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    • Regarding the predictive value of the antidepressant effects

    2022-08-11

    Regarding the predictive value of the antidepressant effects of VP2.51 treatment (Fig. 4), different GSK-3 inhibitors produce decreased immobility in forced swim test (Du et al., 2010, Gould and Manji, 2004, Kaidanovich-Beilin et al., 2004, Rosa et al., 2008), with this being a widely used test to assess antidepressant drugs (Castagne et al., 2009). Here we found that a 3.5 weeks treatment of non-stressed mice with VP2.51 decreased the immobility time in this test, while a treatment of up to 8 weeks with this drug did not affect motor behavior as reflected by the basal activity of these mice. Both these findings support that GSK-3 is a potential pharmacological target for depression therapy, being GSK-3 inhibitors potential drug candidates for it. In these animals VP2.51 induced cell proliferation, as judged by the increase in BdrU positive cells, but the effect on immature 3902 was no longer evident (compare results in Fig. 2, Fig. 4). This was expected given that the animals were submitted to FST at the end of the experiment, affecting the survival of immature neurons, the most sensitive neurogenic cells. This finding is consistent with previous findings of a heterogeneous, selective effect on short- and long-term survival of immature neurons after acute stress (Llorens-Martin et al., 2006, Llorens-Martin et al., 2011). To assess whether VP2.51 administration might be useful as a therapeutic treatment, we induced depressant-like behavior through a modified two-day forced swim test protocol in adult mice. Although this protocol cannot be considered as a model resembling major depression, it is reproducible and more feasible for the present work than unpredictable chronic mild stress (UCMS), a paradigm widely used to test the therapeutic potential of antidepressant drugs (Ma et al., 2013, Silva et al., 2008). Indeed, there is great variability in the application of both protocols in different laboratories and controversial results reported in the literature for UCMS (for further discussion on this point of view, see for example Dedic and Deussing, 2011). Following VP2.51 treatment of stressed mice, we analyzed the animal's behavior in either a tail suspension test or the elevated plus maze, and we found that VP2.51 induced a significant and specific antidepressant effect, in the absence of an overt anxiolytic effect (results depicted in Fig. 5). This is relevant if we consider VP2.51 as a potential treatment against depressive moods, where specificity is a desirable feature for such therapies. It should be noted that this same protocol was reported to induce depressive-like behavior that lasted for several weeks, which was not reverted after re-exposure to the same stimulus, even when combined with environmental enrichment, thereby being a reliable, reproducible stressful intervention (Llorens-Martin et al., 2011), mediated by a considerable increase in blood corticosterone levels (Llorens-Martin et al., 2016). In parallel, VP2.51 treatment had also a therapeutic effect on neurogenic cell populations. The forced swim test decreases the survival of one-week old immature neurons (Llorens-Martin et al., 2007), as mentioned before, while the alterations in proliferation induced by acute stress are recovered after 24 h (Heine et al., 2004). Here we found a significant increase in both proliferation and immature neuron survival after drug treatment. Importantly, the effect on proliferation was prominent in the ventral region of the hippocampal dentate gyrus, supporting the hypothetical regional specificity of hippocampal functions (Barkus et al., 2010, Fanselow and Dong, 2010). It is noteworthy that the increased adult hippocampal neurogenesis induced by VP2.51 is especially pronounced in ventral regions, an area potentially involved in mood traits (for which we found significant effects) rather than in cognition. To determine the impact of VP2.51 on normal behavior, we also evaluated the activity and the short- and long-term memory, of control mice that received long-term (8 weeks) VP2.51 treatment. Indeed, VP2.51 did not significantly affect normal activity, nor spatial and context associated learning and memory. The dose of 2.5 mg/kg over 3.5 weeks which induced a therapeutic effect in previously stressed mice neither affected activity. Likewise, no changes in basal activity were detected in genetically modified mice (either GSK-3β+/- or overexpressing GSK-3β (Gould and Manji, 2004, Rosa et al., 2008), although the activity in GSK-3β KO mice does augment (Kaidanovich-Beilin et al., 2009).