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

20 Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy and Health Sciences, Houston, TX, United
States of America
21 Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland OH., 44106, USA and Department of
Psychiatry, Mt. Sinai School of Medicine, New York, NY, United States of America
22 Department of Child Health – Child Health Research Institute, & Department of Obstetrics, Gynecology and Women’s Health School of
Medicine, University of Missouri, MO, United States of America
23 Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, Italy
24 Division of Personalized Neuromodulation and Patient Care, PeakLogic, LLC, Del Mar, CA, United States of America
25 Future Biologics, Lawrenceville, Georgia, 30043, United States of America
26 Department of Psychology, UC San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States of America
27 Department of Psychiatry, UC Riverside School of Medicine, Riverside, CA, United States of America
28 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States of America

Abstract
The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied
genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly
through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to
elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene
listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative
reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not
adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2
variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal
deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative
methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20
articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or
histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum
and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism,
it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly
harness the idea of potentially removing negative mRNA-reduced expression by inducing “dopamine homeostasis.”

Keywords: Dopamine D2 receptor; Epigenetic modification; Neurological disorders; Stress

1. Introduction prevention (CDC) reported 106,699 overdose deaths in
the US, with 80,441 of those deaths related to opioids. In
In 2013, Blum’s research team initiated an inquiry into addition, provisional data from the CDC indicated that
the motivations behind alcohol consumption and high opioid deaths in 2022 would rise to approximately 82,998. 7,8
rates of drug-seeking behaviors, particularly in response
to stressful situations. Their goal was to raise awareness Blum et al. established the concept of reward deficiency
1-4
and understanding of the underlying mechanisms driving syndrome (RDS) in 1995 as a potential predictor of
such behaviors. Moreover, they posed additional questions addictive and impulsive behaviors. 5,9-11 This theory has
regarding the millions of individuals who seek out and since been supported by numerous studies, indicating
engage in high-risk novelty situations, pondering the that behavioral, cognitive, and emotional disturbances
consequences of pleasure-seeking behaviors. They observed in psychiatric disorders, including RDS, are
suggested that the answers to these questions may lie linked to functional deficits in neurological pathways. 12-17
within the intricate workings of our brains and perhaps For instance, the D2 dopamine receptor (DRD2) Taq
within our genetic makeup. 5,6 A1 allele has been consistently associated with numerous
America is currently facing the worst opioid epidemic behavioral phenotypes, including aggression, alcoholism,
18
in history. In 2021, the centers for disease control and addictive behaviors, and neuropsychiatric disorders. Both
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Volume 3 Issue 1 (2024) 2 https://doi.org/10.36922/gpd.1966