Blum Kenneth, Badgaiyan Rajendra D, Braverman Eric R, Dushaj Kristina, Li Mona, Thanos Peter K, Demetrovics Zsolt, Febo Marcelo
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.
Department of Psychiatry and Neuroimaging, University of Minnesota, F282/2A West, 2450 Riverside Avenue South, Minneapolis, MN 55454, USA.
J Reward Defic Syndr Addict Sci. 2016;2(1):14-21. doi: 10.17756/jrdsas.2016-023. Epub 2016 Jun 29.
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.
与酒精、尼古丁、阿片类药物等其他滥用药物不同，美国食品药品监督管理局（FDA）尚未批准任何药物用于治疗精神兴奋剂成瘾。多巴胺能信号传导无疑是滥用这类兴奋剂物质的起始及持续动机中的关键因素，这一点已被广泛认可。同样被广泛接受的是，可卡因等精神兴奋剂不仅会影响伏隔核（NAc）中神经元多巴胺的释放，还对多巴胺转运体系统具有强大的抑制作用。可以理解的是，某些个体极易滥用这类物质。痕量胺相关受体1（TAAR1）是一种由痕量胺激活的G蛋白偶联受体。该编码蛋白对多巴胺、5-羟色胺、肾上腺素或组胺几乎没有反应或完全无反应，但对β-苯乙胺、对-酪胺、章鱼胺和色胺反应良好。该基因被认为没有内含子。TAAR1激动剂可降低可卡因和苯丙胺的神经化学作用，并减轻与这两种精神兴奋剂相关的成瘾和滥用行为。其机制包括阻断边缘系统中多巴胺的发放率，从而降低多巴胺能亢进特征/状态，而TAAR1拮抗剂的作用则相反。基于多项研究，人们认为在奖赏缺乏综合征（RDS）中，紧张性多巴胺释放减弱而相位性多巴胺释放增强，导致多巴胺能/谷氨酸能减退特征。经过包括神经影像学研究在内的多项临床试验，多巴胺前体复合物KB220已被证明可增强人类（戒除海洛因成瘾者）、未经处理的啮齿动物模型静息态功能连接，并调节戒除精神兴奋剂滥用者扣带回中的广泛θ波活动。在本文中，我们假设KB220可能通过实际平衡（优化）TAAR1对谷氨酸能系统的作用来诱导其对静息态功能连接的作用，从而实现该系统的优化。这将导致NAc多巴胺的正常化和稳态释放。这种提出的优化而非TAAR1的增强激活，应会使个体状态良好。不幸的是，过度激活而非优化TAAR1系统将导致多巴胺能减退状态延长，因此不仅会导致对精神活性物质的渴望增强，还会导致对其他与药物相关甚至非药物相关的RDS行为的渴望增强。这一假设需要大量研究，鉴于全球范围内的药物和行为成瘾流行情况，这一研究似乎是必要的。
