Psychoactive bath salts and the glutamate system

描述（由申请人提供）：精神活性浴盐（PABS）是一种危险的设计卡西酮鸡尾酒，正在非法药物领域站稳脚跟。卡西酮具有滥用危险和毒性，与可卡因和常被滥用的安非他明衍生物具有相同的药理特征。甲氧麻黄酮（4-甲基甲卡西酮，MEPH）和MDPV（亚甲基二氧基戊酮）是两种设计的卡西酮，分别在英国和美国的吸毒者中很受欢迎，尽管立法将其视为犯罪。PABS的危害主要来自轶事报道和调查。有限的临床前工作已经确定，MEPH和MDPV是有益的和增强的，但对单胺具有不同的作用；MEPH是一种刺激单胺释放的非选择性转运蛋白底物，MDPV是一种有效的多巴胺和去甲肾上腺素转运阻断剂。在设计卡西酮的神经药理学方面的一个空白是缺乏关于它们与谷氨酸系统相互作用的知识。现有的精神兴奋剂，特别是可卡因，会导致大脑奖赏谷氨酸系统失调，这是滥用的潜在原因，特别是与复发有关。此外，一些有希望的候选人来管理精神兴奋剂成瘾调节谷氨酸转运体和受体的活性。本文提出的研究结果将填补这一知识空白，提供有关皮质边缘谷氨酸系统，特别是细胞外谷氨酸和谷氨酸运输系统在PABS神经药理作用中的作用的第一个全面信息。需要验证的假设是，设计型卡西酮（MEPH和MDPV）破坏大鼠NAcc核心的谷氨酸功能，并在大鼠自我给药（SA）模型中产生增强和寻药特性，这些特性被谷氨酸转运蛋白亚型1 （GLT-1）和半胱氨酸-谷氨酸交换（即系统Xc -1）的调节剂减弱。系统Xc -1是基础谷氨酸的主要来源，而GLT-1则清除突触外谷氨酸，这两种转运体在慢性可卡因戒断期间的功能障碍会促进可卡因寻求的复发。我们将谷氨酸和PABS联系起来的假设得到了证据的支持，证据表明GLT-1转运蛋白表达在从慢性卡西酮治疗方案中退出时减少，谷氨酸受体拮抗剂减少了由反复、间歇性合成卡西酮暴露产生的多动症。神经化学和行为方法的结合将在以下具体目标中验证这一假设：1)确定MEPH和MDPV暴露阶段NAcc核心细胞外谷氨酸水平和谷氨酸转运蛋白功能的变化；2)研究GLT-1 （CTX）和系统Xc- （n -乙酰半胱氨酸）的激活剂在多大程度上影响静脉注射MEPH和MDPV自我给药（SA）。我们的结果预期的积极影响是确定谷氨酸系统，特别是GLT-1和系统Xc-，作为在PABS中发现的取代卡西酮的神经药理作用的中介。

DESCRIPTION (provided by applicant): Psychoactive bath salts (PABS) are dangerous cocktails of designer cathinones that are gaining a foothold in the illicit drug scene. The cathinones possess abuse liability and toxicity and share pharmacological features with cocaine and commonly abused amphetamine derivatives. Mephedrone (4-methylmethcathinone, MEPH) and MDPV (methylenedioxypyrovalerone) are two designer cathinones that remain popular with drug abusers in the UK and US, respectively, despite legislation to criminalize their possession. The hazards of PABS have been derived mostly from anecdotal reports and surveys. Limited preclinical work has established that MEPH and MDPV are rewarding and reinforcing but exert distinct effects on monoamines; MEPH is a non-selective transporter substrate that stimulates monoamine release, and MDPV is a potent dopamine and norepinephrine transport blocker. A gap in the neuropharmacological profiles of designer cathinones is the lack of knowledge about their interactions with glutamate systems. Established psychostimulants, notably cocaine, produce dysregulation of brain reward glutamate systems that underlies their abuse potential, especially as it relates to relapse. Furthermore, several promising candidates to manage psychostimulant addiction modulate glutamate transporter and receptor activity. Results from studies proposed herein will fill this gap in knowledge by providing the first comprehensive information about the role of the corticolimbic glutamate system, especially extracellular glutamate and the glutamate transport system, in the neuropharmacological effects of PABS. The hypothesis to be tested is that designer cathinones (MEPH and MDPV) disrupt glutamate function in the NAcc core of rats and produce reinforcing and drug-seeking properties in a rat model of self-administration (SA) that are attenuated by modulators of glutamate transporter subtype 1 (GLT-1) and cysteine-glutamate exchange (i.e. system Xcˉ). System Xcˉ is the major source of basal glutamate whereas GLT-1 clears extrasynaptic -- glutamate, and dysfunction of both transporters during withdrawal from a chronic cocaine regimen facilitates relapse to cocaine seeking. Our hypothesis linking glutamate and PABS is supported by evidence that GLT-1 transporter expression is reduced during withdrawal from a chronic designer cathinone regimen and that a glutamate receptor antagonist reduces hyperactivity produced by repeated, intermittent synthetic cathinone exposure. A combination of neurochemical and behavioral approaches will test the hypothesis in the following Specific Aims: 1) Identify changes in extracellular glutamate levels and glutamate transporter function in the NAcc core across stages of MEPH and MDPV exposure and 2) Investigate the extent to which activators of GLT-1 (CTX) and system Xc- (N-acetylcysteine) affect intravenous MEPH and MDPV self-administration (SA). The expected positive impact of our results is the identification of the glutamate system, especially GLT-1 and system Xc-, as a mediator of the neuropharmacological effects of substituted cathinones found in PABS.