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

the DRD1 and DRD2 genes are linked to reward pathways induced by drugs can lead to epigenetic alterations, which
and mechanisms. The culmination of biochemical processes may contribute to aberrant cellular functions that facilitate
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in mesolimbic regions leads to rewarding phenomena, the pathogenesis of psychoactive substance dependence.
particularly in the nucleus accumbens (NAc), where increased Nestler’s group has previously proposed that gaining
dopamine levels in synaptic spaces interact with DRD1, insights into epigenetic processes holds therapeutic
DRD2, and other receptor subtypes. 21,22 Positron emission promise. Targeting significant drug-induced epigenetic
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tomography studies have provided further insights, alterations within the brain could potentially disrupt the
demonstrating lower DRD2 availability in individuals cycle of drug dependence, thereby preventing individuals
with dependence on cannabis, psychostimulants, opioids, from succumbing to a relentless cycle of addiction. 35
or alcohol, as well as those who are obese, compared to Comprehending the intricacies of the neuroepigenetic
control subjects. 23-28 landscape necessitates acknowledging the array of

Furthermore, studies have revealed an association epigenetic modifications. Among these, a significant
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between the A1 and B1 minor alleles of the DRD2 gene epigenetic change occurring in adverse environments
and cocaine use disorder (CUD). These findings suggest involves histone post-translational modifications (PTMs),
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that genetic variations in the DRD2 gene, located on such as methylation and even dopaminylation. 36,37
chromosome 11 at the q22-q23 region, contribute to an Essentially, chromatin consists of DNA that is intricately
increased susceptibility to psychostimulant use disorder wound around histone protein octamers and forms
(PUD). Interestingly, these observations align with early nucleosomes, which subsequently allows for compact
research by Gold’s group, which hinted at the potential packaging within the cell nucleus. This structural
therapeutic efficacy of bromocriptine, a D2 agonist, in arrangement serves as an adaptable scaffold that responds to
combating cocaine abuse and dependence. Unlike the external stimuli. Notably, histones are rich in arginine and
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DRD2 Taq A1 allele, which is associated with decreased lysine residues, contributing to their highly basic nature.
D2 receptor levels, the main variant, DRD2 Taq A2 allele, PTMs of these residues and others on histone N-terminal
is characterized by normal D2 receptor levels, possibly tails, extending from the nucleosome core, modulate the
offering protection against psychostimulant misuse and physical properties and charge distribution of chromatin,
abuse. 30 thereby regulating DNA-associated processes.
Historically, Dackis and Gold were among the first to Histone subunits undergo a multitude of PTMs, including
propose the use of the potent D2 agonist bromocriptine but not limited to acetylation, methylation, phosphorylation,
as an epigenetic therapy for severe cocaine dependence. adenosine diphosphate ribosylation, ubiquitylation, and
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However, clinical trials revealed that bromocriptine led to sumoylation, with an expanding array of newly identified
the down-regulation of DRD2 receptors and did not prove modifications. 38,39 These modifications occur on over 50
to be effective for this purpose, resulting in its limited distinct sites across histone proteins. 38,39
clinical utilization. 31 According to Allis et al., “histone PTMs are reversible;
This commentary has uncovered a plethora of studies they are dynamically deposited by “writer” enzymes,
delineating epigenetic alterations occurring within the recognized by “reader” proteins which mediate the cellular
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DRD2 gene across both substance-related and non- response, and removed by “eraser’ enzymes.” Studies have
substance-related RDS behaviors. demonstrated that the expression and activity of numerous
writer, eraser, and reader proteins are dysregulated in both
2. Epigenetics and addictive behaviors addicted individuals and animal models of addiction. 40-42
This dysregulation has spurred interest in the development
Epigenetics refers to the molecular modifications imposed of novel epigenetic therapies for addiction. The restoration
on chromatin within the nucleus of a cell, playing a of normal function to these proteins, either through small
crucial role in regulating various DNA-related processes, molecule interventions or functional food complexes that
including chromatin organization, DNA repair, RNA help rebalance neurotransmitter levels, such as dopamine,
transcription, and splicing, among other essential cellular represents a promising avenue for anti-addiction epigenetic
functions. Substance use disorder (SUD) serves as a treatments. 43-52
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prime example of how environmental factors can influence
gene expression. In this regard, a person’s experiences, 3. Epigenetic biomarkers
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particularly volitional repetitive drug use, can modify the
epigenome in the brain in a way that is specific to certain 3.1. DNA methylation
brain regions and cell types. It is hypothesized that A biomarker is a quantitative, measurable indicator of a
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dysregulation and modification of DNA-related processes biological molecule, state, or condition. DNA methylation
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Volume 3 Issue 1 (2024) 3 https://doi.org/10.36922/gpd.1966