Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling.
Recent advances in schizophrenia (SZ) research indicate that the telencephalic gamma-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD(67)), reelin and other GABAergic promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD(67)-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.
Guidotti
Alessandro
A
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor Street, Chicago, IL 60612, USA. aguidotti@psych.uic.edu
Dong
Erbo
E
Kundakovic
Marija
M
Satta
Rosalba
R
Grayson
Dennis R
DR
Costa
Erminio
E
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D044127:Epigenesis, Genetic; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000502:physiology; D000091042:Reelin Protein; D012097:Repressor Proteins / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014150:Antipsychotic Agents; D015816:Cell Adhesion Molecules, Neuronal; C411744:DMAP1 protein, human; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D000091042:Reelin Protein; D012097:Repressor Proteins; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D003596:Cytosine; C000717127:RELN protein, human; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1