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

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.