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

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