Epigenetic mechanisms of alcoholism and stress-related disorders

Abstract

Stress-related disorders, such as anxiety, early life stress, and posttraumatic stress disorder appear to be important factors in promoting alcoholism, as alcohol consumption can temporarily attenuate the negative affective symptoms of these disorders. Several molecules involved in signaling pathways may contribute to the neuroadaptation induced during alcohol dependence and stress disorders, and among these, brain-derived neurotrophic factor (BDNF), corticotropin releasing factor (CRF), neuropeptide Y (NPY) and opioid peptides (i.e., nociceptin and dynorphin) are involved in the interaction of stress and alcohol. In fact, alterations in the expression and function of these molecules have been associated with the pathophysiology of stress-related disorders and alcoholism. In recent years, various studies have focused on the epigenetic mechanisms that regulate chromatin architecture, thereby modifying gene expression. Interestingly, epigenetic modifications in specific brain regions have been shown to be associated with the neurobiology of psychiatric disorders, including alcoholism and stress. In particular, the enzymes responsible for chromatin remodeling (i.e., histone deacetylases and methyltransferases, DNA methyltransferases) have been identified as common molecular mechanisms for the interaction of stress and alcohol and have become promising therapeutic targets to treat or prevent alcoholism and associated emotional disorders.

Keywords: Alcohol; Anxiety; DNA methylation; Epigenetic; HDAC; Histone methylation; Stress.

Fig. 1. Relationship among stress, anxiety, and alcohol consumption

Stress and other psychiatric disorders, such as anxiety, can increase the susceptibility to develop alcohol addiction, as subjects consume alcohol in an attempt to self-medicate and attenuate the negative symptoms of mood disorders.

Fig. 2. Alcohol modulates anxiety through activation of cAMP-responsive element binding (CREB) protein and chromatin remodeling and changes in synaptic plasticity-associated gene expression in amydaloid circuitry

Acute alcohol exposure activates CREB phosphorylation and increases CREB binding protein (CBP) expression, which may lead to an increase in histone acetylation (relaxed chromatin) and an increase in expression of brain-derived neurotrophic factor (BDNF) and activity regulated cytoskeleton-associated (Arc) protein genes. These actions may be responsible for the anxiolytic response of alcohol. On the other hand, withdrawal after chronic ethanol produces an opposite response on the levels of phosphorylated CREB (pCREB) and CBP. This is associated with a decrease in histone acetylation (condensed chromatin) and BDNF and Arc, and can result in the development of anxiety-like behaviors (Pandey, Ugale, et al., 2008; Pandey , Zhang, et al., 2008). Also, innate deficits in histone acetylation and BDNF and Arc expression in the amygdaloid circuitry has been implicated in anxiety-like and excessive alcohol drinking behaviors (Moonat et al., 2013).

Fig. 3. Regulation of chromatin states by alcohol and stress

The acetylation of histones, as well as low levels of DNA and histone methylation, induce the relaxed state of chromatin promoting gene transcription. Chronic use of alcohol and stress-related disorders can recruit histone deacetylases (HDACs) resulting in the reduction of the acetylation levels of histones. At the same time, other enzymes, such as the DNA methytransferases (DNMTs), are activated and add methyl groups to cytosines residue of the DNA. These modifications result in a condensed chromatin structure less accessible to transcription factors. Therefore, the transcription of genes that are crucial for synaptic function is reduced. The reduction of synaptic plasticity events contributes to the development and maintenance of alcohol addiction and stress or anxiety can increase the susceptibility to develop alcoholism.