Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (36), p.13614-13619
• Main Authors: Dong, E, Nelson, M, Grayson, D.R, Costa, E, Guidotti, A
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Antibodies; Antipsychotic agents; Benzodiazepines - pharmacology; Biological Sciences; Bipolar disorder; Brain; Brain - drug effects; Brain - metabolism; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Clozapine - pharmacology; Disorders; DNA; DNA Methylation - drug effects; Dosage; Effects; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Gene expression; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Haloperidol - pharmacology; Histones - metabolism; Lysine - metabolism; Male; Methylation; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Promoter Regions, Genetic - genetics; Psychotropic drugs; Rodents; Schizophrenia; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Sulpiride - pharmacology; Valproic Acid - pharmacology; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0805493105

Cortical GABAergic dysfunction, a hallmark of both schizophrenia (SZ) and bipolar (BP) disorder pathophysiologies may relate to the hypermethylation of GABAergic gene promoters (i.e., reelin and GAD67). Benefits elicited by a combination of atypical antipsychotics with valproate (VPA) (a histone deacetylase inhibitor that may also activate brain DNA demethylation) in SZ or BP disorder treatment prompted us to investigate whether the beneficial action of this association depends on induction of a putative DNA demethylase activity. To monitor this activity, we measured the ratio of 5-methyl cytosine to unmethylated cytosine in reelin and GAD67 promoters in the mouse frontal cortex and striatum. We compared normal mice with mice pretreated with L-methionine (5.2 mmol/kg s.c. twice a day for 7 days) to hypermethylate promoters, including reelin and GAD67. Clinically relevant doses of clozapine (CLZ) (3.8 to 15 μmol/kg twice a day s.c. for 3 days) and sulpiride (SULP) (12.5 to 50 μmol/kg twice a day for 3 days) but not clinically relevant doses of haloperidol (HAL) (1.3 to 4 μmol/kg twice a day s.c. for 3 days) or olanzapine (OLZ) (4 to 15 μmol/kg twice a day for 3 days) exhibited dose-related increases in the cortical and striatal demethylation of hypermethylated reelin and GAD67 promoters. These effects of CLZ and SULP were dramatically potentiated by a clinically relevant VPA dose (0.5 mmol/kg twice a day for 3 days). By activating a DNA demethylase, the association of CLZ or SULP with VPA may facilitate a chromatin remodeling that normalizes the GABAergic gene expression down-regulation detected in the telencephalic regions of SZ and BP patients.