- animal model
- forced swimming
Current antidepressant pharmacotherapy remains unsatisfactory because of its limited adherence and partial therapeutic efficacy. Accordingly, there is a crucial need of validated animal models that fully reflect the nature of the disease and do not only separate facets of the disorder.
We read with great interest the recent publication of Mul et al. (2016) reporting that, although the 5 d forced swimming stress model (5D-FSSM) of depression effectively increased floating behavior for 4 weeks, other depressive-like indexes, such as the sucrose preference test, were unaltered. Hence, they conclude that the 5D-FSSM model lacks “construct or face validity to model human depression.”
As these data clearly contrast with those from previous published studies (Sun et al., 2011; Serchov et al., 2015), an obvious question is why? We propose that the study of Mul et al., (2016; as well as certain other studies) fails to take into account a critical factor: the time of day at which the swimming stress tests are conducted. In contrast to the study of Mul et al. (2016), who performed stress tests during the light phase when mice are inactive and normally sleep, we and others (Sun et al., 2011) have found stable depressive-like behaviors when the 5D-FSSM is conducted during the dark phase [zeitgeber time 14 (ZT14)] when nocturnal mice are active, but not at ZT1 during the light (inactive) resting phase (Fig. 1). These data clearly show that the time of stress is crucial for the induction of the depressive-like behavior.
Daily variations in anxiety-like behavior are also observed in rodents. Nakano et al. (2016) showed in C57BL/6 mice a rhythmic expression of anxiety-like behavior with increased anxiety-like behavior in the early part of the dark phase. A recent study (Ben-Hamo et al., 2016) using circadian desynchrony to induce depression like-behaviors in rats further revealed opposite responses of behavioral despair according to whether the forced swim test was performed during the light or the dark phase. Similar chronobiological responses have also been described by Ushijima et al. (2005), who showed that the effects of antidepressants are weak during the light phase but potent during the dark phase. In humans as well, circadian variation of mood is a characteristic feature in depressed patients (Peeters et al., 2006). Hence, appropriate timing is essential to accurately assess anxiety- and depressive-like behaviors in rodents and humans.
The importance of time-of-day (circadian) effects on the etiology of mood disorders and the timing of drug treatments (chronotherapy) as well as of the significant role of clock genes (Landgraf et al., 2014) has been increasingly recognized (Turek, 2016). We thus caution that, depending on the day-night activity pattern of the animal, negative results can be a question of inappropriate timing.
Acknowledgments: We thank Renaud Rovera for technical assistance.
The authors declare no competing financial interests.
This research was supported by INSERM and Claude Bernard University-Lyon 1, France.
- Received February 8, 2017.
- Revision received March 18, 2017.
- Accepted March 22, 2017.
- Copyright © 2017 Delcourte et al.
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