Article

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

Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA .
Theoretical Biology and Medical Modelling (Impact Factor: 1.27). 12/2008; 5:24. DOI: 10.1186/1742-4682-5-24
Source: PubMed

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.

Download full-text

Full-text

Available from: Kenneth Blum, Jul 28, 2015
0 Followers
 · 
238 Views
  • Source
    • "Nicotine replacement therapies were the first pharmacological treatments approved by the Food and Drug Administration (FDA) for use in smoking cessation therapy, followed by bupropion and varenicline. Even if the effectiveness of nicotine replacement therapies, bupropion and varenicline appear to be high (Blum et al., 2008), doubling or tripling the smoking cessation rates in controlled studies (Le Foll and George, 2007), the real impact of these therapies has been questioned due to high rates of relapse in the long term (Alpert et al., 2013). There may be multiple reasons explaining those discrepancies such as the fact that clinical trial inclusion criteria do not always allow for generalization of results to the overall population of smokers. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tobacco produces an impressive burden of disease resulting in premature death in half of users. Despite effective smoking cessation medications (nicotine replacement therapies, bupropion and varenicline), there is a very high rate of relapse following quit attempts. The use of efficient strategies for the development of novel treatments is a necessity. A 'bench to bedside strategy' was initially used to develop cannabinoid CB1 receptor antagonists for the treatment of nicotine addiction. Unfortunately, after being tested on experimental animals, what seemed to be an interesting approach for the treatment of nicotine addiction resulted in serious unwanted side effects when tested in humans. Current research is focusing again on pre-clinical models in an effort to eliminate unwanted side effects while preserving the initially observed efficacy. A 'bed side to bench strategy' was used to study the role of the insula (part of the frontal cortex) in nicotine addiction. This line of research started based on clinical observations that patients suffering stroke-induced lesions to the insula showed a greater likelihood to report immediate smoking cessation without craving or relapse. Subsequently, animal models of addiction are used to explore the role of insula in addiction. Due to the inherent limitations existing in clinical versus preclinical studies, the possibility of close interaction between both models seems to be critical for the successful development of novel therapeutic strategies for nicotine dependence.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 10/2013; 52. DOI:10.1016/j.pnpbp.2013.10.009 · 4.03 Impact Factor
  • Source
    • "In summary, the DA system modulates the aspects of learning, reward and motivation (Hyman, 2005; Wise, 1998) and chronic drug use leads to a decrease in postsynaptic DA receptor availability. Therefore, increasing DA receptor availability is a potential treatment strategy for drug dependence (Blum et al., 2008; Nader et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug dependence is a chronic brain disease characterized by recurrent episodes of relapse, even when the person is motivated to quit. Relapse is a major problem and new pharmacotherapies are needed to prevent relapse episodes. The nicotinic acetylcholine receptor (nAChR) plays an important role in nicotine dependence, alcohol consumption and cue-induced cocaine craving. Stimulation of the nAChR has been found to alter and modulate cell firing in brain areas important for the maintenance of drug dependence. Varenicline, an alpha4beta2 nAChR partial agonist and an alpha7 nAChR full agonist registered for the treatment of nicotine dependence, significantly reduces nicotine craving and prevents relapse. In addition, varenicline reduces alcohol consumption in rats. Based on a review of the available literature, we hypothesize a potential role for varenicline in the prevention of relapse in patients recovering from drug dependence other than nicotine dependence.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 12/2009; 20(2):69-79. DOI:10.1016/j.euroneuro.2009.11.001 · 5.40 Impact Factor
  • Source
    • "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 [1]. 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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic mediated physiological processes that rely on both pharmacological and nutritional principles hold great promise for the successful therapeutic targeting of reduced carbohydrate craving, body-friendly fat loss, healthy body recomposition, and overall wellness. By integrating an assembly of scientific knowledge on inheritable characteristics and environmental mediators of gene expression, we review the relationship of genes, hormones, neurotransmitters, and nutrients as they correct unwanted weight gain coupled with unhappiness. In contrast to a simple one-locus, one-mechanism focus on pharmaceuticals alone, we hypothesize that the use of nutrigenomic treatment targeting multi-physiological neurological, immunological, and metabolic pathways will enable clinicians to intercede in the process of lipogenesis by promoting lipolysis while attenuating aberrant glucose cravings. In turn, this approach will enhance wellness in a safe and predictable manner through the use of a Genetic Positioning System (GPS) Map. The GPS Map, while presently incomplete, ultimately will serve not only as a blueprint for personalized medicine in the treatment of obesity, but also for the development of strategies for reducing many harmful addictive behaviors and promoting optimal health by using substances compatible with the body's immune system.
    Medical Hypotheses 06/2009; 73(3):427-34. DOI:10.1016/j.mehy.2009.02.037 · 1.07 Impact Factor
Show more