Synthetic Psychoactive "Bath Salt" Effects on Brain Activity and Behavior

合成精神活性“浴盐”对大脑活动和行为的影响

• 批准号: 9913490
• 负责人: Stephen John Kohut
• 金额: $ 75.76万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913490
• 关键词: Address; Animals; Behavior; Behavioral; Behavioral Model; Biological; Brain; Data; Development; Dopamine; Dose; Drug abuse; Drug usage; Equilibrium; Female; Food; Functional Magnetic Resonance Imaging; Hair; Individual; Ketones; Maps; Measures; Mediating; Methamphetamine; Monkeys; Neurons; Pattern; Pharmaceutical Preparations; Pharmacology; Phenethylamines; Play; Preparation; Procedures; Production; Public Health; Recording of previous events; Relapse; Role; Saimiri; Sampling; Self Administration; Serotonin; Structure; Work; addiction; awake; bath salts; behavioral pharmacology; brain behavior; cathinone; design; drug discrimination; drug market; drug of abuse; drug relapse; drug seeking behavior; ecstasy; extracellular; imaging study; improved; innovation; insight; male; methamphetamine use; neural circuit; neurochemistry; neuroimaging; nonhuman primate; novel; novel strategies; programs; relating to nervous system; response; reuptake; sex; treatment strategy; vocalization

Abstract The abuse of substituted cathinones, the main psychoactive components of “bath salts” and other illicit preparations, has emerged as a persistent public health concern over the past decade. Substituted cathinones, like other phenethylamines including methamphetamine (MA) or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), produce their psychoactive effects through monoaminergic actions resulting from their ability to either block the reuptake or increase the release of neuronal dopamine (DA) and/or serotonin (5-HT). New cathinones are continually being introduced into the underground drug market and differ in one or more structural features, but the balance of neurochemical activity at DA and/or 5-HT transporters is thought to be a key feature that mediates the expression of their MA- or MDMA-like effects (i.e., stimulant or entactogen). However, little is known about how substituted cathinones alter neural activity and whether, like their abuse-related behavioral effects, regional patterns of activation may be related to the balance of their monoaminergic actions. This application, in response to PAR 18-510, is designed to address this issue and proposes cutting-edge, integrated behavioral pharmacology and neuroimaging studies in nonhuman primates to examine the abuse-related behavioral and neural effects of substituted cathinones that vary in selectivity for DA and 5-HT release. First, as drug history is known to play an important role in individual vulnerability to different types of drug abuse and relapse, substituted cathinones will be compared in different groups of both male and female subjects that discriminate or self- administer either MA (DA-selective) or MDMA (5-HT-selective). Next, using well-validated and translationally- relevant animal behavioral models, the subjective, reinforcing, and relapse-inducing (reinstatement) effects of selected cathinones will be compared to those of MA and MDMA. Finally, awake fMRI studies, conducted at ultra-high field strength (9.4T), will be employed in the same subjects to identify key features in the patterns of regional brain activity (neural signature) produced by substituted cathinones that may be related to their MA-like or MDMA-like abuse-related effects. Overall, our planned studies will yield key insights to improve our understanding of the roles of drug history and sex in the abuse-related behavioral effects and neural signatures of different types of synthetic cathinones and, more generally, abused drugs with DA- and/or 5-HT-mediated actions. Such information is essential for accelerating the development of novel treatment strategies for the management of addiction to cathinones and other monoaminergic drugs.

摘要 滥用“浴盐”的主要精神活性成分取代卡西酮和其他非法药物， 在过去十年中，预防和治疗艾滋病已成为一个持续的公共卫生问题。取代卡西酮， 与其它苯乙胺类包括甲基苯丙胺（MA）或（+/-）-3，4-亚甲二氧基甲基苯丙胺一样 （MDMA），通过单胺能作用产生其精神活性作用， 阻断神经元多巴胺（DA）和/或5-羟色胺（5-HT）的再摄取或增加其释放。新卡西酮 不断地被引入地下毒品市场，并且在一个或多个结构特征上有所不同， 但DA和/或5-HT转运体的神经化学活性的平衡被认为是一个关键特征， 介导它们的MA或MDMA样作用的表达（即，兴奋剂或内毒素）。然而， 关于取代卡西酮如何改变神经活动，以及是否，像他们滥用相关的行为影响， 局部激活模式可能与它们的单胺能作用的平衡有关。本申请以 响应PAR 18-510，旨在解决这一问题，并提出了尖端的，综合的行为 在非人灵长类动物中进行药理学和神经影像学研究，以检查滥用相关的行为和 取代的卡西酮对DA和5-HT释放的选择性不同的神经效应。首先，药物历史 已知在个人易受不同类型药物滥用和复吸方面发挥重要作用， 卡西酮将在不同的男性和女性受试者组中进行比较，这些受试者具有歧视性或自我歧视性， 给予MA（DA选择性）或MDMA（5-HT选择性）。接下来，使用经过验证和验证的- 相关的动物行为模型，主观的，加强的，和复发诱导（恢复）的影响， 选择的卡西酮将与MA和MDMA进行比较。最后，清醒时的功能磁共振成像研究，在 超高场强（9.4T），将在相同的主题，以确定模式的关键特征， 由取代的卡西酮产生的局部脑活动（神经信号），可能与其MA样 或类似MDMA的滥用相关效应。总的来说，我们计划的研究将产生关键的见解，以提高我们的 了解吸毒史和性别在滥用相关行为效应和神经特征中的作用 不同类型的合成卡西酮，更普遍的是，滥用药物与DA和/或5-HT介导的 行动这些信息对于加速开发新的治疗策略是必不可少的。 对卡西酮和其他单胺能药物成瘾的管理。