Medication Development for Methanphetamine Abuse

在METH过量诱导的高热和癫痫发作的急诊室治疗中幸存的甲基苯丙胺（METH）滥用者需要在随后的1-2周内进行治疗，不仅是为了治疗最初的危及生命的症状，而且是为了预防随后的坏死/凋亡级联反应，这不是当前的治疗方法。 在最初的高热和癫痫发作期间的策略与由于中风等条件而制定的缺氧/兴奋毒性的策略没有什么不同。 然而，该申请提出的主要问题是，是否可以开发针对METH中毒和由METH狂欢引起的功能变化的预防性和/或戒断治疗。另一个需要的主要治疗方法是治疗慢性METH狂欢戒断期间的长时间无活力（非典型抑郁）。 长期治疗的另一个方面涉及METH诱导的致敏与快速升级至高剂量METH滥用之间的假设关系，即使在数月的禁欲之后。 最后，应该有一个压倒一切的关注，即如果重新引入甲基，为各种条件提出的任何治疗都不会增强毒性。该项目的目标是开发一种慢性METH滥用的动物模型，描述与该模型相关的病理学特征，并检查人类METH滥用和戒断的现实模型的假定药物治疗。 我们建议，慢性METH给药方案将更接近人体状况，残留的神经化学和行为变化可能与经常使用的急性一天METH过量模型所描述的变化有很大不同。此外，我们计划通过使用1）最先进的电化学技术，如快速循环伏安法（FCV）（可区分多巴胺（DA）释放和摄取）和FCV结合光释放笼状DA方法，以及2）组织学、HPLC和电泳（Western Blot）方法来更全面地表征两种模型，以表征神经病理学和功能变化。 我们还计划更广泛地跟踪METH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药物谱来预防和/或逆转METH诱导的功能变化和神经病理学。

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.