In the present study, the effects of both single (6 mmol L-serine/10 ml/kg orally administrated) and chronic (2% L-serine solution freely given for 28 days) treatments on depression-like behavior were evaluated in Wistar rats, representing the control, and Wistar Kyoto rats, representing an animal model of depression. Both single and chronic L-serine treatments decreased the duration of immobility, which is an index of a depressive-like state, in the forced swimming test in both strains. However, the decreases in the duration of immobility appear to be regulated differently by the different mechanisms involved in single and chronic L-serine treatments. In the prefrontal cortex and hippocampus, single L-serine treatment increased the concentrations of L-serine, but not D-serine, while chronic L-serine treatment increased those of D-serine, but not L-serine. These data suggest that the antidepressant-like effects of single and chronic L-serine treatments may have been induced by the increased L-serine and D-serine concentrations, respectively, in the brain. In addition, chronic L-serine treatment increased cystathionine concentrations in the hippocampus and prefrontal cortex in Wistar rats, but not in Wistar Kyoto rats, suggesting that Wistar Kyoto rats have an abnormality in the serine-cystathionine metabolic pathway. In conclusion, single and chronic L-serine treatments may induce antidepressant-like effects via the different mechanisms related to serine metabolism in the brain.
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