Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling

Trends Pharmacol Sci. 2009 Feb;30(2):55-60. doi: 10.1016/j.tips.2008.10.010. Epub 2008 Dec 26.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Chromatin Assembly and Disassembly / drug effects*
  • Cytosine / metabolism
  • DNA Methylation
  • Drug Synergism
  • Drug Therapy, Combination
  • Epigenesis, Genetic
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Genetic Predisposition to Disease
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Histone Deacetylase Inhibitors
  • Histones / metabolism
  • Humans
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Nicotinic Agonists / pharmacology
  • Nicotinic Agonists / therapeutic use
  • Receptors, Nicotinic / physiology
  • Repressor Proteins / metabolism
  • Schizophrenia / drug therapy
  • Schizophrenia / genetics
  • Schizophrenia / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Valproic Acid / pharmacology*
  • Valproic Acid / therapeutic use
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Antipsychotic Agents
  • Cell Adhesion Molecules, Neuronal
  • DMAP1 protein, human
  • Extracellular Matrix Proteins
  • Histone Deacetylase Inhibitors
  • Histones
  • Nerve Tissue Proteins
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • Repressor Proteins
  • gamma-Aminobutyric Acid
  • Valproic Acid
  • Cytosine
  • Serine Endopeptidases
  • reelin protein
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1