LG839: Anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome

Blum, Kenneth; Chen, Amanda L C; Chen, Thomas J H; Rhoades, Patrick; Prihoda, Thomas J.; Downs, Bernard W.; Waite, Roger L.; Williams, Lonna; Braverman, Eric R.; Braverman, Dasha; Arcuri, Vanessa; Kerner, Mallory; Blum, Seth H.; Palomo, Tomás

doi:10.1007/s12325-008-0093-z

Cited by 45 publications

(29 citation statements)

References 38 publications

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“…In addition, reduced release of mesolimbic DA affected both by genes and by the environment, play a significant role in craving behavior and more importantly in relapse [165,166,167,168,169] as well as many RDS behaviors [170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193] …”

Section: Discussionmentioning

confidence: 99%

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Blum

Chen

Oscar‐Berman

et al. 2011

IJERPH

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114

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Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

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Section: Discussionmentioning

confidence: 99%

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Blum

Chen

Oscar‐Berman

et al. 2011

IJERPH

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114

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“…Since that time there have been no less than 3738 (Pubmed-6-23-14) peer reviewed articles on many peripheral and central nervous system (CNS) behaviors and physiological processes. Understandably addiction or even the broader term RDS involves very complex gene × environment interaction and one cannot expect that a single gene like the DRD2 gene would have a powerful effect by itself, however, albeit many negative findings, there is still a plethora of evidence for the role of the DRD2 gene polymorphisms and a number (small sample of studies represented herein) of addictive and other reward dependent behaviors including: alcohol dependence (Pato et al, 1993; Ponce et al, 2003; Munafò et al, 2007; Smith et al, 2008; Pinto et al, 2009; Grzywacz et al, 2012; Wang et al, 2013); drug dependence (Li et al, 2004; Xu et al, 2004; Young et al, 2004; Barratt et al, 2006; Li et al, 2006; Hou and Li, 2009; Chen et al, 2011a,b; Al-Eitan et al, 2012; Jacobs et al, 2013; Lee et al, 2013; Ohmoto et al, 2013; Sullivan et al, 2013; Suraj Singh et al, 2013; Vereczkei et al, 2013; Wang et al, 2013; Clarke et al, 2014; Roussotte et al, 2014; Schuck et al, 2014); mood disorders (Vaske et al, 2009; Huertas et al, 2010; Zhu et al, 2011; Zou et al, 2012; Hettinger et al, 2012; Jutras-Aswad et al, 2012; Tsuchimine et al, 2012; Whitmer and Gotlib, 2012; Zai et al, 2012; Peciña et al, 2013; Zhang et al, 2014); rearing behaviors (Mills-Koonce et al, 2007; Bakermans-Kranenburg and van Ijzendoorn, 2011; Beaver and Belsky, 2012; Masarik et al, 2014); obesity (Spangler et al, 2004; Fang et al, 2005; Huang et al, 2005; Epstein et al, 2007; Nisoli et al, 2007; Barnard et al, 2008; Blum et al, 2008; Eny et al, 2009; Epstein et al, 2010; Mathes et al, 2010; Stice et al, 2010; van Strien et al, 2010; Jabłoński, 2011; Anitha et al, 2012; Chen et al, 2012; Winkler et al, 2012; Ariza et al, 2013; Car...…”

Section: Controversial Findingsmentioning

confidence: 99%

Dopamine and glucose, obesity, and reward deficiency syndrome

2014

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Obesity as a result of overeating as well as a number of well described eating disorders has been accurately considered to be a world-wide epidemic. Recently a number of theories backed by a plethora of scientifically sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Our laboratory has published on the concept known as Reward Deficiency Syndrome (RDS) which is a genetic and epigenetic phenomena leading to impairment of the brain reward circuitry resulting in a hypo-dopaminergic function. RDS involves the interactions of powerful neurotransmitters and results in abnormal craving behavior. A number of important facts which could help translate to potential therapeutic targets espoused in this focused review include: (1) consumption of alcohol in large quantities or carbohydrates binging stimulates the brain’s production of and utilization of dopamine; (2) in the meso-limbic system the enkephalinergic neurons are in close proximity, to glucose receptors; (3) highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; (4) a significant correlation between blood glucose and cerebrospinal fluid concentrations of homovanillic acid the dopamine metabolite; (5) 2-deoxyglucose (2DG), the glucose analog, in pharmacological doses is associated with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and fMRI in humans support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and for the most part, implicate the involvement of DA-modulated reward circuits in pathologic eating behaviors. Based on a consensus of neuroscience research treatment of both glucose and drug like cocaine, opiates should incorporate dopamine agonist therapy in contrast to current theories and practices that utilizes dopamine antagonistic therapy. Considering that up until now clinical utilization of powerful dopamine D2 agonists have failed due to chronic down regulation of D2 receptors newer targets based on novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of reward deficiency.

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“…In addition, Blum’s group systematically evaluated the impact of polymorphisms of these five candidate genes as important targets for the development of a DNA-customized nutraceutical KB220z to combat obesity with special emphasis on body re-composition as measured by BMI [22]. A total of 21 individuals were evaluated in a preliminary investigational study of KB220z.…”

Section: Kb220z and Dna For Obesitymentioning

confidence: 99%

Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms

Blum

Simpatico

Badgaiyan

et al. 2015

J Reward Defic Syndr

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Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2]) to associate with severe alcoholism serves as a blue-print for the development of “Personalized Medicine” in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term “Reward Deficiency Syndrome (RDS)” to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as “Genetic Addiction Risk Score” (GARSpDX)™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASI-Media Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci. KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. We propose a Reward Deficiency System Solution that promotes early identification and stratification of risk alleles by utilizing GARSDx, allowing for customized nutrigenomic targeting of these risk alleles by altering KB220Z ingredients as an algorithmic function of carrying these polymorphic DNA–SNPS, potentially yielding the first ever nutrigenomic solution for addiction and pain.

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LG839: Anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome

Abstract: If these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality to combat obesity.

Cited by 45 publications

References 38 publications

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Dopamine and glucose, obesity, and reward deficiency syndrome

Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms

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