Histone deacetylase inhibition decreases preference without affecting aversion for nicotine

Area of Science:

• Neuroscience
• Epigenetics
• Pharmacology

Background:

• Epigenetic mechanisms, including histone deacetylases (HDACs), are implicated in the long-term effects of substance abuse.
• Nicotine addiction involves long-term brain changes, but the underlying epigenetic mechanisms for nicotine preference are not fully understood.

Purpose of the Study:

• To investigate the role of histone deacetylase 2 (HDAC2) in nicotine preference.
• To evaluate the efficacy of phenylbutyrate, an HDAC inhibitor, in reducing nicotine-conditioned place preference.

Main Methods:

• Utilized a nicotine-conditioned place preference protocol in rats.
• Administered phenylbutyrate and assessed its effects on nicotine preference and aversion.
• Measured histone acetylation (H3K9ac), phosphorylated cAMP-response element-binding protein (pCREB), HDAC2, and methyl-CpG-binding protein 2 (MECP2) expression via immunohistochemistry in the striatum and prefrontal cortex.

Main Results:

• Phenylbutyrate significantly reduced nicotine preference without affecting aversion to nicotine.
• The administered dose of phenylbutyrate effectively inhibited HDAC activity.
• pCREB was involved in establishing nicotine preference but not in its reduction by phenylbutyrate.
• Striatal HDAC2 expression changes correlated with phenylbutyrate's behavioral effects, suggesting its role in nicotine preference.

Conclusions:

• HDAC2 activity in the striatum is implicated in the synaptic plasticity underlying nicotine preference.
• Phenylbutyrate's ability to reduce nicotine preference suggests a potential therapeutic strategy targeting epigenetic mechanisms in addiction.