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Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences

Kenneth Blum1,2,3,4,5,6,7,8,9* Abdalla Bowirrat1 David Baron2 Igor Elman9,10 Milan T. Makale11 Jean Lud Cadet12 Panayotis K. Thanos13 Colin Hanna13 Rania Ahmed13 Marjorie C. Gondre-Lewis14 Catherine A. Dennen15 Eric R. Braverman6 Diwanshu Soni2 Paul Carney16 Jag Khalsa17 Edward J. Modestino18 Debmalya Barh7,19 Debasis Bagchi20 Rajendra D. Badgaiyan21 Thomas McLaughlin6 Rene Cortese22 Mauro Ceccanti23 Kevin T. Murphy24 Ashim Gupta25 Miles T. Makale26 Keerthy Sunder9,27 Mark S. Gold28
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1 Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel
2 Division of Addiction Research & Education, Center for Sports, Exercise & Mental Health, Western University of the Health Sciences, Pomona, CA, United States of America
3 Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary
4 Department of Psychiatry, University of Vermont, Burlington, VT 05405, United States of America
5 Department of Psychiatry, Wright University Boonshoft School of Medicine, Dayton, OH, United States of America
6 Division of Nutrigenomics, The Kenneth Blum Behavioral Neurogenetic Institute, Austin, TX United States of America
7 Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur, West Bengal, India
8 Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, FL, United States of America
9 Division of Personalized Neuromodulation Research, Sunder Foundation, Palm Springs, CA, United States of America
10 Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, United States of America
11 Department of Radiation Medicine and Applied Sciences, UC San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States of America
12 Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD., United States of America
13 Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY; Department of Psychology, State University of New York at Buffalo, Buffalo, NY., United States of America
14 Department of Anatomy, Howard University College of Medicine, and Developmental Neuropsychopharmacology Laboratory, Howard University College of Medicine, Washington D.C., United States of America
15 Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, United States of America
16 Division Pediatric Neurology, University of Missouri, School of Medicine, Columbia, MO., United States of America
17 Department of Microbiology, Immunology and Tropical Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, United States of America
18 Department of Psychology, Curry College, Milton, MA., United States of America
19 Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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
Submitted: 29 September 2023 | Accepted: 14 December 2023 | Published: 29 March 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

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.”

Dopamine D2 receptor
Epigenetic modification
Neurological disorders
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Conflict of interest
Kenneth Blum holds patents, both domestic and foreign, related to pro-dopamine regulation complexes and genetic testing for addiction risk. Other authors declare no conflict of interest.
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Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing