Dissecting the Abuse Liability of Synthetic Cathinone Stimulants

合成精神活性卡西酮药物（“浴盐”）的使用在全世界继续扩大 在美国，尽管国际上采取了法律的控制措施，但在美国联邦 在美国多个州，甚至美国地方司法管辖区内。现有的兴奋剂，如 由于可卡因和甲基苯丙胺具有高度成瘾性，可能是急性致命的，并可能导致长期- 长期的大脑改变对健康和福祉有许多影响。最近的研究表明，3，4- 亚甲二氧基吡咯戊酮（MDPV）是一种高度有效的兴奋剂，可预测滥用 责任等于或大于可卡因和甲基苯丙胺。化合物如 甲基异黄酮和甲基异黄酮产生类似于3，4-二甲基异黄酮的主观性质。 亚甲二氧基甲基安非他明（MDMA），但表现出更大的倾向， 用于人类报告和啮齿动物自我给药研究。该项目响应的目标 PAR-14-106合成精神活性药物及其有害的战略对策 通过确定合成卡西酮成瘾倾向的结构决定因素的影响。 卡西酮结构的巨大多样性存在于娱乐市场，部分原因是法律的 控制较早出现的药物。这一现实要求采取既能促进 了解目前流行的药物的作用，并产生更好的预测， 其设计基序可能在新兴化合物中传达增加的滥用倾向。为此， 目标I和目标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，以加强效力和功效， 卡西酮。MDPV的一个显著特征是延长的碳链，其赋予增强的 亲脂性目的III的目的是确定是否兴奋剂药物在静脉自我- 给药受到亲脂性的影响，亲脂性影响脑进入的速度。总的来说，这些建议 对各种合成卡西酮的增强作用的研究将促进我们对 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.