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（通过应用程序提供）：精神活性浴盐（PAB）是设计师Cathinones的危险鸡尾酒，在非法毒品现场获得了立足点。 Cathinones潜在的滥用责任和毒性，并与可卡因和通常滥用的苯丙胺衍生物共享药物特征。甲基麻黄酮（4-甲基甲性甲性苯酚，MEPH）和MDPV（甲基苯二甲甲基二回甲甲酮）是两个设计师Cathinones，分别在英国和我们的毒品滥用者中流行，尽管立法将其立场定为刑事犯罪。 PAB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具有回报和增强，但对单胺产生了明显的影响。 MEPH是一种非选择性转运蛋白底物，可刺激单胺释放，MDPV是一种潜在的多巴胺和去甲肾上腺素传输阻滞剂。设计师Cathinones神经药理学概况的差距是缺乏有关其与谷氨酸系统相互作用的知识。已建立的心理刺激剂，尤其是可卡因，产生了脑部奖励谷氨酸系统的失调，其滥用潜力是基于其滥用潜力的基础，尤其是与继电器有关的情况。此外，几位承诺候选人管理精神刺激成瘾调节谷氨酸转运蛋白和受体活性。本文提出的研究的结果将通过提供有关谷氨酸谷氨酸系统的作用，尤其是细胞外谷氨酸和谷氨酸传输系统在PABS的神经药物效应中的第一个全面信息，从而填补这一差距。要检验的假设是，设计师Cathinones（MEPH和MDPV）破坏了大鼠NACC核心中的谷氨酸功能，并在大鼠自我管理模型（SA）中产生加强和寻求药物的特性，这些模型被谷氨酸调节剂减弱。转运蛋白亚型1（GLT-1）和半胱氨酸 - 谷氨酸交换（即系统XC）。 System XC是碱性谷氨酸的主要来源，而GLT-1在从慢性可卡因方案中退出期间，两种转运蛋白在撤离可卡因寻求可卡因时都会清除两种转运蛋白的功能障碍。我们的假设与谷氨酸和PAB相关的假设得到了证据，证明GLT-1转运蛋白表达在从慢性设计师Cathinoone方案中撤离期间降低，并且谷氨酸受体拮抗剂减少了反复的间歇性合成Cathinoone暴露产生的多动症。神经化学方法和行为方法的结合将在以下具体目的中检验假设：1）确定跨NACC核心中细胞外谷氨酸水平的变化以及MEPH和MDPV暴露阶段的NACC核心中的变化，以及2）研究与GLT-1 me（CTX）和System Xc- cyp-clycysy-clysy-clysy-clysy-proft contsy的程度自我管理（SA）。我们结果的预期积极影响是鉴定谷氨酸系统，尤其是GLT-1和System XC-，是在PAB中发现的取代Cathinones神经药理学作用的介体。