PMID- 22767372 OWN - NLM STAT- MEDLINE DCOM- 20130111 LR - 20131121 IS - 1461-7285 (Electronic) IS - 0269-8811 (Linking) VI - 26 IP - 9 DP - 2012 Sep TI - A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia. PG - 1218-30 LID - 10.1177/0269881112450780 [doi] AB - Clozapine has markedly superior clinical properties compared to other antipsychotic drugs but the side effects of agranulocytosis, weight gain and diabetes limit its use. The reason why clozapine is more effective is not well understood. We studied messenger RNA (mRNA) gene expression in the mouse brain to identify pathways changed by clozapine compared to those changed by haloperidol so that we could identify which changes were specific to clozapine. Data interpretation was performed using an over-representation analysis (ORA) of gene ontology (GO), pathways and gene-by-gene differences. Clozapine significantly changed gene expression in pathways related to neuronal growth and differentiation to a greater extent than haloperidol; including the microtubule-associated protein kinase (MAPK) signalling and GO terms related to axonogenesis and neuroblast proliferation. Several genes implicated genetically or functionally in schizophrenia such as frizzled homolog 3 (FZD3), U2AF homology motif kinase 1 (UHMK1), pericentriolar material 1 (PCM1) and brain-derived neurotrophic factor (BDNF) were changed by clozapine but not by haloperidol. Furthermore, when compared to untreated controls clozapine specifically regulated transcripts related to the glutamate system, microtubule function, presynaptic proteins and pathways associated with synaptic transmission such as clathrin cage assembly. Compared to untreated controls haloperidol modulated expression of neurotoxic and apoptotic responses such as NF-kappa B and caspase pathways, whilst clozapine did not. Pathways involving lipid and carbohydrate metabolism and appetite regulation were also more affected by clozapine than by haloperidol. FAU - Rizig, Mie A AU - Rizig MA AD - Molecular Psychiatry Laboratory, University College London, London, UK. FAU - McQuillin, Andrew AU - McQuillin A FAU - Ng, Aylwin AU - Ng A FAU - Robinson, Michelle AU - Robinson M FAU - Harrison, Andrew AU - Harrison A FAU - Zvelebil, Marketa AU - Zvelebil M FAU - Hunt, Steve P AU - Hunt SP FAU - Gurling, Hugh M AU - Gurling HM LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120705 PL - United States TA - J Psychopharmacol JT - Journal of psychopharmacology (Oxford, England) JID - 8907828 RN - 0 (Antipsychotic Agents) RN - 0 (Cell Cycle Proteins) RN - 0 (Microtubule Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (RNA, Messenger) RN - J60AR2IKIC (Clozapine) RN - J6292F8L3D (Haloperidol) SB - IM MH - Animals MH - Antipsychotic Agents/blood/*pharmacology MH - Brain/*drug effects/metabolism MH - Cell Cycle Proteins/genetics/metabolism MH - Clozapine/blood/*pharmacology MH - Disease Models, Animal MH - Gene Expression Profiling MH - Gene Expression Regulation/*drug effects MH - Haloperidol/blood/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microtubule Proteins/genetics/metabolism MH - Nerve Tissue Proteins/genetics/metabolism MH - Neurons/*drug effects/metabolism MH - Oligonucleotide Array Sequence Analysis MH - Organ Specificity MH - Pilot Projects MH - RNA, Messenger/metabolism MH - Schizophrenia/drug therapy/*metabolism EDAT- 2012/07/07 06:00 MHDA- 2013/01/12 06:00 CRDT- 2012/07/07 06:00 PHST- 2012/07/07 06:00 [entrez] PHST- 2012/07/07 06:00 [pubmed] PHST- 2013/01/12 06:00 [medline] AID - 0269881112450780 [pii] AID - 10.1177/0269881112450780 [doi] PST - ppublish SO - J Psychopharmacol. 2012 Sep;26(9):1218-30. doi: 10.1177/0269881112450780. Epub 2012 Jul 5.