Inhibition of PLCβ1 signaling pathway regulates methamphetamine self-administration and neurotoxicity in rats

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 (PLC beta 1) 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 PLC beta 1 were significantly upregulated in vivo and in vitro. Inhibition of PLC beta 1 effectively alleviated METH-induced neurotoxicity and METH self-administration (SA) by central blockade of the PLC beta 1 involved signalling pathway. PLC beta 1 blockade significantly decreased the reinforcing and motivation effects of METH. PLC beta 1 involved signalling pathway, as well as a more specific role of PLC beta 1, involved the inhibitory effects of CAN on METH-induced behavioural dysfunction and neurotoxicity. Collectively, our findings reveal a novel role of PLC beta 1 in METH-induced neurotoxicity and METH use disorder.

Automated summary

Studies have shown that AT1R and PLC beta 1 are involved in METH-induced neurotoxicity and addiction, with inhibition of PLC beta 1 alleviating these effects, and CAN exerting inhibitory effects on METH-induced behavioral disorders and neurotoxicity.