Brain sigma-1 receptor stimulation improves mental disorder and cardiac function in mice with myocardial infarction

Mental disorder after myocardial infarction (MI) is reported by many epidemiological studies and is associated with a poor prognosis. The reduction of brain sigma-1 receptor (S1R) plays an important role in the pathogenesis of mental disorder, and we recently demonstrated that the reduction of brain S1R causes sympathoexcitation. However, the role of brain S1R in the association between MI and mental disorder, such as depression or cognitive impairment, remains unclear. To investigate this, we performed left coronary artery ligation on mice to produce an MI model (MI-mice). Compared with sham-operated controls (Sham-mice), MI-mice showed augmented sympathetic activity, decreased cardiac function, and lower S1R expression in both the hypothalamus and hippocampus. Furthermore, MI-mice displayed decreased Y-maze spontaneous alternation (a maker of spatial working memory), decreased circadian variation in locomotor activity, and increased immobility time in the tail suspension test (markers of depression-like behavior). Intracerebroventricular infusion of the S1R agonist PRE084 in MI-mice improved both mental disorder and cardiac function with lowered sympathetic activity and the recovery of the S1R expression in both the hypothalamus and hippocampus. These results indicate that brain S1R is decreased in MI-mice and that this plays an important role in the coexistence of increased heart failure via sympathoexcitation and mental disorders, such as depression or cognitive impairment.