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: 10359764
• 负责人: Stephen John Kohut
• 金额: $ 77.06万
• 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/10359764
• 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; Stimulant; Work; abuse liability; 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 滥用取代卡西酮、“浴盐”的主要精神活性成分和其他非法成分 在过去的十年里，准备工作已经成为一个持续的公共卫生问题。取代卡西诺酮， 像其他苯乙胺一样，包括甲基苯丙胺(MA)或(+/-)-3，4-亚甲二氧基甲基苯丙胺 (MDMA)，通过单胺能动作产生其精神活性效应，这是由于它们有能力 阻断再摄取或增加神经元多巴胺(DA)和/或5-羟色胺(5-HT)的释放。新卡西尼酮 不断被引入地下毒品市场，并在一个或多个结构特征上有所不同， 但多巴胺和/或5-羟色胺转运体的神经化学活动平衡被认为是 介导其MA或MDMA样效应(即刺激剂或内分泌激素)的表达。然而，人们对此知之甚少 关于取代卡西酮如何改变神经活动，以及是否像它们与滥用有关的行为影响一样， 激活的区域模式可能与它们的单胺能活动的平衡有关。此应用程序，在 对PAR 18-510的响应旨在解决这一问题，并提出尖端、集成的行为 非人灵长类动物的药理学和神经成像研究，以检查与虐待相关的行为和 对DA和5-羟色胺释放选择性不同的取代卡西酮的神经效应。首先，由于吸毒史是 已知在不同类型的药物滥用和复发的个体易感性中发挥重要作用 卡西诺酮将在不同的男性和女性受试者中进行比较，这些受试者歧视或自我 服用MA(DA选择性)或MDMA(5-羟色胺选择性)。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、强化和诱发(恢复)复发的作用 选定的卡西酮将与MA和MDMA的卡西酮进行比较。最后，觉醒功能磁共振研究，在 超高场强(9.4T)，将在相同的对象中使用，以确定模式中的关键特征 取代卡西酮产生的局部脑活动(神经特征)可能与其MA样蛋白有关 或类似MDMA的滥用相关效应。总体而言，我们计划的研究将产生关键的见解，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，更广泛地说，与DA和/或5-羟色胺介导的滥用药物 行为。这些信息对于加速开发新的治疗策略是必不可少的。 卡西诺酮和其他单胺类药物成瘾的管理。