Psychoactive bath salts and the glutamate system

描述（由申请人提供）：精神活性浴盐（PABS）是一种危险的鸡尾酒设计师卡西酮，正在非法药物领域站稳脚跟。卡西酮具有滥用倾向和毒性，与可卡因和通常滥用的安非他明衍生物具有相同的药理学特征。甲卡西酮（4-甲基甲卡西酮，MEPH）和MDPV（亚甲二氧基吡咯戊酮）是两种设计师卡西酮，分别在英国和美国仍然受到药物滥用者的欢迎，尽管立法将其拥有定为刑事犯罪。PABS的危害主要来自轶事报告和调查。有限的临床前工作已经确定，MEPH和MDPV是奖励和加强，但对单胺产生不同的影响; MEPH是一种非选择性转运底物，刺激单胺释放，MDPV是一种有效的多巴胺和去甲肾上腺素转运阻滞剂。设计师卡西酮的神经药理学概况中的一个空白是缺乏关于其与谷氨酸系统相互作用的知识。既定的精神兴奋剂，特别是可卡因，产生大脑奖励谷氨酸系统的失调，这是其滥用潜力的基础，特别是当它与复发有关时。此外，一些有前途的候选人来管理精神兴奋剂成瘾调节谷氨酸转运蛋白和受体的活性。本文提出的研究结果将填补这一知识空白，提供第一个全面的信息皮质边缘谷氨酸系统的作用，特别是细胞外谷氨酸和谷氨酸转运系统，在神经药理学作用的PABS。待检验的假设是，设计者卡西酮（MEPH和MDPV）破坏大鼠NAcc核心中的谷氨酸功能，并在大鼠自我给药（SA）模型中产生增强和药物寻求特性，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 β）的调节剂减弱。系统XC-1是基础谷氨酸的主要来源，而GLT-1清除突触外谷氨酸，并且在从慢性可卡因方案戒断期间两种转运蛋白的功能障碍促进可卡因寻求的复发。我们的假设连接谷氨酸和PABS的证据支持，GLT-1转运蛋白的表达减少，在退出慢性设计师卡西酮方案，谷氨酸受体拮抗剂减少重复，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组合将在以下特定目的中检验假设：1）确定MEPH和MDPV暴露各阶段NAcc核心中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）激活剂影响静脉内MEPH和MDPV自我给药（SA）的程度。我们的研究结果的预期积极影响是谷氨酸系统，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学作用的介质的鉴定。

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.