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

Table 1. Epigenetics of substance use disorder
Type of substance Findings References
Cannabis Higher histone methylation onto DRD2 gene with family history Oyaci et al. 105
DNA methylation on DRD2 promotor Gerra et al. 106
Prenatal Δ-9- tetrahydrocannabinol (THC) exposure with an increase in histone methylation DRD2 gene DiNieri et al. 107
Tobacco DNA methylation on NCAM1-TTC12-ANKK1-DRD2 gene cluster associated with risk for cigarettes per day Liu et al. 109
Alcohol Enhanced global histone methylation Pandey et al. 111
DRD2 promoter DNA methylation was positively associated with responses to alcohol severity Bidwell et al. 112
DRD2 DNA methylation was significantly associated with alcohol problem severity Hagerty et al. 114
DNA methylation at the DRD2 gene was significantly increased in association with familial high-risk status Hill and Sharma 116
Craving was significantly associated with DRD2-gene methylation Hillemacher et al. 117
Psychostimulants METH-treated mice also showed (i) decreased global levels of total H3ac and H4ac and increased global González et al. 121
levels of 5-methylcytosine (5-mC) and (ii) decreased H3ac enrichment at promoters of DRD2
In both human and animal self-administration experiments, the histone mark Damez-Werno et al. 122
protein-R- methyltransferase-6 (PRMT6) and asymmetric demethylation of R2 on histone
H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc.
METH induced a decrease in DNA methylation of a number of dopamine-related genes (i.e., DRD3, Nohesara et al. 124
DRD4, and COMT) in patients with METH psychosis but not in non-METH psychosis patients.
Opioids Specifically, rs4867798-CpG_174872884 and rs5326-CpG_174872884 in the DRD1 gene showed Zhang et al. 125
hypermethylation

potential biomarkers or targets for the development of ANKK1-DRD2 gene cluster in addiction susceptibility
pharmacological therapeutic agents. among individuals of European and African descent.
In a study by DiNieri et al., utilizing an animal model Building on this foundation, Liu and colleagues conducted
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of prenatal exposure to delta-9-tetrahydrocannabinol next-generation bisulfite sequencing to uncover smoking-
(THC), it was observed that prenatal cannabis exposure led associated DMRs. Through haplotype-based association
to a reduction in DRD2 messenger RNA expression in the analysis, they identified a significant association between
NAc, a crucial brain reward region. Furthermore, Hurd’s cigarettes per day and the C-T-A-G haplotype in DRD2,
group identified histone methylation differences in the formed by rs4245148, rs4581480, rs4648317, and rs11214613.
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offspring of pregnant rats exposed to THC. Chromatin Furthermore, the study identified four significant smoking-
immunoprecipitation of the adult NAc revealed an increase associated DMRs, with three residing in the DRD2/ANKK1
in the 2meH3K9 repressive mark and a decrease in 3meH3K4 region. These findings elucidate a notable association of
and RNA polymerase II at the DRD2 gene locus in the variants and haplotypes within the ANKK1/DRD2 region
THC-exposed offspring. This diminished DRD2 expression with nicotine dependence among Chinese male smokers.
correlates with reduced DRD2 binding sites and heightened Importantly, the results also underscore the pivotal role of
sensitivity to opiate reward in adulthood. Moreover, the study DNA methylation in facilitating such associations.
suggested that maternal cannabis use alters the epigenetic 5.1.3. Alcohol
mechanisms governing histone lysine methylation, thereby
influencing the developmental regulation of mesolimbic Strong correlations have been observed between DRD2
DRD2 in offspring. This subsequent reduction in DRD2 may binding potential and neural responses to rewarding
increase the susceptibility of the offspring to addiction in the stimuli and substance use. 89-104 Consequently, disruptions
future. Of interest, earlier work from Blum’s laboratory in DRD2 function constitute a critical component of
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demonstrated significant alteration of the vas deferens from theoretical models elucidating the pathophysiology of
110
prenatal exposure to THC in that there was an increased substance dependence. Moreover, as proposed by Pandey
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sensitivity to enkephalins, in agreement with the findings of et al., epigenetic modifications may serve as fundamental
DiNieri et al. 107 molecular mechanisms influencing how alcohol exposure
impacts the brain.
5.1.2. Tobacco This idea has been investigated by Bidwell et al.,
As highlighted by Liu et al., previous research has who demonstrated that, after controlling for age, DRD2
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underscored the importance of the NCAM1-TTC12- promoter DNA methylation was positively associated

Volume 3 Issue 1 (2024) 7 https://doi.org/10.36922/gpd.1966