Bath Salts: abuse-related and toxic effects

项目摘要/摘要 “特制毒品”于2009年初进入美国娱乐毒品市场。到2011年，“浴盐，” 最常见的是合成卡西诺酮和其他药物的混合物，如咖啡因，被与许多媒体联系在一起 奇怪和暴力行为的报告，占急诊室就诊的2万多人次。在近10年里 自推出以来，可供使用的合成卡西酮的数量已从3种(MDPV， 甲基酮和甲氧麻黄酮)增加到140以上。根据我们实验室和其他实验室的工作，我们现在知道加固 卡西酮的影响是连续存在的，而甲酮等药物的作用相对较弱。 (可卡因和甲酮)，以及诸如mdpv和α-pvp这样的药物，它们是非常强大的增强剂，能够 保持比可卡因或甲基苯丙胺更强的反应水平。除了证据之外，还有 表明可卡因的增强效果与合成卡西酮类药物，如mdpv和α-pvp有直接关系。 由于它们对DAT的选择性高于SERT，我们的实验室还表明，这些增强(和毒性)效应可能是 当MDPV和甲酮等药物与其他药物联合使用时，协同作用增强 盐“成分，如咖啡因。 在过去的5年里，我们学到了许多关于人工合成的药理和滥用相关的影响。 卡西诺酮；然而，在这段时间里，合成毒品市场和娱乐毒品使用的景观更多 总的来说，已经发生了戏剧性的变化。2013年，海洛因开始取代处方阿片类药物，成为阿片类药物使用者的药物 选择；到2014年，合成阿片类药物，主要是芬太尼，已经充斥市场。这些变化发生的同时， 与阿片类药物有关的死亡发生率，从2013年的约25,000例增加到2017年的47,000例，其中一半以上(约28,000例)是 与合成阿片类药物有关，如芬太尼。在此期间，与兴奋剂(如可卡因、 甲基苯丙胺和合成卡西酮)，从#年的不到10,000增加了一倍多 2013年，到2017年超过24,000人。此外，越来越明显的是，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，美国正处于多种药物滥用的流行之中，其影响正在以越来越大的速度增加 指数率。本研究的目的是：1)确定α-PVP自主给药的影响。 青春期对强迫性吸食药物的发展和对阿片类药物滥用的易感性；2)特征 与滥用有关的兴奋剂和阿片类药物的毒性作用之间的相互作用；以及3)检查 哪些阿片类药物依赖和戒断影响与滥用相关和中毒之间的相互作用的性质 兴奋剂和阿片类药物混合的影响。总之，这些研究将提供有关 与联合使用来自不同药理类别的多种物质相关的复杂性 努力开发新的、有效的治疗与滥用有关的治疗方法和多物质滥用的毒性影响。

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.