Post-mortem brain analysis reveals altered monoaminergic system in the dorsolateral prefrontal cortex and hippocampus in chronic schizophrenia

Schizophrenia is a multifactorial psychiatric disorder with acknowledged evidence implicating monoaminergic neurotransmission, particularly dopamine (DA), serotonin (5-HT), and norepinephrine (NE), in pathophysiology and response to treatments. However, the composition and interaction among these monoamines and their catabolites in key brain regions remain unclear. In this study, using high-performance liquid chromatography (HPLC), we quantified the levels of DA, 5-HT, NE and their metabolites, HVA, DOPAC, and 5-HIAA, along with protein levels of key monoamine-metabolizing enzymes (MAO-A, MAO-B, and COMT isoforms) in post-mortem dorsolateral prefrontal cortex (DLPFC) and hippocampus from chronic schizophrenia patients and healthy controls. Although we found no significant differences in monoamine or enzyme levels between diagnostic groups, partial correlation analyses revealed remarkable schizophrenia-specific alterations in the interactions between monoamines and their catabolites. In particular, patients exhibited distinct 5-HT-DOPAC correlations in both areas, suggesting an abnormal interaction between serotonergic and dopaminergic metabolism. Additionally, correlations between DA and NE in the DLPFC were weaker in individuals with schizophrenia than in healthy controls, potentially impairing cognitive function and salience processing. Furthermore, we observed increased 5-HIAA-5-HT correlation in the hippocampus of schizophrenia patients, which may reflect abnormal serotonin turnover. These findings suggest that while monoamine levels per se do not differ significantly between groups, their interaction are profoundly altered. Our results offer novel insights into monoaminergic crosstalk in the DLPFC and hippocampus, and suggest new directions for understanding the neurochemical basis of schizophrenia and developing future trajectories for antipsychotic treatments.