Abstract
Depressive disorder is defined as a psychiatric disease characterized by the core symptoms of anhedonia and learned helplessness. Currently, the treatment of depression still calls for medications with high effectiveness, rapid action, and few side effects, although many drugs, including fluoxetine and ketamine, have been approved for clinical usage by the Food and Drug Administration (FDA). In this study, we focused on calcitonin as an amylin receptor polypeptide, of which the antidepressant effect has not been reported, even if calcitonin gene-related peptides have been previously demonstrated to improve depressive-like behaviors in rodents. Here, the antidepressant potential of salmon calcitonin (sCT) was first evaluated in a chronic restraint stress (CRS) mouse model of depression. We observed that the immobility duration in CRS mice was significantly increased during the tail suspension test and forced swimming test. Furthermore, a single administration of sCT was found to successfully rescue depressive-like behaviors in CRS mice. Lastly, AC187 as a potent amylin receptor antagonist was applied to investigate the roles of amylin receptors in depression. We found that AC187 significantly eliminated the antidepressant effects of sCT. Taken together, our data revealed that sCT could ameliorate a depressive-like phenotype probably via the amylin signaling pathway. sCT should be considered as a potential therapeutic candidate for depressive disorder in the future.
Highlights
Major depressive disorder is a life-threatening chronic mental disease affecting more than 20% of the population worldwide (Yan et al, 2010)
To explore the therapeutic effects on depression, we established an animal model of chronic restraint stress (CRS), which is widely used to screen for antidepressants (Campos et al, 2013; Li Y et al, 2021; Lee et al, 2021)
We found that the immobility time of CRS mice was significantly increased in both TST and FST [t(18) = 2.268, p < 0.05, Figure 1C; t(17) = 2.266, p < 0.05, Figure 1D], suggesting that our model of depression was successfully established
Summary
Major depressive disorder is a life-threatening chronic mental disease affecting more than 20% of the population worldwide (Yan et al, 2010). Depression is a psychiatric disorder characterized by low mood and lack of interest in work, life, and social activities, which often leads to suicidal attempts and suicides (Marinova et al, 2014). The range of available medications for depression treatment in the clinic is relatively limited and traditionally restricted to fluoxetine and ketamine. Fluoxetine works usually after a long treatment period of 2–4 weeks and is ineffective in patients with severe depression, via selectively inhibiting 5hydroxytryptamine (5-HT) reuptake to enhance the extracellular 5-HT level (Hirschfeld, 2000; Al-Harbi, 2012). Ketamine exerts an antidepressant effect via different mechanisms, including but not limited to blocking N-methylD-aspartate (NMDA) receptor, activating α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor, and regulating synaptic plasticity (Newport et al, 2015; Zanos et al, 2018). There is an increasing demand to develop new medications with high antidepressant capacity and safety
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