Histone Methyltransferase G9a Plays an Essential Role on Nicotine Preference in Zebrafish

Area of Science:

• Neuroscience
• Epigenetics
• Pharmacology

Background:

• Psychostimulants, like nicotine, influence behavior through epigenetic mechanisms.
• While DNA methylation and HDAC inhibition are known to affect nicotine reward, the role of histone methylation remains unclear.

Purpose of the Study:

• To investigate the role of histone methylation, specifically H3K9me2, in nicotine-induced conditioned place preference (CPP) in zebrafish.
• To assess the impact of inhibiting the H3K9 methyltransferase G9a/GLP on nicotine reward.

Main Methods:

• Zebrafish were treated with BIX-01294, a G9a/GLP inhibitor, before nicotine conditioning.
• Transcriptional expression of nicotinic acetylcholine receptor subunits and epigenetic enzymes was analyzed.
• H3K9me2 protein levels were measured in reward pathway structures.
• The effect of a lysine demethylase inhibitor, daminozide, was also evaluated.

Main Results:

• BIX-01294 exhibited a dual effect, inhibiting nicotine reward at high doses and potentiating it at low doses.
• Nicotine-CPP was associated with upregulated expression of α6/α7 nicotinic acetylcholine receptor subunits, G9a, DNMT3, and HDAC-1.
• BIX-01294 dose-dependently reduced H3K9me2 protein levels in the reward pathway.
• Daminozide abolished nicotine-CPP and drug seeking.

Conclusions:

• H3K9 methylation catalyzed by G9a/GLP is crucial for the induction of nicotine-CPP.
• Differential inhibition of G9a/GLP by BIX-01294 modulates nicotine reward.
• H3K9me2 represents a potential therapeutic target for nicotine addiction and other substance use disorders.