Neurochemical and Behavioral Effects of Synthetic Cathinones

 描述(由申请人提供)：滥用越来越多的结构多样的合成卡西酮是一个严重的公共卫生问题。这些药物的滥用令人关切的原因有很多，包括滥用甲基苯丙胺和亚甲二氧基甲基苯丙胺等与结构有关的药物会导致持续的神经化学和认知缺陷。因此，一些合成的卡西诺酮很可能同样会造成有害的影响。然而，令人惊讶的是，关于这些药物对单胺能神经元功能的持续影响，人们知之甚少。在评估合成卡西诺酮的影响时，一个重要的考虑因素是，随着越来越多的这类药物被禁止，非法经营活动引入了化学上新颖的替代品，以逃避监管限制。因此，如PAR 14-106所述，重要的是制定普通合成卡西酮与运输者等实体的相互作用情况，以便根据其潜在的滥用倾向和毒性情况对其进行分类。这样的模板也将有助于预测这些新化合物在不同发育阶段的影响，这是这项PAR的另一个重要重点。作为这个模板的贡献者之一，我们将测试这样一种假设，即多巴胺转运体(DAT)和囊泡单胺转运体2(VMAT2)功能的不同变化预测了合成卡西酮和相关药物的持续性神经化学、突触后和功能后果的差异；这种影响受到最初类似物暴露的发育阶段的影响。将通过完成以下目标来测试这一点：1)评估非或有暴露于三种已建立的合成卡西酮(甲氧麻黄酮、美卡西酮和3，4-亚甲基二氧吡咯戊酮)中每一类的代表对DAT和VMAT2定位和功能的急性影响。我们将使用青春期和幼年成年大鼠进行这些研究，我们已经确定，这些转运蛋白的功能可以随着年龄的不同而受到不同的调节。此外，我们还将评估这些药物对导致精神刺激剂诱导的神经毒性的参数的影响，包括反应物种的形成和谷氨酸的释放。2)研究药物引起的单胺转运体功能改变与行为和神经化学结果之间的关系，包括这些药物将：a)导致持续性单胺能缺陷；b)改变神经降压素水平；c)自我给药的可能性。如果自行给药，我们将像其他人最近的研究一样评估由此产生的持续性神经化学效应，我们证明了偶发和非偶发刺激剂暴露的影响之间的重要区别。3)评估合成卡西酮、可卡因、冰毒和/或MDMA联合给药对多巴胺能神经元持续神经化学影响的持续影响。其他人和我们已经证明，双重或连续暴露于精神刺激剂可以深刻改变他们的神经毒性特征，因此将对这个问题进行评估。

 DESCRIPTION (provided by applicant): The abuse of an increasing number of structurally diverse synthetic cathinones is a serious public health problem. The abuse of these agents is of concern for many reasons; including the fact that abuse of structurally related agents such as methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) can cause persistent neurochemical and cognitive deficits. Thus, it is likely that some synthetic cathinones might likewise cause detrimental effects. Still, surprisingly little is known concerning the persistent impact of these agents on monoaminergic neuronal function. An important consideration in evaluating the impact of synthetic cathinones is that as increasing numbers of these agents are banned, illicit operations introduce chemically novel replacements to evade regulatory restrictions. Thus, as described in PAR 14-106, it is important to develop interaction profiles of common synthetic cathinones with entities such as transporters in order to classify them according to their potential abuse liability and toxicity profiles. Such templates will also b useful to anticipate the impact of these novel compounds at various developmental stages, another important focus of this PAR. As one contributor to this template, we will test the hypothesis that differential alterations in dopamine transporter (DAT) and vesicular monoamine transporter-2 (VMAT2) function predict differences in the persistent neurochemical, post-synaptic and functional consequences of synthetic cathinones and related agents; an effect impacted by the developmental stage of initial analog exposure. This will be tested by completing the following aims: 1) Evaluate the acute impact of non-contingent exposure to representatives of each of three established classes of synthetic cathinones (mephedrone, methcathinone and 3,4-methylenedioxypyrovalerone) on DAT and VMAT2 localization and function. We will conduct these studies using both adolescent and young adult rats as others and we have established that these transporters' functions can be differentially regulated as a function of age. Additionally, we will evaluate the impact of these agents on parameters demonstrated to contribute to psychostimulant-induced neurotoxicity, including reactive species formation and glutamate release. 2) Investigate the relationship between drug-induced alterations in monoamine transporter function with behavioral and neurochemical functional outcomes, including the likelihood that these agents will: a) cause persistent monoaminergic deficits; b) alter neurotensin levels, and c) be self-administrated. If self-administered, we will evaluate consequent persistent neurochemical effects as recent studies from others and we demonstrate important distinctions between the impact of contingent and non-contingent stimulant exposure. 3) Evaluate the persistent impact of co-administration of synthetic cathinones with each other, cocaine, METH and/or MDMA on the persistent neurochemical impact on dopaminergic neurons. Others and we have demonstrated that dual or sequential exposure to psychostimulants can profoundly alter their neurotoxic profiles, and thus this issue will be evaluated.