Inhibition of Methamphetamine Self-Administration and Reinstatement by Central Blockade of Angiotensin II Receptor in Rats

Xu, Xingshun; Pan, Jian; Li, Xingxing; Cui, Yan; Mao, Zijuan; Wu, Boliang; Xu, Huachong; Zhou, Wenhua; Liu, Yu

doi:10.1124/jpet.118.255729

Cited by 17 publications

(16 citation statements)

References 62 publications

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“…With 4 h/d drug access, heroin or MA self-administration were stable both over time and across doses after 10-d training (15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…With 4 h/d drug access, heroin or MA self-administration were stable both over time and across doses after 10-d training ( 15 – 18 ). The dose–effect curve of heroin showed a negative linear trend, and the active response decreased following the dose increase, consistently with the reinforcement theory ( 19 ).The limbic dopaminergic system was proposed as the neurobiological substrate for the rewarding effects of both opiates and psychostimulants.…”

Section: Discussionmentioning

confidence: 99%

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Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats

et al. 2020

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Heroin and methamphetamine are both popular illicit drugs in China. Previous clinical data showed that habitual users of either heroin or methamphetamine abuse the other drug for substitution in case of unavailability of their preferred drug. The present study aimed to observe whether heroin can substitute the methamphetamine reinforcement effect in rats, and vice versa. Rats were trained to self-administer heroin or methamphetamine (both 50 mg/kg/infusion) under an FR1 reinforcing schedule for 10 days. After having extracted the dose-effect curve of the two drugs, we administered methamphetamine at different doses (12.5-200 mg/kg/infusion) to replace heroin during the period of self-administration, and vice versa. The heroin dose-effect curve showed an inverted U-shaped trend, and the total intake dose of heroin significantly increased when the training dose increased from 50 to 100 or 200 mg/kg/infusion. Following replacement with methamphetamine, the total dose-effect curve shifted leftwards and upwards. By contrast, although the dose-effect curve of methamphetamine also showed an inverted U-shaped trend, the total dose of methamphetamine significantly decreased when the training dose decreased from 50 to 25 mg/kg/infusion; conversely, when the methamphetamine training dose increased, the total dose did not change significantly. The total dose-effect curve shifted rightwards after heroin was substituted with methamphetamine. Although heroin and methamphetamine had their own independent reward effects, low doses of methamphetamine can replace the heroin reward effect, while high doses of heroin can replace the methamphetamine reward effect. These results demonstrated that heroin and methamphetamine can substitute each other in terms of reinforcement effects in rats.

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“…With 4 h/d drug access, heroin or MA self-administration were stable both over time and across doses after 10-d training (15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats

et al. 2020

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“…Moreover, METH was found to augment brain ANG II/AT-1R signaling, promoting neuronal senescence, and neurocognitive deficits, further emphasizing the connection between RAS and DAS in both neurodegenerative and addictive disorders (136,137). Conversely, ARBs are currently being tested for METH addiction, as preclinical studies have reported decreased selfadministration of this stimulant in candesartan-treated rodents (138). This points to the fact that a better understanding of COVID-19 may have unintended consequences: improved treatment of addictions.…”

Section: The Virus the Ras And The Dasmentioning

confidence: 99%

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).

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“…Male Sprague-Dawley (SD) rats was purchased from Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China. The animals were individually housed under a standard environment that was previously described (Xu et al, 2019). The experimental protocol was approved by the Institutional Animal Care and Use Committee of Ningbo University.…”

Section: Animalsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Fan

Ruan

et al.

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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 elementbinding 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.

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Inhibition of Methamphetamine Self-Administration and Reinstatement by Central Blockade of Angiotensin II Receptor in Rats

Cited by 17 publications

References 62 publications

Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats

Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats

Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis

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

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