NEUROCHEMICAL ALTERATIONS BY DESIGNER DRUGS

描述：(申请人摘要) 甲卡西酮(MCAT)是一种日益被滥用的苯基异丙胺 在中西部和全国各地，由于其强大的刺激性 特性以及合成它的简易性。因为它的 随着MCAT的流行，MCAT最近被归类为附表I药物。 虽然对MCAT的研究很少，但它的短期 醉酒和严重的成瘾模式被比作可卡因 可卡因或冰毒。我们最近报道说，单一和多个 MCAT给药引起锥体外区和脑区的神经化学缺陷 长达72小时的边缘多巴胺能和5-羟色胺能系统 治疗。由于这些观察，我们建议MCAT施加 对锥体外系和边缘的深远的短期和长期影响 单胺能系统，并具有显著的神经毒性潜力。这 将通过实现以下具体目标来检验假设： A.确定单一MCAT的短期和长期单胺能效应 行政管理。这将通过微透析评估[I]来实现 MCAT对单胺释放的影响，[II]测定He MCAT诱导的单胺类系统神经化学改变的持久性 单次给药后，[III]评估体温过高在 对MCAT的单胺反应，[IV]确定MCAT对 自由基的形成和[v]监测大脑中MCAT的存在 单次注射后24小时。 B.确定多个MCAT管理对以下方面的长期影响 单胺能系统。这将通过[I]测量单胺能来实现 在治疗后30天内多次使用MCAT的效果，[II] 确定哪些因素负责调解长期的 MCAT多次给药后单胺能系统的变化。 C.比较MCAT的单胺能反应与其引起的反应 自然产生的(在Chat植物中发现的)脱甲基化类似物，以及 可能是活性代谢物卡西诺酮。 这些研究的发现将有助于(1)教育现在和未来 向使用者介绍滥用MCAT的风险，(2)确定适当的治疗方法 管理MCAT诱导的毒性的策略，以及(3)提供洞察力 苯基异丙胺的性质，使它们对或 包括5-羟色胺能系统和多巴胺能系统。

DESCRIPTION: (Applicant's Abstract) Methcathinone (mCAT) is a phenylisopropylamine which is increasingly abused in the Midwest and across this country due to its potent stimulant properties and the ease with which it is synthesized. Because of its emerging popularity, mCAT was recently classified as a Schedule I drug. Although little research on mCAT has been conducted, its short-term intoxication and severe addiction patterns have been compared to crack cocaine or methamphetamine. We recently reported that single and multiple mCAT administrations caused neurochemical deficits in extrapyramidal and limbic dopaminergic and serotonergic systems as long as 72 h after treatment. Because of these observations, we propose that mCAT exerts profound short- and long-term effects on extrapyramidal and limbic monoaminergic systems and has significant neurotoxic potential. This hypothesis will be tested by achieving the following Specific Aims: A. Identify the short and long-term monoaminergic effects of a single mCAT administration. This will be achieved by [i] assessing with microdialysis the effects of mCAT on the release of monoamines, [ii] determining he persistence of mCAT-induced neurochemical changes in monoaminergic systems after a single administration, [iii] evaluating the role of hyperthermia in the monoamine responses to mCAT, [iv] determining the effects of mCAT on free radical formation and [v] monitoring the presence of mCAT in the brain for 24 h after a single injection. B. Identify long-term consequences of multiple administrations of mCAT on monoaminergic systems. This will be achieved by [i] measuring monoaminergic effects of multiple mCAT administrations up to 30 d after treatment, [ii] identifying factors which are responsible for mediating the long-term changes in the monoaminergic systems after multiple mCAT administrations. C. Compare monoaminergic responses to mCAT with those caused by its naturally occurring (found in the Chat plant) demethylated analog, and possible active metabolite, cathinone. The findings from these studies will help (1) educate current and future users about the risks of mCAT abuse, (2) identify appropriate therapeutic strategies for managing mCAT-induced toxicities, and (3) provide insight to the properties of phenylisopropylamines which make them toxic to either or both the serotonergic and dopaminergic systems.