National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, #1 Keyuan Road 4, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, China.
Department of Food Science and Technology, College of Light Industry, Textile and Food Engineering, Sichuan University, Chengdu, 610065, China.
Neurotherapeutics. 2018 Apr;15(2):500-510. doi: 10.1007/s13311-018-0613-8.
Methamphetamine (METH) abuse has become a major public health concern worldwide without approved pharmacotherapies. The brain renin-angiotensin system (RAS) is involved in the regulation of neuronal function as well as neurological disorders. Angiotensin II (Ang II), which interacts with Ang II type 1 receptor (AT-R) in the brain, plays an important role as a neuromodulator in dopaminergic transmission. However, the role of brain RAS in METH-induced behavior is largely unknown. Here, we revealed that repeated METH administration significantly upregulated the expression of AT-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT-R blocker telmisartan, which can penetrate the brain-blood barrier (BBB), or genetic deletion of AT-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT with lentiviral virus expressing AT reversed the weakened locomotor activity of AT mice treated with METH. Losartan alleviated METH-induced cytotoxicity in SH-SY5Y cells in vitro, which was accompanied by upregulated expressions of D3R and dopamine transporter. In addition, intraperitoneal injection of perindopril, which is a specific ACE inhibitor and can penetrate BBB, significantly attenuated METH-induced hyperlocomotor activity. Collectively, our results show that blockade of brain RAS attenuates METH-induced hyperlocomotion and neurotoxicity possibly through modulation of D3R expression. Our findings reveal a novel role of Ang II-AT-R in METH-induced hyperlocomotion.
甲基苯丙胺（METH）滥用已成为全球主要的公共卫生问题，但尚无批准的药物治疗方法。脑肾素-血管紧张素系统（RAS）参与神经元功能以及神经紊乱的调节。血管紧张素 II（Ang II）与脑内的血管紧张素 II 型 1 受体（AT-R）相互作用，作为多巴胺能传递的神经调节剂发挥重要作用。然而，脑 RAS 在 METH 诱导的行为中的作用在很大程度上尚不清楚。在这里，我们发现重复 METH 给药可显著上调小鼠纹状体中 AT-R 的表达，但下调多巴胺 D3 受体（D3R）的表达。一种可以穿透血脑屏障（BBB）的特定 AT-R 阻断剂替米沙坦，或 AT-R 的基因缺失足以减轻 METH 引发的小鼠过度活跃。然而，不能穿透 BBB 的腹腔内注射 AT-R 阻断剂洛沙坦未能减轻 METH 引起的行为。此外，用表达 AT 的慢病毒病毒在纹状体中再表达 AT 逆转了用 METH 治疗的 AT 小鼠运动活动减弱。洛沙坦在体外减轻了 METH 诱导的 SH-SY5Y 细胞的细胞毒性，同时伴随着 D3R 和多巴胺转运蛋白表达的上调。此外，腹腔内注射可以穿透 BBB 的特定 ACE 抑制剂培哚普利可显著减轻 METH 诱导的过度活跃。总之，我们的结果表明，阻断脑 RAS 可通过调节 D3R 表达来减轻 METH 诱导的过度活跃和神经毒性。我们的研究结果揭示了 Ang II-AT-R 在 METH 诱导的过度活跃中的新作用。
