Hypothesizing that, A Pro-Dopamine Regulator (KB220Z) Should Optimize, but Not Hyper-Activate the Activity of Trace Amine-Associated Receptor 1 (TAAR-1) and Induce Anti-Craving of Psychostimulants in the Long-Term.

Kenneth Blum,Zsolt Demetrovics,Peter Thanos,Mona Li,Marcelo Febo,Kristina Dushaj,Eric Braverman,Rajendra Badgaiyan

doi:10.17756/jrdsas.2016-023

Abstract

Unlike other drugs of abuse such as alcohol, nicotine, opiates/opioids, the FDA has not approved any agent to treat psychostimulant dependence. Certainly, it is widely acceptable that dopaminergic signaling is a key factor in both the initiation and continued motivation to abuse this class of stimulant substances. It is also well accepted that psychostimulants such as cocaine affect not only the release of neuronal dopamine at the nucleus accumbens (NAc), but also has powerful inhibitory actions on the dopamine transporter system. Understandably, certain individuals are at high risk and very vulnerable to abuse this class of substances. Trace-amine-associated receptor 1 (TAAR1) is a G -protein coupled receptor activated by trace amines. The encoded protein responds little or not at all to dopamine, serotonin, epinephrine, or histamine, but responds well to beta-phenylethylamine, p-tyramine, octopamine, and tryptamine. This gene is thought to be intronless. TAAR1 agonists reduce the neurochemical effects of cocaine and amphetamines as well as attenuate addiction and abuse associated with these two psychostimulants. The mechanism involves blocking the firing rate of dopamine in the limbic system thereby decreasing a hyperdopaminergic trait/state, whereby the opposite is true for TAAR1 antagonists. Based on many studies, it is accepted that in Reward Deficiency Syndrome (RDS), there is weakened tonic and improved phasic dopamine discharge leading to a hypodopaminergic/glutamatergic trait. The dopamine pro-complex mixture KB220, following many clinical trials including neuroimaging studies, has been shown to enhance resting state functional connectivity in humans (abstinent heroin addicts), naïve rodent models, and regulates extensive theta action in the cingulate gyrus of abstinent psychostimulant abusers. In this article, we are hypothesizing that KB220 may induce its action on resting state functional connectivity, for example, by actually balancing (optimizing) the effects of TAAR1 on the glutamatergic system allowing for optimization of this system. This will lead to a normalized and homeostatic release of NAc dopamine. This proposed optimization, and not enhanced activation of TAAR1, should lead to well-being of the individual. Hyper-activation instead of optimizing the TAAR1 system unfortunately will lead to a prolonged hypodopaminergic state and as such, will cause enhanced craving for not only psychoactive substances, but also other drug-related and even non-drug related RDS behaviors. This hypothesis will require extensive research, which seems warranted based on the global epidemic of drug and behavioral addictions.

Highlights

Borowsky et al [1] identified the trace-amine-associated receptor 1 (TAAR1)
In unpublished work, we have examined the effects of a DA precursor complex (KB220Z a pro–dopamine complex regulator) on functional connectivity and have observed that there is a significant increase in functional connectivity strength in the PFC and nucleus accumbens (NAc) of rats (Figure 1)
While these reviewed data are noteworthy because they examined the concept that pharmacologically regulating trace amine associated receptor (TAAR) 1 can decrease cocaine addiction utilizing animal representations with suitable translational and predictive scores, we are proposing that TAAR1 agonists may be beneficial only in the short–term, but should not be utilized in longterm treatment in humans due to interference with natural dopaminergic regulation

Summary

Introduction

Borowsky et al [1] identified the trace-amine-associated receptor 1 (TAAR1). Trace-amineassociated receptor 1 (TAAR1) is a G -protein coupled receptor activated by trace amines. Dopamine homeostasis treatment strategies, like dopamine agonist therapy, along with glutamatergic optimization using NAC may maintain dopamine function, which seems to be a fascinating method to relapse prevention in psychoactive drug and behavioral addictions It is well-known that the central nervous system (CNS) rewarding properties of ethanol, cocaine, and heroin may activate a common catechoaminegic (primary Dopamine) reward system in the mesolimbic circuitry of the brain. It was discovered that TAAR 1 agonists exhibit extremely encouraging antipsychotic-like outcomes in preclinical studies and show excellent therapeutic profiles than current antipsychotics because they subdue feeding and reduce body weight in animals; lacking the main unfavorable effect of weight gain as seen when taking some antipsychotics These data align with the view that TAAR 1 agonists could functionally regulate the dopaminergic system and it is an expected hypothesis that these compounds may modify stimulant abuse. While additional work is required in this fruitful area of research and understanding that that SP/NK1 receptor system is involved in processing of positive incentive anticipation and plays a role in accentuating positive valence in association with the primary dopaminergic pathways in the reward circuit, any definitive conclusions of our hypothesis and even other endogenous systems linked to appropriate psychostimulant therapy must await additional scientific evidence [60]

Our hypothesis and conclusion

Findings

Funding Sources