Proteome and pathway effects of chronic haloperidol treatment in mouse hippocampus

Proteomic exploration of the effects of psychotropic drugs on specific brain areas in rodents has the potential to uncover novel molecular networks and pathways affected by psychotropic medications, and may inform etiologic hypotheses on mental disorders. Haloperidol, a widely used first-generation antipsychotic, has been shown to produce structural and functional changes of the hippocampus, a brain region also implicated in the neuropathology of disorders such as schizophrenia and bipolar disorder. Seven adult male C57BL/6 mice were injected daily intraperitoneally with 0.5 mg/kg of haloperidol, for 28 days. A control group of six animals was injected with vehicle only (saline). Protein levels of postmortem hippocampus homogenate were determined using label-free LC/MS/MS. In the treatment group, 216 differentially expressed hippocampal proteins were identified as compared to controls. Ingenuity pathway analysis implicated oxidative phosphorylation and mitochondrial function as top canonical pathways, and local networks involved in tubulin-mediated cytoskeleton dynamics, clathrin-mediated endocytosis, and extracellular signal-regulated kinase and c-Jun N-terminal kinase signaling. The findings of this study could stimulate further research into the cellular mechanisms associated with haloperidol treatment and the pathophysiology of psychotic disorders, assisting treatment biomarker discovery. All MS data have been deposited in the ProteomeXchange with identifier PXD002250 (http://proteomecentral.proteomexchange.org/dataset/PXD002250).