title: Antipsychotic treatment alters protein expression associated with presynaptic function and nervous system development in rat frontal cortex.
abstract: Haloperidol and olanzapine are widely used antipsychotic drugs in the treatment of schizophrenia and other psychotic disorders. Despite extensive research efforts within the biopharmaceutical industry and academia, the exact molecular mechanisms of their action remain largely unknown. Since the response of patients to existing medications can be variable and often includes severe side effects, it is critical to increase our knowledge on their mechanism of action to guide clinical usage and new drug development. In this study, we have employed the label-free liquid chromatography tandem mass spectrometry (LC-MSE) to identify differentially expressed proteins in rat frontal cortex following subchronic treatment with haloperidol or olanzapine. Subcellular fractionation was performed to increased proteomic coverage and provided insight into the subcellular location involved in the mechanism of drug action. LC-MSE profiling identified 531 and 741 annotated proteins in fractions I (cytoplasmic-) and II (membrane enriched-) in two drug treatments. Fifty-nine of these proteins were altered significantly by haloperidol treatment, 74 by olanzapine and 21 were common to both treatments. Pathway analysis revealed that both drugs altered similar classes of proteins associated with cellular assembly/organization, nervous system development/function (particularly presynaptic function) and neurological disorders, which indicate a common mechanism of action. The top affected canonical signaling pathways differed between the two treatments. The haloperidol data set showed a stronger association with Huntington's disease signaling, while olanzapine treatment showed stronger effects on glycolysis/gluconeogenesis. This could either relate to a difference in clinical efficacy or side effect profile of the two compounds. The results were consistent with the findings reported previously by targeted studies, demonstrating the validity of this approach. However, we have also identified many novel proteins which have not been found previously to be associated with these drugs. Further study of these proteins could provide new insights into the etiology of the disease or the mechanism of antipsychotic medications.
authors.affiliation: Institute of Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QT, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.forename: Man K
authors.initials: MK
authors.lastname: Chan
authors.forename: Helen E
authors.initials: HE
authors.lastname: Lockstone
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Pietsch
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Jackie
authors.initials: J
authors.lastname: Cilia
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hill
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Robbins
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Benzel
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Umrania
authors.forename: Paul C
authors.initials: PC
authors.lastname: Guest
authors.forename: Yishai
authors.initials: Y
authors.lastname: Levin
authors.forename: Peter R
authors.initials: PR
authors.lastname: Maycox
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology*; D002853:Chromatography, Liquid / Q000379:methods; D003902:Detergents / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D009420:Nervous System / Q000187:drug effects; D000077152:Olanzapine; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission
chemical_list: D014150:Antipsychotic Agents; D003902:Detergents; D001569:Benzodiazepines; D006220:Haloperidol; D000077152:Olanzapine