Medication Development for Methanphetamine Abuse

甲基苯丙胺(冰毒)滥用者在因冰毒过量引起的体温过高和癫痫发作而在急诊室接受治疗后幸存下来，需要在接下来的1-2周内不仅治疗最初威胁生命的症状，而且还预防随后的坏死/凋亡级联反应，这不是目前的治疗方法。在最初的体温过高和癫痫发作期间的策略与因中风等条件而制定的缺氧/兴奋性策略没有什么不同。然而，这一应用提出的主要问题是，是否可以开发预防和/或戒断治疗，以应对冰毒和由冰毒暴饮暴食引起的功能变化。另一个需要的主要治疗武器是治疗慢性冰毒暴饮期停药期间延长的无痛期(非典型抑郁症)。长期治疗的另一个方面涉及冰毒致敏和迅速升级为高剂量冰毒滥用之间的假设关系，即使在戒毒几个月后也是如此。最后，应该有一个压倒一切的关切，即如果重新引入冰毒，针对各种情况提出的任何治疗方法都不会增强毒性。该项目的目标是开发一种慢性冰毒滥用的动物模型，描述与该模型相关的病理特征，并为现实的人类冰毒滥用和戒断模型检查可能的药物治疗。我们认为，慢性冰毒剂量方案将更接近人类的情况，残留的神经化学和行为变化可能与经常使用的急性单日冰毒过量模型所描述的显著不同。此外，我们计划通过使用1)最先进的电化学技术来更全面地表征这两种模型，例如可以区分多巴胺(DA)释放和摄取的快速循环伏安法(FCV)，以及FCV与光释放笼式DA方法相结合的方法，以及2)组织学、高效液相和电泳法(Western Blot)来表征神经病理和功能变化。我们还计划更广泛地跟踪冰毒治疗后的残留行为状态。最后，我们将尝试使用根据我们对慢性模型的表征结果选择的一系列药物来预防和/或逆转冰毒引起的功能变化和神经病理。

Methamphetamine (METH) abusers surviving emergency room treatment for METH overdose induced hyperthermia and seizures require treatment in the ensuing 1-2 weeks not only for the initial life-threatening symptoms but also for the prevention of the subsequent necrotic/apoptotic cascades which are not a current therapy. The strategy during the initial hyperthermia and seizures is not unlike those being formulated for hypoxia/excitoxicity due to such conditions as stroke. However the main question posed by this application is whether preventative and/or withdrawal treatment for METH toxicity and functional changes induced by METH binges could be developed. The other major treatment arm that is needed is for the treatment of the extended period of anergia (atypical depression) during withdrawal from chronic METH binges. Another aspect of long-term treatment relates to the hypothesized relationship between METH induced sensitization and the rapid escalation to high dose METH abuse, even after months of abstinence. Finally there should be an overriding concern that any treatment proposed for various conditions does not potentiate toxicity if METH is reintroduced. The goal of this project is to develop an animal model for chronic METH abuse, characterize the pathologies associated with this model and examine putative drug treatments for a realistic model of human METH abuse and withdrawal. We propose that a chronic METH dosing regimen will more closely approximate the human condition and that residual neurochemical and behavioral changes may be substantially different from those described for the frequently used acute one-day METH overdose model. Furthermore we plan to more fully characterize both models by using 1) state of the art electrochemical techniques such as Fast Cyclic Voltammetry (FCV) which can differentiate between dopamine (DA) release and uptake, and FCV coupled with photo-released caged DA methodology and 2) histological, HPLC and electrophoresis (Western Blot) methods to characterize the neuropathological and functional changes. We also plan to more extensively follow the residual behavioral states after METH treatment. Finally we will attempt to prevent and/or reverse the METH induced functional changes and neuropathologies using a spectrum of drugs chosen with respect to the results of our characterization of the chronic model.