Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

Abstract

Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT 4 receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT 4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT 4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety-and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT 4 receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT 4 receptor activation is necessary for these effects of SSRIs. 5-HT 4 receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.

Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine

“…However, this quality of FST and TST, when compared to other set of tests, was demonstrated only by one group, following rarely-used chronic corticosterone treatment (David et al, 2009;Mendez-David et al, 2014). Moreover, the treatment had no basal effect as corticosterone injections did not increase the immobility levels measured by FST (David et al, 2009, Fig.…”

“…Moreover, the treatment had no basal effect as corticosterone injections did not increase the immobility levels measured by FST (David et al, 2009, Fig. 1D) and TST (Mendez-David et al, 2014;Fig. 3P) in control mice, nor were acute vs. chronic effects of fluoxetine-delivery investigated.…”

The role of serotonin in adult hippocampal neurogenesis

“…5-HT1A, 5-HT2B, 2C and 5-HT4 receptors are soaring candidates for contribution to the antidepressant response, as they regulate normal development of dendritic spine density and synapse formation of pyramidal and granule cells in the DG, elicit long-term plastic changes that decrease anxiety-like behavior, and mediate normal maturation of late-stage progenitor cells (Yan et al, 1997, Santarelli et al, 2003, Banasr et al, 2004, Klempin et al, 2010, Kobayashi et al, 2010, Diaz et al, 2012, Mendez-David et al, 2014. In human studies, increased angiogenesis correlates with increased numbers of neural precursor cells in the DG following SSRI or tricyclic antidepressant (TCA) treatment (Boldrini et al, 2012).…”

“…receptors (Kobayashi et al, 2010, Mendez-David et al, 2014). As we have seen, differential receptor targeting on sequential steps in the course of adult neurogenesis modulates proliferation and survival of hippocampal precursor cells ( Figure 1B) (Brezun and Daszuta, 2000, Encinas et al, 2006, Klempin et al, 2010.…”

Identifying novel interventional strategies for psychiatric disorders: integrating genomics, ‘enviromics’ and gene–environment interactions in valid preclinical models

“…Moreover this has been shown to align with animal models where adult neurogenesis has been shown to play a critical role in anxiety (Kheirbek et al, 2012;Mendez-David et al, 2014) and depression (Boldrini et al, 2012), as well as altered dendritic complexity and changes in brain-derived neurotrophic factor (BDNF), a neurotrophic factor known to be involved in neural plasticity and critical periods of brain development. Indeed, some current pharmacotherapies have been shown to achieve at least part of their effects by targeting these systems (Boldrini et al, 2012;Mendez-David et al, 2014). For example, re-opening critical periods of plasticity with selective 5-HT re-uptake inhibitor, antidepressant drugs (Karpova et al, 2009) or increasing basal cellular plasticity (with drugs that target BDNF), in combination with environmental approaches such as cognitive behavioural therapy, may provide significant relief of symptoms and allow for rewiring of the disrupted neural circuitry.…”