Brain Renin–Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity

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.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Fip5R7