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Review
. 2012;34(4):495-505.
doi: 10.35946/arcr.v34.4.13.

Stress, epigenetics, and alcoholism

Sachin Moonat  1 , Subhash C Pandey
Affiliations
Review

Stress, epigenetics, and alcoholism

Sachin Moonat et al. Alcohol Res. 2012.

Abstract

Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism.

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Figures

Figure 1
Figure 1
A psychiatric model for the relationship between stress, anxiety, and alcohol consumption and its modulation by brain-derived neurotrophic factor (BDNF) and synaptic plasticity. Exposure to stress is thought to result in the modulation of BDNF and synaptic plasticity in various brain regions. These changes may result in increased vulnerability to the development of stress-related disorders such as anxiety. Vulnerability to alcohol consumption also may be increased, either directly due to stress exposure or in response to the development of anxiety.
Figure 2
Figure 2
The coordinated actions of proteins involved in epigenetic modifications that regulate gene transcriptional processes. During the 3rst step in the conversion of genetic information encoded in the DNA into gene products (i.e., during gene transcription), the DNA to be transcribed is associated with histone proteins (light blue) that are modified by the addition of acetyl groups (green). This modification results in a relaxed chromatin configuration that allows the transcriptional machinery access to the DNA. Enzymes, DNA methyltransferases (DNMTs), can add methyl groups (red) to the DNA at certain sequences of DNA building blocks (i.e., CpG islands). This methylation causes recruitment of methyl binding domain (MBD) protein complexes that also include repressor proteins, such as histone deacetylases (HDAC). The HDACs remove acetyl groups from histone proteins, resulting in a condensed chromatin that limits the binding of the transcriptional machinery, thereby decreasing gene transcription. Thus, activation of both DNMT and HDAC causes a reduction in gene transcription. Treatment with DNMT inhibitors and HDAC inhibitors may block these enzymatic processes and return the chromatin to a relaxed state, allowing gene transcription.
Figure 3
Figure 3
A hypothetical model for the role of brain-derived neurotrophic factor (BDNF) signaling and chromatin remodeling in central amygdaloid brain regions in the regulation of anxiety induced by acute ethanol and ethanol withdrawal. BDNF binding to tyrosine receptor kinase B (TrkB) triggers several signaling cascades that culminate in the activation of transcription factors, Elk-1 and cAMP-responsive element binding protein (CREB). Under normal conditions, histone deacetylase (HDAC) levels and histone acetylation are adequate to allow for normally regulated chromatin structure and gene transcription. Acute ethanol exposure inhibits HDAC, resulting in increased histone acetylation and an open chromatin conformation. This may lead to increased transcription of BDNF as well as higher levels of a protein, activity-regulated cytoskeleton associated protein (Arc), thereby increasing dendritic spine density. The modulation of these synaptic factors results in anxiety-reducing (i.e., anxiolytic) behavioral effects. In contrast during withdrawal from chronic ethanol exposure HDAC activity increases, resulting in a reduction of histone acetylation that in turn closes the chromatin conformation and reduces gene transcription. The resulting low BDNF levels decrease Arc and dendritic spine density, all of which are associated with anxiety-like behaviors. This model is further supported by the fact that exogenous infusion of BDNF into the CeA reduces anxiety-like behaviors in ethanol withdrawn rats and is associated with increased BDNF and Arc levels (Moonat et al. 2010; Pandey et al. 2008a, 2008b).
Figure 4
Figure 4
A hypothetical model for the role of amygdaloid brain-derived neurotrophic factor (BDNF) in the regulation of activity-regulated cytoskeleton-associated protein (Arc) and dendritic spine density in the comorbidity between innate anxiety and alcohol preference. Genetic factors may lead to innately low levels of amygdaloid BDNF that result in reduced Arc and dendritic spine density and which are associated with a predisposition to innate anxiety-like behaviors. Acute ethanol exposure increases BDNF signaling and associated synaptic factors, Arc, and dendritic spine density and results in a reduction of innate anxiety. Taken together, innate anxiety and a reduction of this anxiety by acute ethanol may be responsible for the development of alcoholism (Moonat et al. 2011).
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