Inhibition of PLCβ1 signaling pathway regulates methamphetamine self-administration and neurotoxicity in rats
Introduction
Long-term METH exposure has been shown to produce a wide range of psychological problems, including psychological distress, depression, suicide, anxiety, violent behaviours, and psychosis (Darke et al., 2008; Lecomte et al., 2018; Ma et al., 2018; McKetin et al., 2018; Potvin et al., 2018). Significant cognitive dysfunctions, including attention, prospective memory, retrospective memory, and executive operations, have also been suggested to be associated with long-term use of METH and interfere with daily function (Henry et al., 2010; Newton et al., 2004; Rendell et al., 2009; Simon et al., 2000, 2002). In line with the clinical studies, METH administration produces a multitude of behavioural abnormalities, including object and spatial memory impairments in the animals (Potvin et al., 2018; Rogers et al., 2008). Neurotoxicity is suggested to be one of the main mechanisms underlying METH-induced cognitive deficits. Exposure to high-dose METH leads to neuronal or glial toxicity in striatum, prefrontal cortex and amygdala in both rats and mice (Mark et al., 2004; Tata and Yamamoto, 2008; Veerasakul et al., 2016; Zhu et al., 2006). These comorbid disorders may further deteriorate the consequences of METH use disorder, indicating the need for “trans-diagnostic treatment approaches” (Bernheim et al., 2016; Hartel-Petri et al., 2017). Due to the lack of effective pharmacological treatment for METH use disorder, the medications specifically targeting the improvement of cognitive impairments may be promising to treat METH use disorder (Bernheim et al., 2016; Moszczynska and Callan, 2017; Soares and Pereira, 2019; Zhong et al., 2016).
Angiotensin II (Ang II) acts as a neuropeptide, neuromodulator, neurotransmitter, and neurohormone in the central nervous system (CNS) (Bali and Jaggi, 2013). It has been suggested to have a significant impact on several neurological and psychological disorders, such as Huntington's chorea, epilepsy, Alzheimer's disease, Parkinson's disease, and depression (Bali and Jaggi, 2013; Hariharan et al., 2014; Kehoe et al., 2019; Krasniqi and Daci, 2019; Labandeira-Garcia et al., 2016; Vian et al., 2017; Wright and Harding, 2019; Wright et al., 2008). Due to the high co-morbidity of METH use disorder and psychological disorders, some studies have investigated the role of angiotensin II in drug use disorder. Acute and chronic cocaine treatment increases angiotensin converting enzyme (ACE) activity and messenger RNA (mRNA) expression in the striatum and frontal cortex of rats (Visniauskas et al., 2012). ACE inhibitor, captopril, produces analgesic effects and can affect morphine-induced conditioned place preference and withdrawal signs in rats (Alaei and Hosseini, 2007). A growing number of studies have specifically focused the role of Ang II in the behavioural effects of drugs of abuse. For example, repeated METH administration upregulates AT1R mRNA and protein expression in the striatum of mice (Jiang et al., 2018). An AT1R blocker, telmisartan, has shown to attenuate METH-induced hyperlocomotion in mice (Jiang et al., 2018). The interaction between AT1R and amphetamine has been shown to contribute to long-term repeated amphetamine administration in rats (Marchese et al., 2016). In addition, the development of oxidative/inflammatory conditions could be modulated by AT1R in rats exposed to amphetamine (Marchese et al., 2020).
Our previous studies have also demonstrated that AT1R blockade significantly decreased METH self-administration (SA) and cue-/drug-induced reinstatement, in conjunction with counter-regulation of dopamine receptors and AT1R (Xu et al., 2019). The current study was designed to further explore the mechanism underlying the inhibitory effects of AT1R on the behavioural effects of METH, focusing on the phospholipase C β1 (PLCβ1)-cAMP response element-binding protein (CREB) signalling pathway. Firstly, the effect of AT1R blockade on various behavioural and neurotoxic effects induced by METH was investigated both in vivo and in vitro. Moreover, the role of PLCβ1-PKCα-CREB signalling pathway in the behavioural and neurotoxic effect of METH was examined. The potential impact of PLCβ1 blockade on the reinforcing and motivational effect of METH was finally studied, using METH SA and drug/cue-induced reinstatement animal model.
