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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
Statement of
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
RMID: 0030083315
DOI: 10.1007/s13311-018-0613-8
Appears in Collections:Medicine publications

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