Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): A commentary
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.
[Show abstract] [Hide abstract] ABSTRACT: The mesolimbic dopamine (DA) system plays a key role in drug reinforcement and is involved in the development of alcohol addiction. Manipulation of the DAergic system represents a promising strategy to control drug-seeking behavior. Previous studies on 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) showed in vivo effects as a DA-ergic modulator. This study was aimed at investigate DA-Phen effects on operant behavior for alcohol seeking behavior, during reinstatement following subsequent periods of alcohol deprivation. For this purpose, male Wistar rats were tested in an operant paradigm of self-administration; behavioral reactivity and anxiety like-behavior during acute abstinence were evaluated. A characterization of DA-Phen CNS targeting by its quantification in the brain was also carried out. Our findings showed that DA-Phen administration was able to reduce relapse in alcohol drinking by 50% and reversed the alterations in behavioral reactivity and emotionality observed during acute abstinence. In conclusion, DA-Phen can reduce reinstatement of alcohol drinking in an operant-drinking paradigm following deprivation periods and reverse abstinence-induced behavioral phenotype. DA-Phen activity seems to be mediated by the modulation of the DAergic transmission. However further studies are needed to characterize DA-Phen pharmacodynamic and pharmacokinetic properties, and its potential therapeutic profile in alcohol addiction.0Comments 0Citations
- "In turn, the increased glutamatergic transmission modulates dopaminergic cell activity in rewarding processes, leading to alcohol addiction. [1, 9,DA-Phen could play a critical role for alcohol-induced reinstatement, probably due to DA-ergic inputs within the basolateral amygdala complex or acting on VTA DA-receptors, so suppressing alcohol seeking [1, 17]. Furthermore, our results agree with findings from other studies on drug-induced reinstatement, like cocaine or morphine, in which D1-like agonists do not generate or promote additive effects, further supporting the use of DA-agonists in treatment of addiction . "
[Show abstract] [Hide abstract] ABSTRACT: There is a growing interest in the study of psychopathic traits from an evolutionary framework; however, there is a lack of comprehensive reviews regarding this issue. To address this gap in the literature, the current paper examines the evolutionary roots of psychopathy by reviewing previous research on this topic. Specifically, the potentially adaptive role of psychopathic traits during human evolution through the lifespan is highlighted. Key areas covered include the evolution of the brain (“old brain, new brain” and the emotion-logic lag), emotion regulation, aggression and its potential adaptive function, and emotions specific to psychopathy including anger and shame/dishonor. This paper (mainly in the light of the Adaptive Calibration Model) discusses how psychopathic features can be seen as a useful heritage, especially for people who have grown in harsh psychosocial backgrounds. The implications of an evolutionary approach for the comprehension and treatment of children, youth, and adults with psychopathic traits are suggested, along with directions for future research.0Comments 4Citations
- "However, an impairment of the mechanisms involved in these natural processes (e.g., a genetic hypodopaminergic activity of the brain) predisposes individuals to seek artificial stimulants and/or pleasure-seeking behaviors that will overcome this hedonic state by triggering dopaminergic centers, creating an artificial state of pleasure (Blum et al., 2008; Esch & Stefano, 2004). The chronic abuse of substances or the systematic display of thrill seeking behaviors can be seriously detrimental, and according to some researchers may lead to the inactivation of the brain reward system -Reward Deficiency Syndrome (Blum et al., 2008; Blum et al., 2012; Esch & Stefano, 2004). When balanced with the other systems, the drive system is a clearly advantage, guiding us toward important life goals (Depue & Morrone-Strupinsky, 2005; Gilbert, 2005 Gilbert, , 2010). "
[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.0Comments 4Citations
- "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. "
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