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: 10576883
• 负责人: Stephen John Kohut
• 金额: $ 69.3万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576883
• 关键词: Acceleration; Address; Animals; Behavior; Behavioral; Behavioral Model; Biological; Brain; Brain region; 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; Phenethylamines; Play; Preparation; Procedures; Production; Public Health; Recording of previous events; Relapse; Role; Saimiri; Sampling; Self Administration; Serotonin; Stimulant; Vulnerable Populations; Work; abuse liability; addiction; awake; bath salts; behavioral pharmacology; cathinone; design; dopaminergic neuron; drug discrimination; drug market; drug of abuse; drug relapse; drug seeking behavior; ecstasy; extracellular; improved; innovation; insight; male; methamphetamine use; neural; neural circuit; neurochemistry; neuroimaging; nonhuman primate; novel; novel strategies; pharmacologic; programs; 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.

抽象的 滥用替代卡西酮、“浴盐”的主要精神活性成分和其他非法物质 过去十年来，已成为一个持续存在的公共卫生问题。替代卡西酮， 与其他苯乙胺一样，包括甲基苯丙胺 (MA) 或 (+/-)-3,4-亚甲二氧基甲基苯丙胺 （MDMA），通过单胺能作用产生其精神作用，这些作用是由于它们能够 阻断神经元多巴胺（DA）和/或血清素（5-HT）的再摄取或增加释放。新卡西酮 不断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 转运蛋白神经化学活性的平衡被认为是一个关键特征 介导其 MA 或 MDMA 样作用的表达（即兴奋剂或诱生剂）。然而，鲜为人知 关于取代卡西酮如何改变神经活动，以及是否像其滥用相关的行为影响一样， 激活的区域模式可能与其单胺能作用的平衡有关。这个应用程序，在 对 PAR 18-510 的回应，旨在解决这个问题并提出尖端的综合行为 在非人类灵长类动物中进行药理学和神经影像学研究，以检查与滥用相关的行为和行为 取代卡西酮对 DA 和 5-HT 释放的选择性不同的神经效应。首先，由于用药史 已知在个人对不同类型药物滥用和复发的脆弱性中发挥重要作用，替代 将在不同组的男性和女性受试者中对卡西酮进行比较，这些受试者有歧视或自我评价 施用 MA（DA 选择性）或 MDMA（5-HT 选择性）。接下来，使用经过充分验证和翻译的- 相关的动物行为模型，主观的、强化的和复发诱导（恢复）的影响 选定的卡西酮将与 MA 和 MDMA 进行比较。最后，清醒功能磁共振成像研究，在 超高场强（9.4T），将用于相同的主题来识别模式中的关键特征 由取代卡西酮产生的区域大脑活动（神经特征）可能与其 MA 样相关 或与 MDMA 类似的滥用相关影响。总的来说，我们计划的研究将产生重要的见解，以改善我们的 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，通过 DA 和/或 5-HT 介导的滥用药物 行动。这些信息对于加速开发新的治疗策略至关重要 管理卡西酮和其他单胺类药物成瘾。