Studies have shown that the central renin-angiotensin system is involved in neurological disorders. Our previous studies have demonstrated that angiotensin II receptor type 1 (AT1R) in the brain could be a potential target against methamphetamine (METH) use disorder. The present study was designed to investigate the underlying mechanisms of the inhibitory effect of AT1R on various behavioural effects of METH. We first examined the effect of AT1R antagonist, candesartan cilexetil (CAN), on behavioural and neurotoxic effects of METH. Furthermore, we studied the role of phospholipase C beta 1 (PLCβ1) blockade behavioural and neurotoxic effects of METH. The results showed that CAN significantly attenuated METH-induced behavioral disorders and neurotoxicity associated with increased oxidative stress. AT1R and PLCβ1 were significantly upregulated in vivo and in vitro. Inhibition of PLCβ1 effectively alleviated METH-induced neurotoxicity and METH self-administration (SA) by central blockade of the PLCβ1 involved signalling pathway. PLCβ1 blockade significantly decreased the reinforcing and motivation effects of METH. PLCβ1 involved signalling pathway, as well as a more specific role of PLCβ1, involved the inhibitory effects of CAN on METH-induced behavioural dysfunction and neurotoxicity. Collectively, our findings reveal a novel role of PLCβ1 in METH-induced neurotoxicity and METH use disorder.
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