Psychoactive bath salts and the glutamate system

 描述(申请人提供)：精神活性浴盐(PABS)是一种危险的卡西诺酮鸡尾酒，正在非法药物领域站稳脚跟。卡西酮具有滥用、易感性和毒性，与可卡因和常见滥用的苯丙胺衍生物具有相同的药理学特征。甲麻黄酮(4-甲基甲卡西酮，meph)和MDPV(亚甲基二氧基吡咯丙酮)是两种设计的卡西酮，在英国和美国分别受到吸毒者的欢迎，尽管立法将持有他们定为犯罪。PABS的危害主要来自轶事报道和调查。有限的临床前研究已经证实，MEPH和MDPV具有奖励和增强作用，但对单胺具有明显的影响；MEPH是一种刺激单胺释放的非选择性转运体底物，而MDPV是一种有效的多巴胺和去甲肾上腺素转运阻滞剂。设计师卡西诺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。现有的心理刺激剂，特别是可卡因，会导致大脑奖励谷氨酸系统的失调，这是它们滥用潜力的基础，特别是与复发有关的时候。此外，几个有希望控制精神刺激成瘾的候选药物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，提供关于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神经药理作用中所起作用的第一个全面信息。需要检验的假设是，设计者卡西酮(meph和mdpv)扰乱了大鼠NAcc核心的谷氨酸功能，并在自我给药(SA)大鼠模型中产生增强和药物寻找特性，而谷氨酸转运体亚型1(GLT-1)和半胱氨酸-谷氨酸交换(即XC系统)的调节剂减弱了这种特性。系统XC是基础谷氨酸的主要来源，而GLT-1清除突触外谷氨酸，两种转运蛋白在慢性可卡因方案戒断期间的功能障碍促进了对可卡因的复发。我们的假设将谷氨酸和PABS联系在一起，有证据支持GLT-1转运体在退出长期设计的卡西酮方案期间表达减少，以及谷氨酸受体拮抗剂减少反复、间歇性合成卡西酮暴露所产生的过度活动。神经化学和行为学方法的结合将在以下特定目标中检验这一假说：1)确定在MEPH和MDPV暴露的各个阶段细胞外谷氨酸水平和NAcc核心中谷氨酸转运体功能的变化，以及2)调查GLT-1(CTX)和系统XC-(N-乙酰半胱氨酸)的激活剂对静脉注射MEPH和MDPV自我给药(SA)的影响程度。我们的结果预期的积极影响是确认谷氨酸系统，特别是GLT-1和XC-系统，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 Xc ). System Xc 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.