Bath Salts: abuse-related and toxic effects

项目总结/摘要 2009年初，“设计师毒品”突然出现在美国娱乐毒品市场。到2011年，“浴盐”， 这些药物通常是合成卡西酮和其他药物如咖啡因的混合物， 奇怪和暴力行为的报告，并占超过20,000急诊室就诊。在近10 自从它们被引入以来，可供使用的合成卡西酮的数量已经从3种（MDPV， 甲氧麻黄酮和甲氧麻黄酮）增加到140以上。根据我们实验室和其他人的工作，我们现在知道， 卡西酮的作用存在于一个连续体中，诸如甲酮之类的药物作为相对温和的促排剂发挥作用 （可卡因>甲酮），以及MDPV和α-PVP等药物作为非常强大的药物， 保持比可卡因或甲基苯丙胺更高的反应水平。除了证据， 表明可卡因和合成卡西酮如MDPV和α-PVP的增强效果直接相关， 我们的实验室还表明，这些增强（和毒性）效应可能是 当药物如MDPV和甲酮与其它“浴”组合施用时， 盐的成分，如咖啡因。 在过去的5年里，我们已经了解了大量的药理学和滥用相关的影响， 卡西酮;然而，与此同时，合成药物市场和娱乐性药物使用的情况更多 发生了巨大的变化2013年，海洛因开始取代处方阿片类药物作为阿片类药物使用者的药物， 选择;到2014年，合成类阿片，主要是芬太尼，充斥市场。这些变化与一个加倍的 阿片类药物相关死亡的发生率从2013年的约25，000人增加到2017年的> 47，000人，其中一半以上（约28，000人）是 与合成阿片类药物如芬太尼有关在同一时间，与兴奋剂有关的过量死亡（例如，可卡因， 甲基苯丙胺和合成卡西酮），在同一时间内从不到10，000人增加了一倍多。 2013年，到2017年超过24，000。此外，越来越清楚的是，这两种现象并没有发生在 隔离，约50%的阿片类药物相关死亡涉及兴奋剂，约50%的兴奋剂相关死亡也涉及 阿片类药物。因此，美国正处于一个多物质滥用流行病，其影响正在增加， 指数速率本研究项目旨在：1）确定α-PVP自我给药在 青春期对强迫性吸毒的发展和以后生活中对阿片类药物滥用的脆弱性的影响; 2）表征 兴奋剂和阿片类药物的滥用相关作用和毒性作用之间的相互作用;以及3）检查 阿片类药物依赖和戒断影响滥用相关和毒性之间相互作用的性质 兴奋剂和类阿片混合物的影响。总之，这些研究将提供有关 与来自不同药理学类别的多种物质的共同使用相关的复杂性， 努力开发新的和有效的治疗方法，以治疗与滥用有关的多种物质滥用的毒性作用。

PROJECT SUMMARY/ABSTRACT “Designer drugs” burst onto the United States (US) recreational drug market in early 2009. By 2011, “bath salts,” which are most often mixtures of synthetic cathinones and other drugs such as caffeine, were linked to numerous press reports of bizarre and violent behavior, and accounted for well over 20,000 emergency room visits. Over the nearly 10 years since their introduction, the number of synthetic cathinones available for use has grown from 3 (MDPV, methylone, and mephedrone) to over 140. Based on work from our lab and others, we now know that the reinforcing effects of cathinones exist on a continuum, with drugs such as methylone functioning as relatively modest reinforcers (cocaine>methylone), and drugs such as MDPV, and α-PVP functioning as exceptionally powerful reinforcers capable of maintaining significantly greater levels of responding than either cocaine or methamphetamine. In addition evidence to show that the reinforcing effectiveness of cocaine and synthetic cathinones, such as MDPV and α-PVP, is directly related to their selectivity for DAT over SERT, our laboratory has also shown that these reinforcing (and toxic) effects can be synergistically enhanced when drugs such as MDPV and methylone are administered in combination with other “bath salts” constituents, such as caffeine. In the last 5 years, we have learned a great deal about the pharmacology and abuse-related effects of synthetic cathinones; however, over this same time the synthetic drug market and the landscape of recreational drug use more broadly have changed dramatically. In 2013, heroin began to supplant prescription opioids as opioid users’ drug of choice; by 2014, synthetic opioids, mainly fentanyl, had flooded the market. These changes coincided with a doubling of the incidence of opioid-related deaths, from ~25,000 in 2013 to >47,000 in 2017, over half of which (~28,000) were linked to synthetic opioids, such as fentanyl. Over this same time, overdose deaths related to stimulants (e.g., cocaine, methamphetamine and synthetic cathinones), have more than doubled over the same time from fewer than 10,000 in 2013, to over 24,000 in 2017. Moreover, it is becoming increasingly clear that these two phenomena are not occurring in isolation, with ~50% of opioid-related deaths involving stimulants, and ~50% of stimulant-related deaths also involving opioids. Thus, the US is in the midst of a polysubstance abuse epidemic, the effects of which are increasing at an exponential rate. This research project aims to 1) determine the impact of self-administration of α-PVP during adolescence on the development of compulsive drug taking and vulnerability to opioid abuse later in life; 2) characterize the interactions between the abuse-related and toxic effects of stimulants and opioids; and 3) examine the degree to which opioid dependence and withdrawal impact the nature of the interactions between the abuse-related and toxic effects of mixtures of stimulants and opioids. Together, these studies will provide essential information about the complexities associated with the co-use of multiple substances from different pharmacological classes that will advance efforts to develop novel and effective treatments for abuse-related and toxic effects of polysubstance abuse.