Inhibition of PLCβ1 signaling pathway regulates methamphetamine
self-administration and neurotoxicity in rats
Abstract
Background and Purpose: Our previous studies have demonstrated that
angiotensin II receptor type 1 (AT1R) in the brain could be a potential
treatment for methamphetamine (METH)-induced dependence. The present
study aimed to investigate the underlying mechanisms of the inhibitory
effect of AT1R on various behavioural effects of METH. Experimental
Approach: We first examined the effect of AT1R antagonist, candesartan
cilexetil (CAN), on behavioural and neurotoxic effects of METH in vivo
and in vitro. We subsequently examine the changes of AT1R and PLCβ1 in
vivo and in vitro. Furthermore, we studied the role of PLCβ1 blockade on
METH-induced neurotoxicity and synaptic plastic changes. We finally
examined the effect of PLCβ1 blockade on the reinforcing and
motivational effects of METH. Key Results: CAN significantly elevated
METH-induced behavioral dysfunction and neurotoxicity associated with
increased oxidative stress. AT1R and phospholipase C β1 (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-protein kinase
C alpha (PKCα)-cAMP response element-binding protein (CREB) signalling
pathway. PLCβ1 blockade significantly decreased the reinforcing and
motivation effects of METH. Conclusion and Implications: PLCβ1-PKCα-CREB
signalling pathway, as well as a more specific role of PLCβ1, involved
the inhibitory effects of CAN on METH-induced behavioural dysfunction
and neurotoxicity. Our findings reveal a novel role of PLCβ1 in
METH-induced neurotoxicity and METH use disorder.