Histone Deacetylase Inhibition Decreases Preference without Affecting Aversion for Nicotine.

PASTOR V, HOST L, ZWILLER J, AND BERNABEU R

JOURNAL OF NEUROCHEMISTRY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2011 vol. 116 p. 636 - 645

0022-3042

Epigenetic mechanisms have recently been shown to beinvolved in the long-term effects of drugs of abuse. A welldescribed epigenetic mechanism modulating transcriptionalactivity consists in the binding to DNA of methyl-CpG bindingproteins, such as MeCP2, recruiting histone deacetylases(HDACs). Nicotine causes long-term changes in the brain, butlittle is known concerning the mechanisms involved in nicotine-preference. Using a nicotine-conditioned place preferenceprotocol, we demonstrate here that the histonedeacetylase inhibitor phenylbutyrate was able to dramaticallyreduce the preference for nicotine, without altering the aversiveproperties of the drug. We measured immunohistochemicallythe acetylation of lysine-9 of histone H3, and theexpression of phosphorylated cAMP-response element-bindingprotein, HDAC2 and methyl-CpG-binding protein 2 in thestriatum and prefrontal cortex of rats displaying nicotinepreferenceor aversion and treated with phenylbutyrate. Weshow that, at the dose administered, the inhibitor was effectivein inhibiting HDAC activity. The data suggest that phosphorylatedcAMP-response element-binding protein participates inthe establishment of conditioned place preference, but notin the reduction of nicotine-preference in response tophenylbutyrate. Moreover, striatal expression of HDAC2 inresponse to phenylbutyrate mirrored the behavioral effects ofthe inhibitor, suggesting that HDAC2 is involved in promotingsynaptic plasticity underlying the preference for nicotine.