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

// Hyun-Sun Park 1, * , Arum Han 1, * , Hye-Lim Yeo 1, 4 , Min-Jung Park 1 , Min-Jung You 1 , Hyun Jin Choi 3 , Chang-Won Hong 5 , Sang-Hyuk Lee 2 , Seung Hyun Kim 4 , Borah Kim 2 and Min-Soo Kwon 1 1 Department of Pharmacology, School of Medicine, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea 2 Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea 3 College of Pharmacy, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea 4 Cell Therapy Center and Department of Neurology, College of Medicine, Hanyang University, Haengdang-dong, Seoul, Republic of Korea 5 Department of Physiology, School of Medicine, Kyungpook National University, Daegu, Gyeongbuk, Republic of Korea * These authors have contributed equally to this work Correspondence to: Borah Kim, email: genie@cha.ac.kr Min-Soo Kwon, email: minsoo100@cha.ac.kr Keywords: depression, regulatory T cell, cytokines, angiotensin II, captopril Received: January 05, 2017     Accepted: July 06, 2017     Published: August 03, 2017 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.