BACKGROUND This study aimed to investigate the antidepressant-like effect of lactate and elucidate its mechanisms in ovariectomized rats with repeated stress. METHODS Two experiments were conducted on female rats in which all groups, except normal, were ovariectomized and underwent immobilization for 14 days. Lactate was administered orally (100, 250, and 500 mg/kg) for 14 consecutive days, and the rats' cutaneous body temperature was measured during the same period. Depression-like behavior in rats was assessed by the tail suspension test (TST) and forced swimming test (FST). Furthermore, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were conducted to evaluate the changes that occurred in the neurotransmitter levels and activity. RESULTS The lactate 100 and 250 groups had reduced time spent immobile in TST and FST and decreased peripheral body temperature. In ELISA tests, the lactate 250 group expressed elevated levels of serotonin and dopamine in many brain areas. Tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and protein kinase C (PKC) immunoreactive cells showed increased density and cell counts in lactate administered groups. CONCLUSIONS Results indicated that lactate has an antidepressant effect that is achieved by activation of PKC and upregulation of TH and TPH expression, which eventually leads to enhanced serotonin and dopamine levels in the menopausal rat's brain.