The present study shows that, when administered repeatedly, S 20098 exerts an antidepressant-like activity in the FST. Moreover, this antidepressant effect is observed both in rats and mice, but is less marked in the latter species.
Acute administration of S 20098 in rats is active and repeated administration significantly decreases the duration of immobility in a dose-dependent manner when administered during the artificial lighting period. In mice, repeated treatment in the evening is active, and the combination of S 20098 with the 5-HT1A or 5-HT1B receptor agonists (8-OH-DPAT, anpirtoline) and the 5-HT1A/1B, 5-HT2A/2C or 5-HT3 antagonists (pindolol, ritanserin, ondansetron) enhances the morning effects of S 20098 given alone. On the other hand, acute melatonin alone is inactive in the FST, and only pretreatments with 8-OH-DPAT or pindolol facilitate the anti-immobility effect of the neurohormone. The 5-HT receptor subtypes that may support the activity of S 20098 in the FST differ from those of prototypical antidepressants, because only 8-OH-DPAT and pindolol can enhance the effects of imipramine and fluoxetine, respectively.
In mice, repeated, but not acute, administration of S 20098 induces antidepressant-like effects in the FST. This effect is related neither to a change in locomotor activity as demonstrated here, nor to a sedative effect because no sedation is observed in mice with S 20098 up to the dose of 128 mg/kg (R.P., unpublished observations, 1989). These results are similar to those of Raghavendra et al,21
who found that melatonin (2.5–10 mg/kg) administered acutely to BALB/c and C57BL/6J mice failed to induce any antidepressant effects, whereas its daily administration reversed the increase in immobility period in the FST. Melatonin or certain melatonin agonists also reduce the immobility of rats in the FST after repeated, but not acute, administration.20,22,28
Melatonin also shows antidepressant activity in the mouse chronic mild stress model,29
although with a less marked effect than fluoxetine.
Interestingly, the activity of S 20098 in the FST does not depend on the time of the administration (morning or evening), which has been already shown in the rat chronic mild stress test.15
This strongly suggests that properties other than its chronobiotic ones5,8,9,10,30,31
may sustain the activity of S 20098 in the FST. Raghavendra et al21
have also reported that circadian variations (noon, early dark, midnight) do not influence the effect of melatonin treatment on the duration of the immobility period in mice, which suggests that the FST may be not sufficiently sensitive to appropriately study compounds with chronobiotic properties in this species.
In mice, the comparison of the efficacy of S 20098 and melatonin was tested under the same conditions, but S 20098 seemed to be more efficacious in the FST than the endogenous ligand. This also suggests that the nonmelatoninergic (or nonchronobiotic) properties of S 20098 are involved in its antidepressant activity. In line with this, manipulation of several serotonergic receptor subtypes in mice can influence the antidepressant-like effects of S 20098 and lead to more powerful effects on the duration of immobility with S 20098 than with melatonin. This indicates that the activity of S 20098 is partly dependent on its interaction with the serotonergic system. S 20098 possesses antagonistic activity at 5-HT2C
that could explain, at least partly, its efficacy in the FST. In line with this, the pretreatment with the 5-HT2A/2C
antagonist ritanserin significantly enhanced the effect of S 20098 at doses of 16 and 64 mg/kg. Although no study with specific antagonists at the 5-HT2C
receptor subtype has been performed in the FST to our knowledge, clinically effective antidepressants that exhibit 5-HT2C
antagonist properties are active in the FST.18,19
The 5-HT1A agonist, 8-OH-DPAT, and ritanserin also favour an antidepressant-like activity of melatonin, suggesting that the potential antidepressant-like property of melatonin can only be revealed in the FST following manipulation of the serotonergic system.
It has been shown that the 5-HT1A
receptors that mediate increased mobility in the FST are located postsynaptically.32
The additive effects of 8-OH-DPAT with S 20098 and imipramine suggest that postsynaptic 5-HT1A
receptors play a role in the ability of these drugs to reduce immobility in the FST. The potentiating effects of pindolol with S 20098 also suggest that antagonism of presynaptic 5-HT1A
receptors plays a role in the ability of this compound to reduce immobility in the FST, unlike imipramine, whose action seems to be mediated by postsynaptic 5-HT1A
receptors. However, the involvement of 5-HT1A
receptors in the mechanism of action of S 20098 is questionable, because it has been demonstrated that this compound, as is the case for melatonin, does not modify the 5-HT1A
autoradiographic signal, the guanosine-
-O-(3-thiotriphosphate) (GTP-γ-S) labelling or the electrophysiologic properties of dorsal raphe and CA1 neurons perfused with 5-HT1A
agonists (ipsapirone and 5-carboxamido-tryptamine) or antagonist (WAY 100635).33
The present study also suggests that 5-HT1B
receptor subtypes may play a role in the activity of S 20098 in the mouse FST and, indeed, there has been some interest, for example, in the antidepressant-like effects of 5-HT3
However, given the absence of affinity of S 20098 for the 5-HT1B
receptors, the involvement of these subtypes in its antidepressant effect appears rather unlikely.
Finally, the results of the present study suggest a role for 5-HT2A/C
receptors in the action of imipramine and fluoxetine, respectively. Whereas the antagonism of 5-HT2A/C
receptors is important in the action of tricyclic antidepressants in the FST, the antagonism of 5-HT3
receptors may play a partial role in the anti-immobility effects of the SSRIs.23
In conclusion, repeated treatment with S 20098 exerts an antidepressant-like activity in the FST both in rats and mice, with a mechanism of action that differs from that of traditional antidepressants.
The antidepressant-like effect of S 20098 depends, at least partially, on its melatonin agonist properties. Furthermore, manipulation of the serotonergic system can influence its effects in the mouse FST and, by comparison, the weaker impact of melatonin in combination with 5-HT agonists and antagonists indicates that the activity of S 20098 is also based on its interaction with the 5-HT system. Finally, while exhibiting similar antidepressant-like effect in the FST, S 20098, imipramine and fluoxetine have clearly distinct profiles regarding the 5-HT receptor subtypes that may support this activity.
We suggest that the efficacy of S 20098 in the FST involves a combination of both its melatonin agonist and 5-HT2c receptor antagonist properties.