Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression

Cardiovascular diseases are risk factors for depression in humans. We recently proposed that sigma(1) receptor (sigma R-1) stimulation rescued cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) in mice. Importantly, sigma R-1 stimulation reportedly ameliorates depression-like behaviors in rodents. Thus, we hypothesized that impaired sigma R-1 activity in brain triggers depression-like behaviors in animals with cardiovascular disease. Indeed, here we found that cardiac hypertrophy and heart failure induced by TAC were associated with depression-like behaviors concomitant with downregulation of sigma R-1 expression in brain 6 weeks after surgery. sigma R-1 levels significantly decreased in astrocytes in both the hippocampal CA1 region and dentate gyrus. Oral administration of the specific sigma R-1 agonist SA4503 (0.3-1.0mg/kg) significantly improved TAC-induced depression-like behaviors concomitant with rescued astrocytic sigma R-1 expression in CA1 and the dentate gyrus. Plasma corticosterone levels significantly increased 6 weeks after TAC, and chronic treatment of mice with corticosterone for 3 weeks elicited depression-like behaviors concomitant with reduced astrocytic sigma R-1 expression in hippocampus. Furthermore, the glucocorticoid receptor antagonist mifepristone antagonized depressive-like behaviors and ameliorated decreased hippocampal sigma R-1 expression in TAC mice. We conclude that elevated corticosterone levels trigger hippocampal sigma R-1 downregulation and that sigma R-1 stimulation with SA4503 is an attractive therapy to improve not only cardiac dysfunction but depression-like behaviors associated with heart failure.