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Gene & Protein in Disease Stress-induced epigenetics of the DRD2 gene

with responses to alcohol cues in the left caudate, right consistently been observed in the striatum of individuals
caudate, left putamen, right putamen, and right Nac. 77,112 with AUD and other RDS behaviors. The reduced DRD2
This finding indicated that robust striatal activation, in binding has been suggested to indicate diminished DRD2
response to reward cues, was linked with DNA methylation density, which, in turn, has been proposed to trigger
at the DRD2 gene. In addition, DRD2 methylation was cravings and increase the likelihood of relapse. Accordingly,
linked to alcohol use disorder (AUD) severity. Specifically, Feltmann et al., surprisingly, unlike others, did not find
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DRD2 methylation was linked to scores on the AUDs DNA methylation differences in the investigated regions of
Identification Test, Impaired Control Scale, and Alcohol the DRD2 gene. However, in Wistar rats, chronic alcohol
Dependence Scale. drinking significantly decreased mRNA levels of the long

Chronic consumption of alcohol and various other isoform of the DRD2 gene in the NAc. In addition, alcohol
illicit drugs has been associated with adverse consequences, drinking also decreased the striatal density of DRD2-
including functional connectivity deficits within neural DRD2 homoreceptor complexes, increased the density of
networks linked to executive control. These deficits A2AR-DRD2 heteroreceptor complexes in the NAc shell
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may indirectly contribute to the development of aberrant and the dorsal striatum, and decreased the density of
alcohol-seeking behavior. Hagerty et al. found that, sigma1R- DRD2 heteroreceptor complexes in the dorsal
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specifically, average DNA methylation at the DRD2 gene was striatum. Interestingly, the chronic alcohol consumption
negatively correlated with left and right executive control in these rats appears to fit well with earlier findings from
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network connectivity, but no correlation was found with the Blum’s laboratory involving Golden Syrian hamsters. In
other networks that were tested. In addition, DRD2 DNA particular, compared to the control hamsters who only
methylation was found to be linked with the severity of alcohol drank water, the experimental hamsters who freely drank
problems. These findings bolster a theoretical framework ethanol after a year had a noticeably lower concentration
linking the neurobiological markers of alcohol consumption of a leucine-enkephalin-like immunoreactive substance in
among polysubstance users to epigenetic influences. their basal ganglia. 120
Individuals with AUD tend to have dopaminergic This discovery suggests that ethanol’s effects involve the
alteration, and those with a family history of AUD may synthesis of endogenous peptidyl opiates, which appears
experience influences on brain development. Hill and akin to the findings of long-term drinking, as presented in
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Sharma discovered a significant positive correlation the Feltmann et al. study. Thus, although we cannot rule out
between familial high-risk status and DNA methylation the possibility of DNA methylation differences occurring
at the DRD2 gene. In fact, significant differences in the in other regions and/or other epigenetic modifications not
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volume of the left inferior temporal, left fusiform, and studied in the Feltmann et al. study, it begs the question
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left insula regions were observed between high-risk and as to the possibility that mRNA expression suppression
low-risk familial risk groups. Previously, these regions by alcohol drinking also reduces the synthesis of DRD2.
have been associated with social cognition. In addition, Feltmann et al. also provided support for the hypothesis
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the DNA methylation of the DRD2 gene was inversely that AUD was associated with a hypodopaminergic system
correlated with the volumes of grey matter in these regions. and proposed the A2AR-DRD2 heteroreceptor complex as
Along similar lines of thinking, Hillemacher et al., a promising novel target for treatment.
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concerned about the role of epigenetics on dopaminergic 5.1.4. Psychostimulant abuse
neurotransmission and its influence on alcohol dependence,
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found a significant increase of DNA methylation at the Recently, Blum et al. proposed that mild D2 receptor
DRD2 gene during alcohol withdrawal/early abstinence. stimulation achieved by certain therapeutic modalities
Furthermore, they discovered a significant association can cause dopamine release, which, in turn, can change
between craving, as measured by the obsessive-compulsive D2-directed mRNA and improve DRD2 function in
drinking scale, and the DNA methylation of the DRD2 gene. humans. This increase in DRD2 activity is thought to
Their findings regarding this association with alcohol craving reduce craving behaviors, particularly in high-risk,
underscore the pivotal role of DRD2 gene DNA methylation genetically compromised populations. Accordingly, Cadet’s
in the neurobiology of addictive behavior. It is worth noting group has conducted eloquent experiments comparing
that the inability to demonstrate significant alterations in methamphetamine (METH) and modafinil in terms of
DNA methylation between controls and patients may stem epigenetic insults. 121
from an inadequate screening of the control group. 118 González et al., demonstrated that repeated
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Moreover, as previously pointed out by several administration of either METH or modafinil to mice resulted
researchers, 89-104 reduced ligand binding of DRD2 has in cognitive effects. In the medial prefrontal cortex, there

Volume 3 Issue 1 (2024) 8 https://doi.org/10.36922/gpd.1966