中枢血管紧张素II在甲基苯丙胺成瘾和神经毒性中的作用

This proposal is to delineate a novel role of the brain angiotensin II (AngII) system in modulation of METH-induced reward and neurotoxicity. We will use a combination of behavioral, pharmacological and neurochemical tools to demonstrate that chronic and neurotoxic METH treatment increases AngII activity. The enhanced brain AngII activity may in turn cause abnormal dopamine transmission and thereby promotes the adverse effects of METH. This proposal will not only elucidate a potential role of brain AngII receptors in the pathogenesis of METH addiction and neurotoxicity, but also implicate AngII receptors as a new drug target for therapeutic intervention. First, this proposal will elucidate a new role of brain AngII system in modulation of METH reward and neurotoxicity. Second, understanding the modulation of dopamine transmission by AngII in drug addiction may be applied to other diseases with dysfunctional dopaminer systems including Huntington’s disease and schizophrenia. Third, there is a high comorbidity of cardiovascular disease and brain disorders such as depression, anxiety and Parkinson’s disease. Delineation of the mechanistic actions of the heart drug (AT1R antagonists) to counteract the adverse effects of METH in the brain will open new avenues for consideration of available compounds with benefits in cardiovascular conditions for the treatment of brain diseases.

甲基苯丙胺成瘾影响多重中枢系统并产生神经毒性，同时伴有认知功能损害和精神障碍。甲基苯丙胺成瘾治疗有必要兼顾其神经毒性和成瘾性才有可能取得更好的效果。中枢血管紧张素II（AngII）在多种神经和精神疾病的潜在作用以及申请者的前期工作提示，中枢AngII以及受体ATR1系统可能会从多角度改善和治疗甲基苯丙胺成瘾以及神经损害，增加治疗的可能性和有效性。本项目拟从分子、基因、行为等不同层次系统研究AngII及其ATR1在甲基苯丙胺成瘾中和神经毒性中的作用。本项目首先探索中枢AngII和ATR1是否通过调控多巴胺和促肾上腺皮质激素释放激素（CRF）参与甲基苯丙胺成瘾的神经生物学机制，其次阐明中枢AngII和ATR1是否通过Nox2-ROS通路改变氧化应激水平从而影响甲基苯丙胺神经毒性，最后深入探索micro RNA是否介导AngII和ATR1参与的甲基苯丙胺成瘾和神经毒性机制。

甲基苯丙胺成瘾影响多重中枢系统并产生神经毒性，同时伴认知功能损害和精神障碍等外在行为表现。甲基苯丙胺成瘾治疗有必要兼顾其神经毒性和成瘾性才有可能取得更好的效果。文献及项目组前期工作表明中枢AngII以及受体系统可能会从多角度改善和治疗甲基苯丙胺成瘾和多重精神障碍和神经损害，增加甲基苯丙胺成瘾治疗的可能性和有效性。本项目从分子、基因、行为等不同层次系统研究AngII和ATR1在甲基苯丙胺成瘾中和神经毒性中的作用。本项目首先探索中枢AngII和ATR1在以及多巴胺的协同机制。其次，本项目阐明中枢AngII通过改变氧化应激水平从而影响甲基苯丙胺神经毒性。最后，本项目探索microRNA是否通过调控AngII以及ATR1,从而影响甲基苯丙胺成瘾的和强化作用和神经毒性。整个项目明确AngII以及ATR1在甲基苯丙胺成瘾和神经毒性中的双重调节作用，为ATR1拮抗剂治疗甲基苯丙胺成瘾提供实验依据，同时有助于认识AngII以及ATR1在中枢的调节机制。