NEUROCHEMICAL ALTERATIONS BY DESIGNER DRUGS

描述：（改编自研究者摘要）由于最近 安非他明（AMPH）类似物的使用急剧增加， 亚甲二氧基甲基苯丙胺（MDMA;摇头丸），重要的是， 这些代理商将被删除。此类苯乙胺的高剂量给药 引起单胺能神经元功能的持续变化，但随着时间的推移， 表情例如，多次注射AMPH或甲基苯丙胺 （METH），而不是MDMA，导致多巴胺（DA）缺乏，甚至在 药物治疗，而类似的治疗与甲基和摇头丸，但不是AMPH， 对5-羟色胺（5-HT;血清素）系统的持续影响。不同 从这些神经毒性的后果，我们最近报告说， 这些药剂的高剂量注射也引起快速且至少部分 DA转运蛋白（DAT）活性的可逆性降低（在全文中提及 这个提议被称为急性转运蛋白反应（ATR），似乎与 DAT蛋白的急性丢失，并由未鉴定的机制介导。自从DAT 是神经元内和神经元外DA浓度的主要调节因子， 相信这种快速ATR可能代表重要的监管现象， METH、AMPH和MDMA给药后ATR的差异可能 有助于这些代理人的独特属性。为了更好地理解两者 DAT的调节和ATR的长期意义 这些药物，我们将测试的假设，即： 苯乙胺与长期DA后果有关， 管理这些代理商。 这将通过完成以下具体目标来实现： 识别与苯乙胺相关的DAT相关ATR的特征 通过阐明其剂量、时间和区域特征，以及 其功能意义。 确定DAT相关ATR的组件与每个 其他和持续的DA赤字（或缺乏）所造成的 苯乙胺给药。 通过识别以下特征来确定DAT相关ATR的唯一性 囊泡单胺和5HT转运蛋白相关的ATR，并检查它们的 与持续性单胺能缺陷（或缺乏单胺能缺陷）有关， 通过苯乙胺给药。 这些研究将确定急性脑梗死和脑梗死之间是否存在关联。 对AMPH类似物的反应及其神经毒性特性。此外，本发明还提供了一种方法， 他们将阐明调节DAT和其他相关转运蛋白的因素 系统.最后，这些研究可能会提供相关机制的见解， 与DA相关的神经和精神疾病，如帕金森氏症， 疾病和精神病。

DESCRIPTION: (Adapted from the Investigator's Abstract) Because of recent dramatic increases in the use of amphetamine (AMPH) analogs such as methylenedioxymethamphetamine (MDMA; Ecstasy), it is important that effects of these agents be elucidated. High-dose administrations of such phenylethylamines cause persistent changes in monoaminergic neuronal function, but with varying expressions. For example, multiple injections of AMPH or methamphetamine (METH), but not MDMA, cause dopamine (DA) deficits persisting even years after drug treatment while similar treatments with METH and MDMA, but not AMPH, have persistent effects on 5-hydroxytryptamine (5HT; serotonin) systems. Distinct from these neurotoxic consequences, we reported recently that multiple high-dose injections of these agents also cause a rapid and at least partially reversible decrease in DA transporter (DAT) activity (referred to throughout this proposal as Acute Transporter Response; ATR) that appears unrelated to an acute loss of DAT protein and is mediated by unidentified mechanisms. Since DAT is a principal regulator of intra- and extra-neuronal DA concentrations, we believe that such rapid ATRs may represent important regulatory phenomena and that differences in ATRs effected by METH, AMPH and MDMA administration may contribute to the unique properties of these agents. To better understand both the regulation of DAT and the long-term significance of the ATR induced by these agents, we will test the hypothesis that: the DAT-related ATRs induced by phenylethylamines are associated with the long-term DA consequences of administering these agents. This will be accomplished by completing the following Specific Aims: Identify the features of the DAT-associated ATR related to phenylethylamine treatment by elucidating its dose, temporal and regional profile, as well as its functional significance. Determine the relationship of the components of the DAT-associated ATR to each other and the persistent DA deficits (or lack thereof) caused by phenylethylamine administration. Determine the uniqueness of the DAT-related ATR by identifying the features of the vesicular monoamine and 5HT transporter-associated ATRs and examining their association with the persistent monoaminergic deficits (or lack thereof) caused by phenylethylamine administration. These studies will determine if an association exists between the acute responses to the AMPH analogs and their neurotoxic properties. In addition, they will elucidate factors that regulate DAT and other related transporter systems. Finally, these studies may provide insight into mechanisms associated with DA-related neurological and psychiatric disorders such as Parkinson's disease and psychosis, respectively.