Mephedrone and addiction: clues from animal models

描述（由申请人提供）：本申请的目的是通过首次全面调查其在药物鉴别和自我给药分析中的主观和强化特性，来检查甲氧麻黄酮（4-甲基甲卡西酮）的滥用风险。甲氧麻黄酮是一种叫做精神活性浴盐（PABS）的危险街头毒品的一种成分，它被认为有滥用的危险，与臭名昭著的毒品具有相同的药理特性，并且显示出毒性，与使用者的死亡和非致命过量有关。甲氧麻黄酮的使用现在在美国很普遍，但对其滥用的责任和风险的了解几乎完全基于对吸毒者和急诊室就诊的调查。使用大鼠获得的有限实验数据提示滥用倾向（例如，中枢神经系统穿透性，多巴胺和5-羟色胺再摄取阻断，边缘多巴胺和5-羟色胺水平增强）。然而，缺乏二级非临床研究，从潜在机制和与现有药物的比较来检查甲氧麻黄酮的滥用责任，这是一个需要填补的关键空白，以便临床医生和政府官员能够预测使用甲氧麻黄酮造成的医疗和经济损失。此外，迄今为止还没有研究检测过甲氧麻黄酮的对映体。这些对映体可能根据对甲卡西酮本身的对映体所观察到的性质而具有不同的药理学性质。我们现在提议评估甲氧麻黄酮及其对映体在实验室大鼠药物鉴别和自我给药试验中的主观和强化特性，并将这些特性与已建立的药物进行比较，以确定甲氧麻黄酮的独特药理学特征。我们假设甲氧麻黄酮表现出一种混合的药理学特征，它与甲基苯丙胺、可卡因和摇头丸等精神兴奋剂具有区别性刺激作用，这些兴奋剂会改变多巴胺、5-羟色胺和谷氨酸系统。我们还假设，大鼠将以类似于其他精神兴奋剂的模式，在递进比率（PR）强化计划下自我施用甲氧麻黄酮，并将表现出等于或大于MDMA的强化强度，可能等于可卡因。同样，在恢复范式中，我们假设甲氧麻黄酮寻求行为将通过非偶然注射甲氧麻黄酮而恢复。进一步的研究将测试选择的DA、5-羟色胺和谷氨酸化合物在PR和恢复过程中的作用，以表征甲氧麻黄酮强化作用的独特药理学。这项研究的基本原理，以及我们的研究结果预期的积极影响，是将甲氧麻黄酮的药理学、主观、强化和药物寻找特性与已确定的滥用药物进行比较，将提供其滥用责任的相对风险的指示，并初步了解潜在的治疗方法来管理这种责任。此外，这将是第一个制备和表征甲氧麻黄酮对映体作用的研究。

DESCRIPTION (provided by applicant): The objective of this application is to examine the abuse liability of mephedrone (4-methylmethcathinone) by providing the first comprehensive investigation of its subjective and reinforcing properties in drug discrimination and self-administration assays. Mephedrone is a component of a dangerous street drug called psychoactive bath salts (PABS) and hypothesized to have abuse liability, share pharmacological properties with notorious drugs, and display toxicity that has been linked to fatalities and non-fatal overdoses in users. Mephedrone use is now commonplace in the United States, but knowledge about its abuse liability and risks is based almost entirely on surveys of drug abusers and emergency room visits. Limited experimental data obtained using rats are suggestive of abuse liability (e.g. CNS penetrability, dopamine and 5-HT reuptake block, and enhancement of limbic dopamine and 5-HT levels). However, an absence of second-tier, nonclinical studies examining the abuse liability of mephedrone in relation to underlying mechanisms and comparison to established drugs is a critical gap that needs to be filled to enable clinicians and government officials to predict medical and economic losses posed by mephedrone use. Moreover, no studies to date have examined the enantiomers of mephedrone. Such enantiomers may have different pharmacological properties based on those observed for the enantiomers of methcathinone itself. We now propose to evaluate the subjective and reinforcing properties of mephedrone, and its enantiomers, in drug discrimination and self-administration assays in laboratory rats and to compare these properties with established drugs to identify unique features of mephedrone pharmacology. We hypothesize that mephedrone exhibits a mixed pharmacological profile in which it shares discriminative stimulus effects with psychostimulants such as methamphetamine, cocaine, and ecstasy that alter dopamine, 5-HT and glutamate systems. We also hypothesize that rats will self-administer mephedrone under a progressive ratio (PR) schedule of reinforcement in a pattern similar to other psychostimulants and will exhibit a reinforcing strength equal to or greater than that of MDMA and perhaps equal to cocaine. Similarly, in a reinstatement paradigm, we hypothesize that mephedrone-seeking behavior will be reinstated by a non- contingent injection of mephedrone. Additional studies will test the effects of select DA, 5-HT, and glutamate compounds in the PR and reinstatement procedures to characterize a unique pharmacology underlying the reinforcing effects of mephedrone. The rationale for the proposed research, and expected positive impact of our results, is that comparison of the pharmacological, subjective, reinforcing, and drug-seeking properties of mephedrone with established drugs of abuse will provide an indication of their relative risk of abuse liability and initial insight into potential therapeutic approaches to manag that liability. Further, this will be the first study to prepare and characterize the effects of th enantiomers of mephedrone.