title: Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis.
abstract: BACKGROUND
  The dopamine (DA) hypothesis of schizophrenia proposes the mental illness is caused by excessive transmission of dopamine in selected brain regions. Multiple lines of evidence, including blockage of dopamine receptors by antipsychotic drugs that are used to treat schizophrenia, support the hypothesis. However, the dopamine D2 receptor (DRD2) blockade cannot explain some important aspects of the therapeutic effect of antipsychotic drugs. In this study, we hypothesized that antipsychotic drugs could affect the transcription of genes in the DA pathway by altering their epigenetic profile.
  
  
  METHODS
  To test this hypothesis, we examined the effect of olanzapine, a commonly used atypical antipsychotic drug, on the DNA methylation status of genes from DA neurotransmission in the brain and liver of rats. Genomic DNA isolated from hippocampus, cerebellum, and liver of olanzapine treated (n = 2) and control (n = 2) rats were analyzed using rat specific methylation arrays.
  
  
  RESULTS
  Our results show that olanzapine causes methylation changes in genes encoding for DA receptors (dopamine D1 receptor, dopamine D2 receptor and dopamine D5 receptor), a DA transporter (solute carrier family 18 member 2), a DA synthesis (differential display clone 8), and a DA metabolism (catechol-O-methyltransferase). We assessed a total of 40 genes in the DA pathway and found 19 to be differentially methylated between olanzapine treated and control rats. Most (17/19) genes showed an increase in methylation, in their promoter regions with in silico analysis strongly indicating a functional potential to suppress transcription in the brain.
  
  
  CONCLUSIONS
  Our results suggest that chronic olanzapine may reduce DA activity by altering gene methylation. It may also explain the delayed therapeutic effect of antipsychotics, which occurs despite rapid dopamine blockade. Furthermore, given the common nature of epigenetic variation, this lends insight into the differential therapeutic response of psychotic patients who display adequate blockage of dopamine receptors.
authors.affiliation: Department of Biology, Molecular Genetics Unit, Western Science Centre, The University of Western Ontario, London, Ontario N6A 5B7 Canada.
authors.forename: Melkaye G
authors.initials: MG
authors.lastname: Melka
authors.affiliation: Department of Biology, Molecular Genetics Unit, Western Science Centre, The University of Western Ontario, London, Ontario N6A 5B7 Canada.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Castellani
authors.affiliation: Department of Biology, Molecular Genetics Unit, Western Science Centre, The University of Western Ontario, London, Ontario N6A 5B7 Canada.
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Laufer
authors.affiliation: Department of Psychiatry, The University of Western Ontario, London, Ontario N6A 5B7 Canada.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Rajakumar
authors.affiliation: Department of Psychiatry, The University of Western Ontario, London, Ontario N6A 5B7 Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: O'Reilly
authors.affiliation: Department of Biology, Molecular Genetics Unit, Western Science Centre, The University of Western Ontario, London, Ontario N6A 5B7 Canada.
authors.forename: Shiva M
authors.initials: SM
authors.lastname: Singh
keywords: DNA methylation; Dopamine; Epigenetics; Olanzapine; Psychosis