Medication Development for Methanphetamine Abuse

甲基苯丙胺（冰毒）滥用者因冰毒过量引起的高热和癫痫发作而在急诊室接受治疗后幸存下来，需要在随后的1-2周内进行治疗，不仅要治疗最初的危及生命的症状，而且要预防随后的坏死/凋亡级联反应，这不是目前的治疗方法。在最初的高热和癫痫发作期间的策略与由于中风等情况引起的缺氧/兴奋性中毒的策略没有什么不同。然而，这一应用提出的主要问题是，是否可以开发出预防和/或戒断治疗冰毒毒性和冰毒引起的功能变化的方法。需要的另一个主要治疗臂是治疗慢性冰毒暴戒期间的长时间无痛感（非典型抑郁）。长期治疗的另一个方面涉及甲基苯丙胺诱导的致敏与快速升级到高剂量甲基苯丙胺滥用之间的假设关系，即使在戒断几个月后也是如此。最后，最重要的是，如果重新引入甲基苯丙胺，任何针对各种情况提出的治疗方法都不会增强毒性。该项目的目标是建立一个慢性冰毒滥用的动物模型，描述与该模型相关的病理特征，并检查假定的药物治疗方法，以建立一个人类冰毒滥用和戒断的现实模型。我们提出，慢性冰毒给药方案将更接近人类状况，残留的神经化学和行为变化可能与经常使用的急性一天冰毒过量模型所描述的大不相同。此外，我们计划通过以下方法更全面地表征这两种模型：1)使用最先进的电化学技术，如快速循环伏安法（FCV），它可以区分多巴胺（DA）的释放和摄取，FCV结合光释放笼式DA方法；2)组织学、HPLC和电泳（Western Blot）方法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，我们将尝试预防和/或逆转甲基苯丙胺诱导的功能改变和神经病理，使用与我们对慢性模型的表征结果相关的药物谱。

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.