Mesolimbic Reward Circuitry and Reward Deficiency Syndrome (RDS): A Commentary on Long Term Dopaminergic Therapy

Abstract

The brain reward circuitry located in the mesolimbic system of the brain regulates our emotional behaviors. It is well know that certain neurotransmitter pathways are involved in maintain homeostatic conditions which dictate normal physiology of reward and associated behaviors (motivation for food, drink and sex). Our laboratory and others have provided? preclinical and clinical evidence that a number of genes? associate with impulsive, compulsive and addictive behaviors.? We have defined these behaviors as having common genetic antecedents? and coined the? term Reward Deficiency Syndrome (RDS). Numerous peer-reviewed studies have now provided evidence that impairment of dopaminergic among other neurotransmitter pathways induce RDFS behaviors. The treatment, however, has been confounded by certain myths and has resulted in failure. We are suggesting a newer and more appropriate approach? as discussed herein. 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 abundant 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.? 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. The authors propose that D2 receptor stimulation can be accomplished via Haveos augmentation, a natural but therapeutic nutraceutical formulation that 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 RDS behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. While we are cognizant that there are potentially over 395 genes that associate with addictive behavior, we are confident that activation of dopaminergic? pathways provide the best approach as we know it to date.