LAUSR

ABSTRACT Although recent investigations of major depressive disorder (MDD) have focused on the monoaminergic system, accumulating evidences suggest that alternative pathophysiological models of MDD and treatment options for patients with MDD are needed. Animals subjected to chronic forced swim stress (CFSS) develop behavioral despair. The purpose of this study was to investigate the in vivo effects of CFSS on systems other than the monoamine system in the rat prefrontal cortex (PFC) with 7T and short‐echo‐time (16.3 ms) proton magnetic resonance spectroscopy (1H MRS). Ten male Wistar rats underwent 14 days of CFSS, and in vivo 1H MRS and forced swim tests were performed before and after CFSS. Point‐resolved spectroscopy was used to quantify metabolite levels in the rat PFC. To investigate spectral overlap in glutamate and glutamine, spectral analyses in the spectra obtained in the in vivo 1H MRS, parametrically matched spectral simulation, and in vitro experiments were performed. The results of the spectral analyses showed that the glutamate/glutamine spectral overlap was not critical, which suggested that in vivo 1H MRS can be used to reliably assess the glutamate system. The rats showed significantly increased immobility times and decreased climbing times in the FST after CFSS, which suggested that the rats developed behavioral despair. The pre‐CFSS and post‐CFSS glutamate and glutamine levels did not significantly differ (p>0.050). The levels of myo‐inositol, total choline, and N‐acetylaspartate, myo‐inositol/creatine, and total choline/creatine increased significantly (p<0.050). Similar findings have been reported in patients with MDD. Taken together, these results suggest that the CFSS‐induced metabolic alterations were similar to those found in patients and that high‐field and short‐echo‐time in vivo 1H MRS can be used to investigate depression‐induced metabolic alterations. Such investigations might provide alternative insights into the nonmonoaminergic pathophysiology and treatment of depression. HIGHLIGHTSChronic forced swim stress induced depression‐like metabolic changes.High‐field proton magnetic resonance spectroscopy and brain metabolite system.Spectral analyses for estimating the spectral overlap in the Glu system.