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: 0.95). 12/2008; 5(1):24. DOI: 10.1186/1742-4682-5-24
Source: PubMed


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


Available from: Kenneth Blum,
  • 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 · 3.69 Impact Factor
  • Source
    • "For example, only DAT/SERT knockout mice exhibit impairment of cocaine CPP [37] and the contribution of DA, 5-HT, and NA transporters to the rewarding, and aversive effects of cocaine seem to vary [34]. Activation of the mesolimbic dopaminergic reward circuitry has been proposed as a modality in the long-term treatment of reward deficiency syndrome and drug addiction disorders [38]. In addition to the abovementioned dose problem, the fact that RHO impairs acquisition or expression of cocaine CPP only at specific doses could be related to the effects that this compound induces monoamines (DA, 5-HT, and NA) and different kinds of monoaminergic precursors, receptors, transporters, or degradation enzymes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel approach to the treatment of adverse effects of drugs of abuse is one which makes use of natural products. The present study investigated the effect of Rhodiola rosea L. hydroalcoholic extract (RHO) on cocaine-induced hyperactivity and conditioned place preference (CPP) in mice. In a first experiment, mice received RHO (15, 20 or 25 mg/kg, IG), cocaine (25 mg/kg, i.p.) (COC), or a combination of both drugs (COC + RHO15, COC + RHO20, and COC + RHO25), and their locomotor activity was evaluated. In a second experiment, the effects of RHO on the acquisition, expression, and reinstatement of cocaine CPP (induced by drug priming or social defeat stress) were evaluated. RHO alone did not increase activity but potentiated the hyperactivity induced by cocaine. Rhodiola did not induce motivational effects by itself but attenuated the acquisition and expression of cocaine-induced CPP. Moreover, it was found that RHO did not block reinstatement. The results indicate that RHO is effective in reducing the rewarding properties of cocaine but is ineffective in preventing priming or stress-induced cocaine reinstatement. In light of these findings, the benefits of Rhodiola rosea L. as a treatment of cocaine addiction would seem to be limited.
    Evidence-based Complementary and Alternative Medicine 09/2013; 2013:697632. DOI:10.1155/2013/697632 · 1.88 Impact Factor
  • Source
    • "In addition, there is considerable evidence in the obese for decreased signaling through the mesolimbic dopamine/D2-receptor system both in rodents (43–49) and humans (50–55), thought to play a pivotal role in both the motivational (‘wanting’) and reinforcement learning component of food and drug reward (56, 57). The incongruity between decreased signaling through this system on one hand and the fact that activation of the system is driving overindulgence leading to obesity on the other hand (51, 57) has been explained by the reward-deficit hypothesis (55, 58, 59). With regard to food reward, this hypothesis suggests that individuals with low dopamine signaling make up by engaging in more eating, thereby restoring a set point for reward generation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Roux-en-Y gastric bypass surgery (RYGB) is currently the most effective treatment for morbid obesity, and clinical studies suggest that RYGB patients change food preferences and the desire to eat. To examine hedonic reactions to palatable foods and food choice behavior in an established rat model of RYGB. Male Sprague-Dawley (SD) rats and selected line obesity-prone rats that were rendered obese on a high-fat diet underwent RYGB or sham surgery and were tested for 'liking' and 'wanting' of palatable foods at different caloric densities 4-6 months after surgery. Compared with sham-operated (obese) and age-matched lean control rats, RYGB rats of both models exhibited more positive orofacial responses to low concentrations of sucrose but fewer to high concentrations. These changes in 'liking' by RYGB rats were translated into a shift of the concentration-response curve in the brief access test, with more vigorous licking of low concentrations of sucrose and corn oil, but less licking of the highest concentrations. The changes in hedonic evaluation also resulted in lower long-term preference/acceptance of high-fat diets compared with sham-operated (obese) rats. Furthermore, the reduced 'wanting' of a palatable reward in the incentive runway seen in sham-operated obese SD rats was fully restored after RYGB to the level found in lean control rats. The results suggest that RYGB leads to a shift in hedonic evaluation, favoring low over high calorie foods and restores obesity-induced alterations in 'liking' and 'wanting'. It remains to be determined whether these effects are simply due to weight loss or specific changes in gut-brain communication. Given the emerging evidence for modulation of cortico-limbic brain structures involved in reward mechanisms by gut hormones, RYGB-induced changes in the secretion of these hormones could potentially be mediating these effects.
    International journal of obesity (2005) 05/2011; 35(5):642-51. DOI:10.1038/ijo.2010.174 · 5.00 Impact Factor
Show more