Dissecting the Abuse Liability of Synthetic Cathinone Stimulants

合成精神活性卡西诺酮药物(“浴盐”)的使用在世界范围内继续扩大。 在美利坚合众国，尽管在国际上做出了法律控制努力，在美国联邦 在美国多个州，甚至是美国当地司法管辖区内。已有的兴奋剂，如 由于可卡因和甲基苯丙胺高度上瘾，可能是急性致命的，并可能导致长期- 术语大脑改变对健康和福祉有许多影响。最近的研究表明，3，4- 亚甲基二氧基吡咯丙酮(MDPV)是一种高效的增强剂，可预测滥用情况 相当于或大于可卡因和甲基苯丙胺的责任。复合词，如 甲氧麻黄酮和甲基酮产生的主观性质类似于3，4- 亚甲基二氧基甲基苯丙胺(MDMA)，但表现出更大的强迫倾向 在人类报告和啮齿动物自我管理研究中使用。该项目响应了 PAR-14-106合成精神活性药物及其危害性应对策略 通过确定合成卡西酮成瘾倾向的结构决定因素的影响。 娱乐市场中存在着卡西酮结构的巨大多样性，这在一定程度上是由法律驱动的。 对较早出现的毒品的控制。这一现实要求采取既能推进 了解当前流行药物的作用，并产生更好的预测 哪些设计主题可能会在新兴化合物中传达更多的滥用倾向。为此， AIM I和AIM II下的研究将阐明3，4-亚甲二氧基和4-亚甲基二氧基的贡献。 甲基芳环取代分别对增强效果和效果的影响 卡西诺酮。MDPV的一个显著特征是具有延长的碳链，从而增强了 亲油性。目标三的目标是确定刺激性药物在静脉注射中的疗效。 给药受到亲脂性的影响，这会影响大脑进入的速度。总的来说，这些建议 研究各种合成卡西酮的增强作用将有助于我们更好地理解 与特制兴奋剂相关的健康风险。

The use of synthetic psychoactive cathinone drugs (“bathsalts”) continues to expand worldwide and in the United States of America despite legal control efforts internationally, at the US federal level, within multiple US states and even the local US jurisdictions. The established stimulants such as cocaine and methamphetamine are highly addictive, can be acutely lethal and can result in long- term brain alterations with many implications for health and well-being. Recent studies show that 3,4- methylenedioxypyrovalerone (MDPV) is a highly potent and efficacious reinforcer, predicting abuse liability equal to or greater than that of cocaine and methamphetamine. Compounds such as Mephedrone and Methylone produce subjective properties that are similar to 3,4- methylenedioxymethamphetamine (MDMA) but have exhibit much greater propensity for compulsive use in human report and rodent self-administration studies. This project responds to the goals of PAR-14-106 Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects by determining structural determinants of the addiction liability of synthetic cathinones. Tremendous diversity of cathinone structure exists in the recreational market, driven in part by legal control of earlier-appearing drugs. This reality demands approaches which can both advance understanding of the actions of currently popular drugs and generate better predictions regarding which design motifs may convey increased abuse liability in emerging compounds. To that end, studies under Aim I and Aim II will elucidate the contributions of the 3,4-methylenedioxy and 4- methyl aromatic ring substitutions, respectively, to the reinforcement potency and efficacy of cathinones. One distinct feature of MDPV is an extended carbon chain which confers enhanced lipophilicity. The goal of Aim III is to determine if stimulant drug efficacy in intravenous self- administration is affected by lipophilicity, which affects speed of brain entry. In total, these proposed studies on the reinforcing effects of various synthetic cathinones will advance our understanding of the health risks associated with designer stimulant drugs.