Review

Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary

Kenneth Blum^1,6,7,9 , Amanda Lih Chuan Chen^{* 2} , Thomas JH Chen³ , Eric R Braverman^4,9 , Jeffrey Reinking^3,5 , Seth H Blum⁶ , Kimberly Cassel⁶ , Bernard W Downs⁷ , Roger L Waite⁷ , Lonna Williams⁷ , Thomas J Prihoda⁸ , Mallory M Kerner⁹ , Tomas Palomo¹⁰ , David E Comings¹¹ , Howard Tung¹² , Patrick Rhoades¹³ and Marlene Oscar-Berman¹⁴

¹Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

²Engineering & Management of Advanced Technology, Chang Jung University, Taiwan, PR China

³Department of Occupational Health and Safety, Chang Jung University, Taiwan, PR China

⁴Department of Neurosurgery, Weill Cornell College of Medicine, New York, NY, USA

⁵Department of Occupational Health and Safety, Chang Jung University, Taiwan, PR China

⁶Department of Psychoneurogenetics, Synaptamine™, Inc., San Antonio, TX, USA

⁷Deparment of Nutrigenomics, LifeGen, Inc, La Jolla, CA, USA

⁸Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA

⁹Department of Neurological Research, Path Research Foundation, New York, NY, USA

¹⁰Hospital Universitario 12 de Octubre, Madrid, Spain

¹¹Carlsbad Science Foundation, Emeritus, City Of Hope National Medical Center, Duarte, CA, USA

¹²University of California, San Diego Medical Center, Neurological Surgery (Brain and spinal disorders), San Diego, CA, USA

¹³Central Valley Pain Management & Wellness Modesto, CA, USA

¹⁴Boston University School of Medicine and Boston VAMC, Boston, MA, USA

author email corresponding author email* Contributed equally

Theoretical Biology and Medical Modelling 2008, 5:24doi:10.1186/1742-4682-5-24

Published:	12 November 2008

Abstract

Background and hypothesis

Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors.

Proposal and conclusion

The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine™, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, 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. Utilizing natural 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.