Abstract
Major depressive disorder (MDD) is a debilitating mental illness affecting people worldwide. Although significant progress has been made in the development of therapeutic agents to treat this condition, fewer than half of all patients respond to currently available antidepressants, highlighting the urgent need for the development of new classes of antidepressant drugs. Here, we found that paeoniflorin (PF) produced rapid and sustained antidepressant-like effects in multiple mouse models of depression, including the forced swimming test and exposure to chronic mild stress (CMS). Moreover, PF decreased the bodyweight of mice without affecting food intake and glucose homeostasis, and also reduced the plasma levels of total ghrelin and the expression of ghrelin O-acyltransferase in the stomach; however, the plasma levels of ghrelin and the ghrelin/total ghrelin ratio were unaffected. Furthermore, PF significantly increased the expression of growth hormone secretagogue receptor 1 alpha (GHSR1α, encoded by the Ghsr gene) in the intestine, whereas the levels of GHSR1α in the brain were only marginally downregulated following subchronic PF treatment. Finally, the genetic deletion of Ghsr attenuated the antidepressant-like effects of PF in mice exposed to CMS. These results suggested that increased GHSR1α expression in the intestine mediates the antidepressant-like effects of PF. Understanding peripheral ghrelin/GHSR signaling may provide new insights for the screening of antidepressant drugs that produce fast-acting and sustained effects.
Highlights
Major depressive disorder (MDD) is a common mental illness that affects at least 322 million people and is expected to be the leading cause of burden of disease globally by 2030 (WHO, 2017; Saman et al, 2018)
The genetic deletion of Ghsr attenuated the antidepressant-like effect of PF. These results suggested that the increased expression of GHSR1α in the intestine may mediate the antidepressant-like effects of PF
Consistent with our previous reports (Yan et al, 2010b; Zhu et al, 2010), fluoxetine and imipramine decreased the duration of immobility during the forced swimming test (FST), whereas haloperidol had no effect
Summary
Major depressive disorder (MDD) is a common mental illness that affects at least 322 million people and is expected to be the leading cause of burden of disease globally by 2030 (WHO, 2017; Saman et al, 2018). Ketamine has serious side-effects that limit its clinical use, including increased dissociative and other psychotomimetic symptoms, cardiovascular manifestations, cognitive impairment, and potential for abuse (Short et al, 2018). These issues emphasize the pressing need for the development of new classes of antidepressant medications with rapid onset of action, greater efficacies and tolerability, and longer-lasting effects (Yan et al, 2011). Peripheral ghrelin administration was shown to induce an antidepressant-like effect in mice during a forced swimming test (FST) (Lutter et al, 2008). A comprehensive understanding of the properties of the GHSR system will facilitate the discovery of new classes of antidepressants, especially from traditional Chinese herbal medicines
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