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Med Hypotheses. 2014 May;82(5):606-14. doi: 10.1016/j.mehy.2014.02.019. Epub 2014 Feb 26.

Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior.

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Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA; Department of Clinical Neurology, Path Research Foundation, New York, NY, USA; Department of Genomics, IGENE, LLC, Austin, TX, USA; Department of Psychiatry, Human Integrated Services Unit University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA; Dominion Diagnostics, LLC, North Kingstown, RI, USA; Department of Addiction Research & Therapy, Malibu Beach Recovery Center, Malibu Beach, CA, USA; RD Solutions, LLC, Research Center, Austin, TX, USA; Department of Nutrigenomics, RD Solutions, LLC, La Jolla, CA, USA. Electronic address:
Departments of Psychiatry and Anatomy & Neurobiology, Boston University School of Medicine and Boston VA Healthcare System, Boston, MA, USA.
Department of Psychiatry and Neuroimaging Laboratory, SUNY-at Buffalo, Buffalo, NY, USA.
Unidad de Alcoholismo y Patología Dual, Servicio de Psiquiatría, Hospital Universitario 12 de Octubre, Av. de Córdoba s/n, Madrid E-28041, Spain.
Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA.


The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD.

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