ABSTRACT
The aim of this study was to identify molecular pathways related to antidepressant response. We administered paroxetine to the DBA/2J mice for 28 days. Following the treatment, the mice were grouped into responders or non-responders depending on the time they spent immobile in the forced swim test. Hippocampal metabolomics and proteomics analyses revealed that chronic paroxetine treatment affects glutamate-related metabolite and protein levels differentially in the two groups. We found significant differences in the expression of N-methyl-d-aspartate receptor and neuronal nitric oxide synthase proteins between the two groups, without any significant alterations in the respective transcript levels. In addition, we found that chronic paroxetine treatment altered the levels of proteins associated with the ubiquitin-proteasome system (UPS). The soluble guanylate cyclase-ß1, proteasome subunit α type-2 and ubiquitination levels were also affected in peripheral blood mononuclear cells from antidepressant responder and non-responder patients suffering from major depressive disorder. We submit that the glutamatergic system and UPS have a crucial role in the antidepressant treatment response in both mice and humans.
Subject(s)
Antidepressive Agents/metabolism , Depressive Disorder, Major/metabolism , Glutamic Acid/metabolism , Nitric Oxide Synthase Type I/drug effects , Paroxetine/metabolism , Proteasome Endopeptidase Complex/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Animals , Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Hippocampus/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Male , Metabolomics , Mice , Mice, Inbred DBA , Nitric Oxide Synthase Type I/metabolism , Paroxetine/administration & dosage , Paroxetine/pharmacology , Proteomics , Receptors, N-Methyl-D-Aspartate/metabolism , Swimming/physiology , UbiquitinABSTRACT
Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery.
