Reward Deficiency Solution System (RDS): A Tale of Three Scientists

Citation: Blum K, Badgaiyan RD, Gold MS (2015) Reward Deficiency Solution System (RDS): A Tale of Three Scientists. J Addict Med Ther Sci 1(1): 011014. DOI: 10.17352/2455-3484.000004 011 by separate national institutes for addiction alcohol and narcotics. This concern was highlighted by the original work of Virginia Davis [8], Gerald Cohen [9], Michael Collins [10] and others [11] who found that common neurochemical mechanisms underlie addiction to alcohol and opiates [12]. Blum and his group coined the term Reward Deficiency Syndrome (RDS) to describe these mechanisms publishing the concept in the Royal Society of Medicine in 1996 [13].


Introduction
Prior to 1990 there was a paucity of studies directed at psychiatric genetics and in fact there was only one study by Egeland et al. [1]. whereby an analysis of the segregation of restriction fragment length polymorphisms (RFLP) in an Old Order Amish population (pedigree) localized a dominant gene linked to a strong predisposition to manic depressive disease to chromosome 11 possibly tyrosine hydroxylase. This finding was retracted in 1989 by Kelsoe et al. [2]. Following these very early studies Blum and Noble and their respective groups reported on the first ever confirmed association of the dopamine D2 receptor gene (DRD2) and severe alcoholism [3]. While this sparked some controversy [4] it was confirmed [5] and remains the most widely studied gene in psychiatric genetics and lead to the development of an entire field of medicine (PubMed 8/8/14-14,661) -known as Psychiatric Genetics.
Specifically, drug and alcohol dependence is considered a relapsing chronic condition with compulsive seeking -behavior (including non-substance addictive behaviors) despite harmful negative consequences. All psychoactive drugs including cannabis, ethanol, opioids, stimulants, nicotine as well as disruptive behaviors such as internet gaming, dysfunction sex, overeating amongst others lead to neuronal release of dopamine [6]. A meta-analysis of the studies carried out by Le Foll et al. [5] evaluating DRD2 and alcohol dependence, indicates a significant association. Overall, this indicates that different aspects of the addiction phenotype are critically influenced by dopaminergic receptors and that variants of those genes seem to influence some addiction phenotypes in humans. Others have shown significant linkage between carriers of the DRD2 Taq A1 allele and familiar alcoholism [7]. receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents [22] as well as cocaine -self administration [23].
Utilizing less powerful dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system [24]. It is our hypothesis that D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors.
In fact, stress and dopamine D2 receptor levels play a significant role in alcohol seeking behaviors. Along these lines Delis et al. [25] observed that in the presence of a stressful environment, low DRD2 levels are associated with increased ethanol intake and preference and that under this condition, increased ethanol consumption could be used as a strategy to alleviate negative mood this also supports dopamine agonist therapy not antagonistic. Moreover, recent work by Willuhn et al. [26] surprisingly found that phasic dopamine decreased in the ventral medium striatum (VSM) as the rate of cocaine intake increased, with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Moreover, administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, demonstrating a causal relationship between diminished dopamine transmission and excessive drug use. This work seems to support the "deficit" rather than the "surfeit" theories related to drug seeking behavior [27].
Understanding the current literature we are further proposing that the true phenotype for addiction is not any one single addictive behavior drug or otherwise but is indeed RDS [28]. The basis of this bold concept has received support from a number of PUBMED listed articles (72 as of 8-12-14). Indeed our laboratory [29] evaluated a number of dopaminergic polymorphisms in two families up to five generations and discovered that polymorphisms of the DRD2 and DAT alleles significantly associated with multiple RDS behaviors (P<0.001) [29]. By demonstrating this association, not only do we confirm the role of dopaminergic polymorphisms in RDS behaviors but demonstrate the importance of a nonspecific RDS phenotype. 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. This research has been underscored by the earlier suggestion that food and drugs are both addictive substances and as such share common neurogenetic and neurobiological mechanisms and as such are subsets of RDS [30].

Proposing RDS Solution
Numerous studies have revealed an association between dopaminergic gene polymorphisms and several reward dependent thoughts and behaviors including addictive, obsessive, compulsive and impulsive tendencies. These interrelated behaviors involving dopaminergic genes have been classified as Reward Deficiency Syndrome (RDS) [31].
Studies published and underway reveal the important utility of a novel panel of candidate genes termed "GARS" enabling the stratification of genetically based severity of addiction liability. One study performed in both the United States and China utilizing GARS, revealed that 74% of abstinent psycho stimulant and heroin dependent patients had a moderate to severe genetic liability [32].
Statistical analysis of data from a urine drug monitoring program; the Comprehensive Analysis of Reported Drugs (CARD) was used to evaluate treatment outcome for RDS, in six eastern states. Two important clinical issues: 1) compliance with prescribed treatment medications during in-patient or out-patient recovery programs; 2) abstinence from all non-prescribed licit or illicit psychoactive drugs, were evaluated. Significant evidence for both non-compliance (P<0.0001) and non-abstinence (P<0.0001) during treatment was found in all states involved. However there was significant improvement as evaluated through a longitudinal analysis for both compliance to treatment medications and abstinence [33].
This important outcome data strongly suggests the need for better therapy. Over the last four decades our laboratory has developed the first dopamine D2 agonist complex (KB220Z) to significantly enhance brain dopamine "sensitivity in the Prefrontal Cortex (PFC), the Cingulate Gyrus (site of relapse) and Nucleus Accumbens (site of reward and craving) utilizing qEEG and fMRI imaging respectively [34]. These latter studies if confirmed will provide the rationale to include KB220Z as a frontline agent to attenuate the negative effect of unwanted hypodopaminergic function or "dopamine resistance" [35]. Rajendra D. Badgaiyan has pioneered novel neuroimaging methods [36,37] to detect dopamine across the entire human brain to assist in the determination of functional connectivity. Studies using this methodology will result in further understanding of how our dopaminergic hard -wiring predicts future abarrant substance and non-substance seeking behavior [38].

Conclusion
Thus, we are proposing for the first time ever a holistic-therapeutic model for RDS which includes GARS (diagnostic); CARD (outcome measure) and KB220 ( prolonged D2 agonist therapy) along with 12 step fellowship and other holistic modalities (e.g. low glycemic index diet; yoga, meditation etc.) known to naturally release neuronal dopamine [35].
The unanswered question is can we overcome DNA polymorphisms by promoting positive epigenetic effects which can be transferred from generation to generation [39]. We have been "licking our pups" enough? Could we possibly attenuate substance and non-substance seeking-behaviors through love? evaluation of "compliance" to prescribed treatment medications and "abstinence" from psychoactive drug abuse in chemical dependence programs: data from the comprehensive analysis of reported drugs. PLoS One 9: e104275.