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

Theoretical Biology and Medical Modelling 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 3 4 5 7 Amanda Lih Chuan Chen 1 Thomas JH Chen 0 Eric R Braverman 6 7 Jeffrey Reinking 0 Seth H Blum 5 Kimberly Cassel 5 Bernard W Downs 4 Roger L Waite 4 Lonna Williams 4 Thomas J Prihoda 8 Mallory M Kerner 7 Tomas Palomo 2 David E Comings 11 Howard Tung 12 Patrick Rhoades 9 Marlene Oscar-Berman 10 0 Department of Occupational Health and Safety, Chang Jung University , Taiwan , PR China 1 Engineering & Management of Advanced Technology, Chang Jung University , Taiwan , PR China 2 Hospital Universitario 12 de Octubre , Madrid , Spain 3 Department of Physiology & Pharmacology, Wake Forest University School of Medicine , Winston-Salem, NC , USA 4 Deparment of Nutrigenomics, LifeGen, Inc , La Jolla, CA , USA 5 Department of Psychoneurogenetics, SynaptamineTM, Inc. , San Antonio, TX , USA 6 Department of Neurosurgery, Weill Cornell College of Medicine , New York, NY , USA 7 Department of Neurological Research, Path Research Foundation , New York, NY , USA 8 Department of Pathology, University of Texas Health Science Center , San Antonio, TX , USA 9 Central Valley Pain Management & Wellness Modesto , CA , USA 10 Boston University School of Medicine and Boston VAMC , Boston, MA , USA 11 Carlsbad Science Foundation, Emeritus, City Of Hope National Medical Center , Duarte, CA , USA 12 University of California, San Diego Medical Center, Neurological Surgery (Brain and spinal disorders) , San Diego, CA , USA 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 - 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. Background It is well known that brain reward circuitry is regulated by neurotransmitter interactions and net release of the substance Dopamine (DA) in the Nucleus accumbens (NAc) [1]. The major loci for feelings of well-being and reward occur in the meso-limbic system of the brain. The natural sequence of events of the "brain reward cascade" leading to reward involves the inter-relationship of at least four important neurochemical pathways: serotonergic (5-HT); enkephalinergic (Enk), GABAergic (GABA), and dopaminergic (DA). The synthesis, vesicle storage, metabolism, release and function of these neurotransmitters are regulated by genes and the expression thereof in terms of messenger RNA (mRNA) directed proteins. It has been postulated that genome orientated research will provide genetic testing that will categorize individuals as to their specific neurochemical makeup and thus provide useful information to assist in appropriate development of the most correct treatment options for the patient requiring psychiatric care [2]. DA is a substance with many important neurochemical functions and has been credited with resultant behavioral effects such as "pleasure," "stress reduction" and "wanting". Simply stated, without the normal functionality of DA, an individual will be lacking hedonic response and an inability to cope with stress [3]. Thus genetic hypodopaminergic activity of the brain predisposes an individual to seek substances and/or behaviors that will overcome this anhedonic state by activating meso-limbic dopaminergic centers [4]. It turns out that these substances and behaviors include: alcohol, opiates, psychostimulants, nicotine, carbohydrates, cannabinoids, gambling, sex, and indulgence in any excessive pleasure or thrill seeking behaviors, like video gaming etc. [5-16]. Use of these substances and engaging in these aforementioned behaviors commonly induces the release of neuronal DA into the synapse at the NAc, the reward center of the brain [3]. Acute indulgence in these behaviors can be classified as self-medicating and leads to a preferential release of DA, which overcomes the hypodopaminergic state for that individual. The resultant self-medication provides a temporary relief of discomfort and a "pseudo feeling" of well-being [17]. Unfortunately, chronic abuse of these psychoactive substances and excessive indulgence in the aberrant behaviors leads to inactivation of the brain reward cas (...truncated)