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

were observed inductions in histone acetylation and DNA Another important facet related to METH-induced
methylation profiles. Mice subjected to repeated METH psychosis may involve both genetic DNA antecedents and
exposure, but not modafinil, exhibited impaired cognitive epigenetic post-translational changes in mRNA expression,
memory, as revealed by the novel object recognition test, for example, on the DRD2 gene. Nohesara et al. found
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with a notable decrease in memory recognition. In addition, that METH induces a decrease in DNA methylation of a
METH-treated mice demonstrated (i) decreased levels number of dopamine-related genes (i.e., DRD3, DRD4,
of histone H3 and H4 acetylation and increased levels of and COMT) in patients with METH psychosis but not
5-mC and (ii) reduced histone H3 acetylation enrichment in non-METH psychosis patients. The suggestion here
at promoters of the DRD2 gene. These findings suggest that is that, in general, METH dependency is linked with a
epigenetic dysregulation, particularly at the DRD2 gene, is reduction in DNA methylation and an open chromatin
associated with the long-term cognitive decline effects of conformation, leading to increased expression of several
METH and its adverse impacts on medial prefrontal cortex important genes involved in the pathogenesis of psychotic
function. Further studies are warranted to elucidate the disorders. Nohesara et al. suggested that these
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specific mechanisms of epigenetic regulation affected by epigenetic modifications may serve as valuable diagnostic
psychostimulant abuse. biomarkers for diagnosing psychosis in METH abusers. In
Changes in histone methylation and acetylation on addition, they support the use of a methyl-rich diet for the
DNA within the NAc and lysine residues have been suppression or prevention of psychosis in these patients,
observed with repeated cocaine administration. Nestler’s thus encouraging further association and interventional
group investigated histone arginine (R) methylation studies involving larger populations.
in models related to reward processing. Specifically, 5.1.5. Opioid abuse
Damez-Werno et al. found that in both animal and
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human self-administration experiments, the histone mark Opioid use disorder (OUD) and other reward-dysregulated
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protein-R- methyltransferase-6 (PRMT6) and asymmetric disorders have a high degree of heritability. Zhang et al.
demethylation of R2 on histone H3 (H3R2me2a) were demonstrated that various methylation quantitative trait
reduced in the rodent and cocaine-dependent human NAc. loci (mQTLs) in the DRD1 and DRD2 genes were identified
In fact, while PRMT6 overexpression in medium spiny in both the healthy control and heroin use disorder groups.
neurons (MSNs) expressing DRD1 (D1-MSNs) is protective Specifically, rs4867798-CpG_174872884 and rs5326-
against cocaine-seeking behaviors, PRMT6 overexpression CpG_174872884 in the DRD1 gene were the unique single-
in D2-MSNs in all NAc neurons has been associated with nucleotide polymorphism-CpG pairs observed in patients
increased cocaine-seeking behaviors. Along these lines, suffering from heroin use disorder. This groundbreaking
Blum et al. hypothesized that dopaminylation (H3R2me2a research suggests that certain dopaminergic mQTLs may
binding) occurs in PUD, and the binding inhibitor Srcin1, be linked with characteristics of OUD by implicating DNA
like the major DRD2 A2 allelic polymorphism, protects methylation and gene expression. However, it underscores
against psychostimulant-seeking behavior by normalizing the necessity for improved screening of controls to reassess
NAc dopamine expression. Moreover, numerous studies the findings regarding DRD2. 120
have verified the association between the DRD2 Taq A1 5.1.6. Eating disorders
allele (30 – 40 lower DRD2 numbers) and severe cocaine
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dependence. According to Lepack et al., acute cocaine Similar to SUD, anorexia nervosa is a multifaceted and
increases dopamine in NAc synapses and causes histone highly heritable disease. 126-128 Rask-Andersen et al.
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H3 glutamine 5 dopaminylation and subsequent inhibition reviewed the relevant literature and discovered that
of DRD2 expression. With prolonged cocaine use, the 175 association studies had been conducted on an anorexia
inhibition of DRD2 expression increases and accompanies nervosa cohort, examining 128 different polymorphisms
cocaine withdrawal. Furthermore, they have reported that related to 43 genes. The strongest correlations indicate that
during cocaine withdrawal, the Src kinase signaling inhibitor certain dopaminergic genes play a key role in regulating
1 (Srcin1 or p140CAP) decreased H3R2me2a binding. Thus, body mass index. Moreover, findings by Frieling et al.
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this inhibited dopaminylation induced a “homeostatic brake.” revealed an increase in the expression of dopamine
Blum’s group suggested that the reduction in Src signaling transporter (DAT) mRNA and a decrease in DRD2
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in NAc D2-MSNs, like the DRD2 Taq A2 allele, a well-known expression. Frieling et al. suggested that the upregulation
genetic mechanism protective against SUD, normalizes the of the DAT gene was accompanied by a hypermethylation
NAc dopamine expression and decreases cocaine cravings of the gene’s promoter in the anorexia nervosa and bulimia
and cocaine-seeking behaviors. Therefore, Srcin1 could be nervosa group, while significant hypermethylation of the
an important target for therapeutic interventions. DRD2 promoter was only present in the anorexia nervosa

Volume 3 Issue 1 (2024) 9 https://doi.org/10.36922/gpd.1966