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https://hdl.handle.net/2440/113959
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Type: | Journal article |
Title: | Brain renin-angiotensin system blockade attenuates methamphetamine-Induced hyperlocomotion and neurotoxicity |
Author: | Jiang, L. Zhu, R. Bu, Q. Li, Y. Shao, X. Gu, H. Kong, J. Luo, L. Long, H. Guo, W. Tian, J. Zhao, Y. Cen, X. |
Citation: | Neurotherapeutics, 2018; 15(2):500-510 |
Publisher: | Springer Verlag |
Issue Date: | 2018 |
ISSN: | 1933-7213 1878-7479 |
Statement of Responsibility: | Linhong Jiang, Ruiming Zhu, Qian Bu, Yan Li, Xue Shao, Hui Gu, Jueying Kong, Li Luo, Hailei Long, Wei Guo, Jingwei Tian, Yinglan Zhao, Xiaobo Cen |
Abstract: | 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 (AT1-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 AT1-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT1-R blocker telmisartan, which can penetrate the brain-blood barrier (BBB), or genetic deletion of AT1-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT1-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT1 with lentiviral virus expressing AT1 reversed the weakened locomotor activity of AT1-/- 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-AT1-R in METH-induced hyperlocomotion. |
Keywords: | AT1-R Angiotensin II D3R Hyperlocomotion Methamphetamine Neurotoxicity |
Rights: | © The American Society for Experimental NeuroTherapeutics, Inc. 2018 |
DOI: | 10.1007/s13311-018-0613-8 |
Published version: | http://dx.doi.org/10.1007/s13311-018-0613-8 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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