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

Using similar brain tissue, Noble et al. conducted a attenuate unwanted behaviors. Adolescent binge drinking
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study investigating the allelic association of the human is widely recognized to induce epigenetic modifications at
DRD2 gene with the binding characteristics of the DRD2 the enhancer region of the activity-regulated cytoskeleton-
receptor in 66 brains obtained from both non-alcoholic associated protein (ARC) immediate-early gene, specifically
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and alcoholic subjects. In this blinded experiment, DNA known as the synaptic activity response element (SARE).
extracted from the cerebral cortex underwent treatment These epigenetic modifications lead to a decrease in ARC
with the restriction endonuclease Taq and was probed with expression in the amygdala, a phenomenon observed in
a 1.5-kb digest of a clone (XhD2G1) of the human DRD2 both rodent models and human studies. 104
gene. The binding characteristics, including the binding In an experiment conducted by Pandey’s group, it
affinity (K ) and the number of binding sites (B ), of was demonstrated that the use of dCas9-P300 resulted
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DRD2 were determined in the caudate nuclei of these in increased histone acetylation at the ARC SARE. This
brains using tritiated spiperone as the ligand. The results intervention effectively normalized deficits in ARC
revealed that compared to nonalcoholic subjects, the expression and consequently led to a reduction in adult
adjusted K was significantly lower in alcoholic subjects, anxiety and excessive alcohol consumption in a rat model
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indicating a higher binding affinity of DRD2 in the latter that examined alcohol exposure during adolescence.
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group. In addition, B was found to be lower in subjects Interestingly, dCas9-Kruppel-associated box (KRAB),
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carrying the A1 allele, which exhibited a strong association in contrast, was found to promote repressive histone
with alcoholism, whereas no significant changes in B methylation at the ARC SARE, resulting in decreased ARC
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were observed in subjects carrying the A2 allele. Moreover, expression, the manifestation of anxiety-like behaviors,
a progressively reduced B was found in subjects with and increased alcohol consumption in the control group.
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A2/A2, A1/A2, and A1/A1 alleles, with subjects carrying
A2/A2 alleles exhibiting the highest mean values and those 5.1. SUD
with A1/A1 alleles exhibiting the lowest. The observed A summary of studies focusing on the epigenetics SUD
polymorphic pattern of the DRD2 gene and its variation in is presented in Table 1. Detailed descriptions of SUD are
receptor expression strongly suggests the involvement of provided in the following subsections.
the dopaminergic system in predisposing individuals to at
least one subtype of severe alcoholism. Subsequent studies 5.1.1. Cannabis
have corroborated these findings, 89-104 and as of February In a study conducted by Oyaci et al., DNA methylation
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22, 2024, a PubMed search using the term “Dopamine D2 levels at the DRD2 gene were compared among patients
Receptor Gene” yielded a total of 5485 listings. based on clinical parameters and DRD2 genotype
While we are cognizant of epigenetic insults affecting distribution. Their findings revealed significant differences
at least seven major neurotransmitter pathways, including in methylation status between groups, particularly
cannabinoidergic, cholinergic, serotonergic, opioidergic, concerning the presence of a family history of CUD or
gluconergic, GABAergic, and glutaminergic, our focus synthetic cannabinoid use disorder (SCUD). One notable
lies on the dopaminergic system, specifically the DRD2 limitation of the study is the utilization of inaccurate
gene. The primary review, which is based on PUBMED controls (the authors did not screen the controls for
listings using the search term “Methylation and the other potentially addictive behaviors such as gambling
Dopamine D2 Receptor Gene,” yielded 378 listings as of and overeating). It is known that without such screening,
February 22, 2024. the presence of the DRD2 A1 allele, for example, could
be as high as 40%. This flaw could have prevented the
5. Epigenetic modifications and DRD2 gene investigators from establishing direct evidence for high
DNA methylation with both CUD and SCUD. In a
While we recognize that many reward genes and associated separate work conducted by Gerra et al., a genetic
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loci have been shown to undergo epigenetic modifications and sociodemographic analysis involving both CUD
after the consumption of drugs of abuse (i.e., alcohol), patients and control groups was performed to explore
the purpose of this commentary is to present a narrative DNA methylation in the DRD2-ANKKI gene region.
that focuses on identifying epigenetic modifications, They identified significant hypermethylation at exon 8 of
specifically in the DRD2 gene. In this commentary, we the DRD2 gene. Interestingly, the study also uncovered
chose not to denote DNA and/or histone methylation, but a correlation between higher education levels and a
instead, we provide a summary based on behavioral effects.
reduced risk of CUD. The authors astutely proposed
A recent study by Bohnsack et al. provides an example that their findings of differentially methylated regions
of targeting and editing epigenetic histone modifications to (DMRs) at exon 8 of the DRD2 gene could serve as

Volume 3 Issue 1 (2024) 6 https://doi.org/10.36922/gpd.1966