Previous research has pointed to the importance of a neuropeptide transmitter called neuropeptide Y (NPY) in managing anxiety, and in modulating alcohol consumption. Low levels of NPY, specifically in the amygdala, have been found in animals that have a preference for alcohol. Additionally, knockout mice who are engineered to lack NPY receptors exhibit an increased proclivity for alcohol.
The aforementioned study explores how those changes occur via epigenetic mechanisms. Epigenetics, literally “on top of” or “in addition to” genetics, studies how genetic packaging affects gene (and subsequently protein) expression.
There are two general avenues of investigation. The first is chromatin remodeling and the second individual gene promoter methylation. These investigators focused on the former.
The complex of DNA and associated nuclear proteins is called chromatin. Chromatin can be densely packed to minimize gene expression or loosely packed to maximize it. Histones, the proteins the DNA wraps around, are methylated when “closed” and acetylated when “open”.
Histone deacetylase inhibitors (HDACs) remove acetyl groups from the histones and lead to a general downregulation in gene expression. The investigators found that alcohol inhibits HDACs and subsequently upregulates NPY gene expression in areas where it has an anxiolytic capacity. Withdrawl, then, upregulated HDACs, downregulated NPY, and caused stress. Administration of a HDAC inhibitor before and during the withdrawl eliminated observable stress.
There are claims that they may have found a novel treatment for alcoholism. I, however, remain skeptical. The anxiolytic effect of the HDAC inhibitor probably has to do with an upregulation of GABA (the primary inhibitory neurotransmitters in the brain) since it is widely reported that HDAC inhibitors have an effect on GABAergic transmission. HDACs are are just too unspecific and, in many ways, carpet bomb gene expression at large. NPY, while certainly a significant part of the picture, may be overshadowed by the HDAC inhibitor induced GABA upregulation.
Nonetheless, it’s a noteworthy article.