Psychoactive bath salts and the glutamate system

精神活性浴盐和谷氨酸系统

• 批准号: 8862040
• 负责人: SCOTT M. RAWLS
• 金额: $ 36.98万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862040
• 关键词: Abstinence; Acetylcysteine; Acute; Affect; Amphetamine Abuse; Amphetamines; Applications Grants; Attenuated; Bathing; Behavioral; Biological; Biological Assay; Brain; Ceftriaxone; Chronic; Cocaine; Coupled; Cues; Cysteine; Cystine; Designer Drugs; Dopamine; Excitatory Amino Acid Antagonists; Exposure to; FDA approved; Family; Functional disorder; GLAST Protein; Glutamate Receptor; Glutamate Transporter; Glutamates; High Pressure Liquid Chromatography; Hyperactive behavior; Illicit Drugs; Intake; Intravenous; Investigation; Knowledge; Laboratories; Limbic System; Link; Mediator of activation protein; Medical Economics; Methamphetamine; Microdialysis; Modeling; N-Methylaspartate; Names; Norepinephrine; Nucleus Accumbens; Pharmaceutical Preparations; Property; Psychostimulant dependence; Psychotropic Drugs; Rattus; Regimen; Reinforcement Schedule; Relapse; Reporting; Research; Rewards; Role; Salts; Self Administration; Self-Administered; Source; Staging; Statutes and Laws; Surveys; System; Testing; Toxic effect; Withdrawal; Work; cathinone; drug abuser; drug candidate; drug efficacy; extracellular; hazard; in vivo; monoamine; neurochemistry; pre-clinical; preference; protein expression; protein function; psychostimulant; public health relevance; response; stimulant abuse; uptake

 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.

 描述（由申请人提供）：精神活性浴盐（PABS）是设计卡西酮的危险混合物，在非法药物领域占据一席之地。卡西酮具有滥用倾向和毒性，并且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。 （4-甲基甲卡西酮，MEPH）和 MDPV（亚甲二氧基吡咯戊酮）是两种设计卡西酮，仍然受到药物滥用者的欢迎在英国和美国，尽管立法将持有 PABS 定为刑事犯罪，但有限的临床前工作已证实 MEPH 和 MDPV 对单胺有不同的作用。是一种非选择性转运底物，可刺激单胺释放，而 MDPV 是一种有效的多巴胺和去甲肾上腺素转运阻滞剂。缺乏对现有精神兴奋剂（尤其是可卡因）与谷氨酸系统相互作用的了解，会导致大脑奖赏谷氨酸系统失调，从而导致其滥用，特别是与复发有关。本文提出的研究结果将通过提供有关皮质边缘谷氨酸系统，特别是细胞外谷氨酸和受体活性的第一个全面信息来填补这一知识空白。谷氨酸转运系统，在 PABS 的神经药理学作用中 待测试的假设是，设计卡西酮（MEPH 和 MDPV）会破坏大鼠 NAcc 核心的谷氨酸功能，并在自我给药的大鼠模型中产生强化和药物寻求特性。 (SA) 被谷氨酸转运蛋白亚型 1 (GLT-1) 调节剂和半胱氨酸-谷氨酸交换（即系统Xc 系统是基础谷氨酸的主要来源，而 GLT-1 则清除突触外谷氨酸，并且在长期可卡因治疗戒断过程中，两种转运蛋白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以下证据的支持。在退出长期设计的卡西酮治疗方案期间，GLT-1 转运蛋白表达会降低，而谷氨酸受体拮抗剂可减少重复、间歇性合成卡西酮暴露所产生的过度活跃。神经化学和行为方法的研究将在以下具体目标中检验这一假设：1）确定 MEPH 和 MDPV 暴露阶段的细胞外谷氨酸水平和 NAcc 核心中谷氨酸转运蛋白功能的变化，2）研究 GLT 激活剂的程度1 (CTX) 和系统 Xc-（N-乙酰半胱氨酸）影响静脉内 MEPH 和 MDPV 自我给药 (SA) 我们结果的预期积极影响是鉴定谷氨酸系统，特别是 GLT-1 和 Xc- 系统，作为 PABS 中取代卡西酮神经药理学作用的介质。