Bath salts: abuse-related and toxic effects

 描述(由申请人提供)：在过去的5年里，合成卡西酮(如MDPV和甲酮)的滥用急剧增加，这些合成卡西酮被称为“浴盐”，可以在互联网上和当地商店广泛购买，被称为“安全的”和“合法的高点”。除了滥用的可能性很高外，“浴盐”也有很高的毒性，其特征是严重的心血管和神经精神并发症。尽管造成这种高滥用和毒性的机制目前尚不清楚，但必须指出的是，“浴盐”通常是多种精神活性药物的混合物，包括两种不同的合成卡西尼酮的混合物，或合成卡西尼酮和咖啡因的混合物。这项建议由三个独立的目标组成，重点是比较“浴盐”混合物(MDPV甲酮、MDPV咖啡因和甲酮咖啡因)与单独合成卡西酮(MDPV和甲酮)的强化效果、复发相关行为和毒性影响。该项目将成熟的滥用(自我给药)和毒性(心血管记录)动物模型与等位基因分析相结合，以评估极具创新性的假说，即常见的“浴盐”混合物有(1)比单独合成卡西酮更有效力和效力的增强剂；(2)比单独合成卡西酮更有效地加强与复发有关的药物刺激的联系；(3)在造成心动过速和高血压以及“浴盐”毒素的其他特征方面比单独合成卡西尼酮更有效。综上所述，拟议研究的结果将提供有关导致“浴盐”滥用和毒性高的因素的基本信息。这一新知识将指导针对不断增加和不断演变的“浴盐”滥用问题开发新的和有针对性的治疗方法。

 DESCRIPTION (provided by applicant): The past 5 years have seen a dramatic increase in the abuse of synthetic cathinones (e.g., MDPV and methylone), which are marketed as "bath salts," and are widely available for purchase on the internet and in local shops as "safe" and "legal highs." In addition to a high potential for abuse, "bath salts" also have a high potential fr toxicity, characterized by severe cardiovascular and neuropsychiatric complications. Although the mechanisms that contribute to these high rates of abuse and toxicity are currently unclear, it is important to note that "bath salts" are most often mixtures of multiple psychoactive drugs, including mixtures of two different synthetic cathinones, or mixtures of a synthetic cathinone and caffeine. This proposal consists of three independent aims focused on comparing the reinforcing effectiveness, relapse-related behaviors, and toxic effects of "bath salts" mixtures (MDPV + methylone, MDPV + caffeine, and methylone + caffeine) with those of synthetic cathinones alone (MDPV and methylone). This project combines well-established animal models of abuse (self-administration) and toxicity (cardiovascular recordings) with isobolographic analysis to evaluate the highly innovative hypotheses that common "bath salts" mixtures are (1) more potent and effective reinforcers than synthetic cathinones alone; (2) more effective at strengthening drug-stimuli associations involved in relapse than synthetic cathinones alone; and (3) more potent and effective at producing tachycardia and hypertension as well as other features of the "bath salts" toxidrome than synthetic cathinones alone. Together, the results of the proposed studies will provide essential information about factors that contribute to the high rates of "bath salts" abuse and toxicity. This new knowledge will guide development of novel and targeted treatments for the ever-increasing and evolving problem of "bath salts" abuse.