) in melatonin secretion have been In contrast, melatonin, which was tested in parallel with reported in patients with diagnosis of major depression.
agomelatine, was effective against the CMS-induced de- Moreover, although a relation between melatonin levels and crease of sucrose intakes only when administered 2 h before depression has been reported by Souetre et al (1989), this the dark phase of the 12-h light/dark cycle, melatonin being has not been confirmed by other authors (Beck-Friis et al, less active than agomelatine at the dose of 10 mg/kgFthe 1995; Rubin et al, 1992; Szymanska et al, 2001).
morning injections of melatonin failed to affect the intakes As there is no demonstration in the literature that a pure in both the stressed and control animals. These results melatonin agonist activity can lead to antidepressant suggest that the antidepressant-like action of agomelatine in activity similar to that of agomelatine, it seems probable the CMS model involves two different mechanisms, which that receptors other than MT1 and MT2 are implicated in the depend on the time of its administration. The effect of mechanism of action of agomelatine. Actually, as shown in evening treatment can be related to the agonistic action on Figure 3, agomelatine was also effective against the CMS- melatonin receptors, which in consequence leads to induced deficit in sucrose consumption when administered normalization of the general impairment of circadian in the morning. At this point of the circadian rhythm rhythms previously observed in animals undergoing the agomelatine is devoid of chronobiotic activity (Van Reeth et CMS procedure (Moreau et al, 1995; Gorka et al, 1996; al, 1997) and its action in the CMS model was not affected Cheeta et al, 1997; D'Aquila et al, 1997). Actually, contrary by an acute injection of the melatonin antagonist. This to the dose-dependent morning activity of agomelatine, the suggests that the morning antidepressant-like action of ceiling effect observed after evening administration can be agomelatine does not depend on its agonism at melatonin related to its chronobiotic activity, which is maximal at 8– receptors. This conclusion is further reinforced by the fact 10 mg/kg (Redman et al, 1995; Martinet et al, 1996). This that, in contrast to its evening efficacy, the morning possibility is strongly supported by the finding that the treatment with melatonin was ineffective against the CMS- melatonin antagonist, S 22153, given acutely to stressed induced anhedonia, and, consistently, the melatonin animals successfully treated with agomelatine and melato- antagonist had no effect on the behavior of stressed animals nin, fully reversed the effectiveness of both agents.
receiving either melatonin or agomelatine at this time of Interestingly, this inhibitory effect of S 22153 was transient in that it was no longer seen in the sucrose test carried out As mentioned earlier, apart from its agonistic properties on the following week, and was not observed in any other at melatonin MT1 and MT2 receptors (Yous et al, 1992; Ying control and stressed animals tested in this study, including et al, 1996; Conway et al, 2000), agomelatine has also a those treated with imipramine and fluoxetine. These data potent antagonistic activity at 5-HT2C receptors (Cussac indicate that the mechanism of therapeutic action of et al, 2002) and numerous findings indicate that reduced evening administration of agomelatine and melatonin in function of 5-HT2C receptors may be involved in the the CMS model of depression differs from that of traditional mechanism by which antidepressants alleviate depression antidepressants, and provides further evidence that the (see Sanchez and Hyttel, 1999). Moreover, the unselective Antidepressant activity of agomelatine in chronic mild stress 5-HT2 antagonist mianserin is an effective antidepressant depressed subjects: plasma melatonin, a biological marker in (Brogden et al, 1978; Montgomery, 1980; De Ridder, 1982), major depression. Biol Psychiatry 19: 1215–1228.
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fluoxetine, maprotiline, amitriptyline, desipramine, and Antagonist properties of the melatonin agonist S 20098 mianserin), have been shown to be effective in the CMS (agomelatine) at recombinant, human (h) serotonin (5-HT2c), model (see Willner, 1997). In view of these data, it can be receptors. Int J Neuropsychopharmacol 5(Suppl 1): S68.
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