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.
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.
Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, PO Box 100256, 1149 Newell Dr, L4-100, Gainesville, FL 32611, USA; Division of Applied Clinical Research and Education, Dominion Diagnostics, LLC., 211 Circuit Dr, North Kingstown, RI 02852, USA; Division of Neuroscience-Based Therapy, Summit Estate Recovery Center, 399 Old Mill Pond Rd, Los Gatos, CA 95033, USA; Division of Clinical Neurology, PATH Foundation NY, 304 Park Ave South, Floor 6, New York, NY 10010, USA; Division of Nutrigenomics, LaVita RDS, 1878 W 12800S, Ste 314, Averton, UT 84085, USA; Department of Psychiatry & Behavioral Sciences, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; Division of Neuroscience Research & Addiction Therapy, Shores Recovery & Treatment Center, Port Saint Louie, FL 34952, USA; Department of Clinical Psychology and Addiction, Eötvös Loránd University, 1064 Budapest, Izabella Street 46, Hungary.
Kenneth
K
Blum
Department of Psychiatry and Neuroimaging, University of Minnesota, F282/2A West, 2450 Riverside Avenue South, Minneapolis, MN 55454, USA.
Rajendra D
RD
Badgaiyan
Division of Clinical Neurology, PATH Foundation NY, 304 Park Ave South, Floor 6, New York, NY 10010, USA.
Eric R
ER
Braverman
Division of Clinical Neurology, PATH Foundation NY, 304 Park Ave South, Floor 6, New York, NY 10010, USA.
Kristina
K
Dushaj
Division of Clinical Neurology, PATH Foundation NY, 304 Park Ave South, Floor 6, New York, NY 10010, USA.
Mona
M
Li
Research Institute on Addictions, University of Buffalo, 1021 Main Street, Buffalo, NY 14203, USA.
Peter K
PK
Thanos
Department of Clinical Psychology and Addiction, Eötvös Loránd University, 1064 Budapest, Izabella Street 46, Hungary.
Zsolt
Z
Demetrovics
Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, PO Box 100256, 1149 Newell Dr, L4-100, Gainesville, FL 32611, USA.
Marcelo
M
Febo
Dopamine homeostasis; Glutamatergic activity; KB220Z; R05166017 (TAAR1 agonist); Reward Deficiency Syndrome (RDS); Trace amine-associated receptor 1 (TAAR-1)