Section snippets
Drugs
METH was dissolved in 0.9% saline (0.9% NaCl). CAN (TCV-116) was purchased from Tokyo Chemical Industry (Tokyo, Japan) and dissolved in dimethyl sulfoxide (DMSO). U73122, a PLCβ1 inhibitor, was purchased from Med Chem Express (HY-13419, Shanghai, China). U73122 was dissolved in 20 μl of Tween 20 and resuspended it in saline solution. CAN and U73122 was administered via oral gavage and intraperitoneal (i.p.) injection, respectively.
Animals
Male Sprague-Dawley (SD) rats (8–10 weeks old, weighting between
Experiment 1: the effect of ATR1 blockade by CAN on the behavioral and neurotoxic effects of METH in rats
The procedures of Experiment 1 are summarized in Fig. 1A. DMSO and CAN was administered 2 h before all behavioral testing. Saline and METH was given 30 min prior to all behavioral testing. During the locomotor adaptation period, the rectal temperature was daily recorded. Based on the distance travelled during the last day of adaptation period, rats were divided into five groups (Saline+10CAN, Saline + DMSO, METH + DMSO, METH+5CAN and METH+10CAN). Immediately before the animals were placed into
Statistics
Data are presented as mean ± SD. P < 0.05 was considered as statistically significant. Body temperature is presented as temperature change from baseline (in °C) and analyzed by one-way analysis of variance (ANOVA) with Bonferroni's post hoc multiple comparisons test. For the locomotor activity test, two-way repeated measures ANOVA was used with Bonferroni's post hoc multiple comparisons to examine the effect of drug treatment on total distance travelled per session across days. For NOR test,
The effect of ATR1 blockade by CAN on the behavioral effects of METH in rats
One-way ANOVA analysis showed a significant group effect on body temperature changes from the baseline (F(4, 30) = 7.807, p < 0.001). Further post hoc analysis showed that the changes of body temperature of the METH + DMSO group was significantly higher than that of the Saline + DMSO group (Fig. 1B; p < 0.01). The body temperature changes from the baseline of both METH+5CAN (Fig. 1B; p < 0.01) and METH+10CAN (Fig. 1B; p < 0.001) groups were significantly lower than METH + DMSO group. There were
Discussion
The present study demonstrated that PLCβ1-PKCα-CREB signaling pathway played an important role in the inhibitory effect of ATR1 on various METH-mediated behavioral effects. Firstly, ATR1 inhibition by CAN significantly attenuated METH-induced behavioral disorders and neurotoxicity associated with increased oxidative stress. Furthermore, the data revealed that PLCβ1-PKCα-CREB signaling pathway, as well as a more specific role of PLCβ1, involved the inhibitory effects of AT1R on METH-induced
Author contributions
X.X. and Y.L. designed the study and prepared the manuscript; X.X., R.F., Y.R., M. X., J.H. performed all the in vivo and vitro experiments studies; M.C., X.L. participated in the analysis of the experiments. W.Z. and Y.L. contributed to the experimental design and revised the manuscript. All authors read and approved the final version of the manuscript.
CRediT authorship contribution statement
Xing Xu: designed the study and prepared the manuscript, performed all the in vivo and vitro experiments studies, All authors read and approved the final version of the manuscript. Runyue Fan: performed all the in vivo and vitro experiments studies, All authors read and approved the final version of the manuscript. Yanqian Ruan: performed all the in vivo and vitro experiments studies, All authors read and approved the final version of the manuscript. Mengjie Xu: performed all the in vivo and
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper
Acknowledgments
Funding: This work was supported in part by the National Natural Science Foundation of China (81671323; 81971247), Zhejiang Provincial Key R & D Plan 2019 (2020C03064), Ningbo R & D Plan (20181ZDYF020172), National Social Science Foundation Key Programs (18ZDA215), and the Program for Innovative Research Team in Ningbo City (2015C110026).
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