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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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