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

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.

journal_name

Trends Pharmacol Sci

authors

Guidotti A,Dong E,Kundakovic M,Satta R,Grayson DR,Costa E

doi

10.1016/j.tips.2008.10.010

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

55-60

issue

2

eissn

0165-6147

issn

1873-3735

pii

S0165-6147(08)00251-4

journal_volume

30

pub_type

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