We have published extensively on the neurogenetics of brain reward systems with reference to the genes related to dopaminergic function in particular. In 1996, we coined “Reward Deficiency Syndrome” (RDS), to portray behaviors found to have gene-based association with hypodopaminergic function. RDS as a useful concept has been embraced in many subsequent studies, to increase our understanding of Substance Use Disorder (SUD), addictions, and other obsessive, compulsive, and impulsive behaviors. Interestingly, albeit others, in one published study, we were able to describe lifetime RDS behaviors in a recovering addict (17 years sober) blindly by assessing resultant Genetic Addiction Risk Score (GARS™) data only. We hypothesize that genetic testing at an early age may be an effective preventive strategy to reduce or eliminate pathological substance and behavioral seeking activity. Here, we consider a select number of genes, their polymorphisms, and associated risks for RDS whereby, utilizing GWAS, there is evidence for convergence to reward candidate genes. The evidence presented serves as a plausible brain-print providing relevant genetic information that will reinforce targeted therapies, to improve recovery and prevent relapse on an individualized basis. The primary driver of RDS is a hypodopaminergic trait (genes) as well as epigenetic states (methylation and deacetylation on chromatin structure). We now have entered a new era in addiction medicine that embraces the neuroscience of addiction and RDS as a pathological condition in brain reward circuitry that calls for appropriate evidence-based therapy and early genetic diagnosis and that requires further intensive investigation.

Attention-deficit-hyperactivity disorder and reward deficiency syndrome Kenneth Blum1,6,7,8,9,10, Amanda Lih-Chuan Chen2, Eric R Braverman3,9, David E Comings4, Thomas JH Chen5, Vanessa Arcuri9, Seth H Blum6, Bernard W Downs7,8, Roger L Waite7, Alison Notaro9, Joel Lubar10, Lonna Williams7, Thomas J Prihoda11, Tomas Palomo12, Marlene Oscar-Berman131Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC; 2Department of Engineering and Management of Advanced Technology, Chang Jung University, Tainan, Taiwan, Republic of China; 3Department of Neurosurgery, Weill College of Medicine, New York, NY; 4Department of Medical Genetics, City of Hope Medical Center, Duarte, CA; 5Department of Occupational Safety and Health, Chang Jung University, Tainan, Taiwan, Republic of China; 6Department of Psychoneurogenetics, Synapatamine, Inc., San Antonio, TX; 7LifeGen, Inc., La Jolla, CA; 8Allied Nutraceutical Research, Lederach, PA; 9PATH Research Foundation, New York, NY; 10Department of Physiology, University of Tennessee, Knoxville, TN; 11Department of Pathology, University of Texas Health Science Center, San Antonio, TX; 12Hospital Universitario 12 de Octubre, Madrid, Spain; 13Boston University School of Medicine, and Boston VA Healthcare System, Boston, MAParts of this manuscript have been published in Theor Biol Med Model (Comings et al 2005), which is an open access journal Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the “brain reward cascade,” especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with defi cient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other “reward genes” are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.Keywords: attention deficit hyperactivity disorder (ADHD), genes, reward dependence, reward deficiency syndrome, treatment, neuropsychological deficits