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研究甲氧麻黄酮（4-甲基甲卡西酮）在药物辨别和自我给药试验中的主观和增强特性，检查其滥用倾向。马诺酮是一种名为精神活性浴盐（PABS）的危险街头药物的组成部分，并被假设具有滥用倾向，与臭名昭著的药物共享药理学特性，并显示与使用者死亡和非致命过量有关的毒性。在美国，使用甲氨蝶呤现在很普遍，但关于其滥用责任和风险的知识几乎完全基于对药物滥用者和急诊室访问的调查。使用大鼠获得的有限实验数据表明存在滥用倾向（例如CNS渗透性、多巴胺和5-HT再摄取阻滞以及边缘多巴胺和5-HT水平增强）。然而，缺乏第二层、非临床研究来审查4-甲基甲卡西酮与潜在机制的滥用倾向以及与已确定药物的比较，这是一个需要填补的关键空白，以便使临床医生和政府官员能够预测4-甲基甲卡西酮使用造成的医疗和经济损失。此外，迄今为止没有研究检查过甲氧麻黄酮的对映异构体。基于对甲卡西酮本身的对映异构体观察到的那些，这样的对映异构体可以具有不同的药理学性质。现在，我们建议评估主观和增强性能的甲氧麻黄酮，其对映异构体，在实验室大鼠的药物歧视和自我管理试验，并比较这些属性与已建立的药物，以确定独特的功能甲氧麻黄酮药理学。我们假设，甲氧麻黄酮表现出混合的药理学特征，其中它与精神兴奋剂，如甲基苯丙胺，可卡因和摇头丸，改变多巴胺，5-HT和谷氨酸系统共享歧视性刺激作用。我们还假设，大鼠将自我管理下的渐进比（PR）的模式类似于其他精神兴奋剂的强化时间表甲氧麻黄酮，并会表现出强化强度等于或大于MDMA，也许等于可卡因。类似地，在复原范例中，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复原。其他研究将测试选择DA，5-HT和谷氨酸化合物在PR和恢复程序中的作用，以表征甲氧麻黄酮增强作用的独特药理学。拟议研究的基本原理以及我们的结果的预期积极影响是，将甲氧麻黄酮的药理学，主观，增强和药物寻求特性与已确定的滥用药物进行比较，将表明其滥用责任的相对风险，并初步了解潜在的治疗方法来管理这种责任。此外，这将是首次制备和表征甲氧麻黄酮对映体的作用的研究。 公共卫生相关性：拟议的研究对公共卫生很重要，因为精神活性浴盐是危险的街头毒品，被认为具有滥用风险，并与臭名昭著的滥用药物共享药理特性。对这些浴盐中所含物质的主观和强化性质的调查，特别是与潜在机制的关系以及与已确定的药物的比较，将使人们对其滥用责任的风险和管理这种责任的潜在治疗方法有新的认识。因此，拟议的研究与NIDA的部分使命有关，即制定战略，减少与药物滥用有关的公共卫生、社会和犯罪问题以及经济损失。

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. PUBLIC HEALTH RELEVANCE: The proposed research is important to public health because psychoactive bath salts are dangerous street drugs that are thought to possess a risk of abuse liability and share pharmacological properties with notorious drugs of abuse. Investigation of the subjective and reinforcing properties of substances contained in those bath salts, especially in relation to underlying mechanisms and comparison to established drugs, will shed new insight into their risk of abuse liability and potential treatments to manage that liability. Thus, the proposed research is relevant to the part of NIDA's mission that pertains to developing strategies to reduce public health, societal and criminal problems and economic losses associated with drug abuse.