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Major depressive disorder (MDD) is a serious mental disorder that affects many people. The neurotransmitter deficiency hypothesis has been the crux of much research on the treatment of depression. Anhedonia, as a core symptom, was closely associated with altered levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and diverse types of glutamate (Glu) receptors in the nucleus accumbens (NAc). However, there were no reports showing how Glu changed in the NAc, and there were other unreported molecules involved in modulating stress-induced anhedonia. Thus, we investigated changes in neurotransmitters and their related metabolites in GABAergic, serotonergic and catecholaminergic pathways in the NAc of a rat model of chronic unpredictable mild stress- (CUMS-) induced anhedonia-like behavior. Then, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to detect target neurotransmitters and related metabolites in the NAc. Finally, the Western blot was used to assess the expression of key enzymes and receptors. Here, we found that the 5-HT level in anhedonia-susceptible (Sus) rats was increased while the Glu level decreased. DA did not show a significant change among CUMS rats. Correspondingly, we detected a reduction in monoamine oxidase-A (MAOA) and Glu receptor 1 levels in anhedonia-Sus rats while Glu receptor 2 (GluR2) and NMDA2B levels were increased in anhedonia-resilient (Res) rats. We also found that the levels of glutamine (Gln), kynurenic acid (Kya), histamine (HA),  L -phenylalanine ( L -Phe), and tyramine (Tyra) were changed after CUMS. These alterations in neurotransmitters may serve as a new insight into understanding the development of anhedonia-like behavior in depression.

Neurotransmitter and Related Metabolic Profiling in the Nucleus Accumbens of Chronic Unpredictable Mild Stress-Induced Anhedonia-Like Rats