Chronic high dose of captopril induces depressive-like behaviors in mice: possible mechanism of regulatory T cell in depression.

Hyun-Sun Park,Borah Kim,Min-Soo Kwon,Seung Hyun Kim,Arum Han,Chang-Won Hong,Min-Jung Park,Sang-Hyuk Lee,Hye-Lim Yeo,Min-Jung You,Hyun Jin Choi

doi:10.18632/oncotarget.19879

Abstract

Major depression has various types of symptoms and disease courses with inconsistent response to monoamine-related antidepressants. Thus, monoamine theory may not be the only pathophysiologic pathway relevant to depression. Recently, it has been suggested that regulatory T cell (Treg) is associated with depression. Based on our previous study that showed decreased regulatory T cell (Treg) population following chronic high-dose captopril (CHC, 40 mg/kg/day * 21 days) administration, we examined whether CHC alone can induce depressive-like behaviors in mice even without stressful stimuli. In this study, we found that CHC induced depressive-like behaviors in tail suspension test (TST) and forced swimming test (FST) without systemic illness, while it did not induce anhedonic behavior, anxiety-like behaviors, or sociality-related behavior. The depressive-like behaviors were rescued by either CHC washout or antidepressant. CHC caused reduction in foxp3 and gata3 mRNA expression in the lymph nodes with elevation in plasma IL-1β and IL-6. Interestingly, CHC increased serum angiotensin II level. In the hippocampus, CHC increased TNF-α and IL-6 mRNA expression with microglia activation while reduced glucocorticoid receptor expression. However, CHC did not affect to hippocampal kynurenine pathway, serotonin level, hypothalamic corticotropin-releasing hormone mRNA level, or serum corticosterone level. Consequently, we propose that CHC may induce a specific form of depressive-like behaviors via Treg reduction and microglial activation.

Highlights

Major depression is one of the most disabling and chronic psychiatric diseases in the modern society
The functional phenotype of microglia is involved in depression and stress vulnerability [19, 20]. These results suggest the possibility that factors associated with regulation of microglial function, such as cytokines [21], angiotensin II (ANG II) [22] and endothelin [23], can be hints to solve the complicated pathophysiology of major depressive disorder
Chronic high dose captopril (CHC) (40 mg/kg/day * 21 days) treated mice exhibited depression-like behaviors in only TST and forced swimming test (FST), but not Sucrose preference test (SP)

Summary

Introduction

Major depression is one of the most disabling and chronic psychiatric diseases in the modern society. There are several evidences that elevated serum and CNS pro-inflammatory cytokines, such as IL-1β, IL-6, IFN-γ, and TNF-α or increased inflammation response are associated with depressive symptom or severity of disease [8,9,10,11]. These factors serve a role as mediators of peripheral inflammation and communicate with the CNS as an inflammation inducer in the CNS. Kynurenine (KYN) pathway has been suggested as a factor linking “cytokine theory” and “monoamine theory” in depression. Change in circulating and the CNS cytokines may be additional candidates involved in depression pathophysiology

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Conclusion