Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization Through the GluN2B-PP2A-AKT Cascade in the Dorsal Striatum of Mice

Chen, Gang; Li, Tao; Xiao, Jing; Wang, Jing; Shang, Qing; Qian, Hongyan; Qiao, Chuchu; Zhang, Ping; Chen, Teng; Liu, Xinshe

doi:10.1007/s11064-020-02966-8

Cited by 16 publications

(8 citation statements)

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“…Extracellular signal-regulated kinase 1/2 (ERK 1/2) constitutes the final component of the MAPK cascade [Raf/MAPK-ERK kinase (MEK)/ERK 1/2], which is crucial in the cellular and molecular mechanisms underlying the compulsive nature of addictive habits because of its ability to regulate cell proliferation and differentiation [10]. Interestingly, in contrast to the hypothesis of Mohan et al [11], who suggested that PP2A is an important negative regulator of ERK 1/2, we observed that the increased activity of PP2A was accompanied with the upregulation of phosphorylated ERK 1/2 (p-ERK 1/2) [12]. Meanwhile, Adams et al [13] demonstrated that PP2A phosphorylated ERK 1/2 by dephosphorylating p-Raf1 (Ser 259).…”

Section: Introductioncontrasting

confidence: 69%

LB100 attenuates methamphetamine-induced behavioral sensitization by inhibiting the Raf1-ERK 1/2 cascade in the caudate putamen

et al. 2021

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Methamphetamine (METH) abuse has become a serious social problem. Behavioral sensitization is a common behavioral paradigm used to study the neurobiological mechanism that underlies drug addiction. Our previous study demonstrated that the activity of protein phosphatase 2A (PP2A) and the level of phosphorylated extracellular signal-related kinase 1/2 (p-ERK 1/2) are increased in the caudate putamen (CPu) of METHsensitive mice. However, the relationship between PP2A and ERK 1/2 in METH-induced behavioral sensitization remains unknown. Some studies have indicated that Raf1 may be involved in this process. In this study, LB100, a PP2A inhibitor for treating solid tumors, was first used to clarify the relationship between PP2A and ERK 1/2. In addition, Western blot was used to examine the levels of p-Raf1 (Ser 259) and p-ERK 1/2 (Thr 202/ Tyr 204) in the CPu, hippocampus (Hip) and nucleus accumbens (NAc). Our results showed that 2 mg/kg LB100 significantly attenuated METH-induced behavioral sensitization. Furthermore, Western blot analysis revealed that pretreatment with 2 mg/kg LB100 remarkably reversed METH-induced reduction of p-Raf1, as well as upregulation of p-ERK 1/2 in the CPu. Taken together, these results indicate that PP2A plays an important role in METH-induced behavioral sensitization and phosphorylates ERK 1/2 by dephosphorylating p-Raf1 in the CPu to further regulate METH-induced behavioral sensitization.

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Section: Introductioncontrasting

confidence: 69%

LB100 attenuates methamphetamine-induced behavioral sensitization by inhibiting the Raf1-ERK 1/2 cascade in the caudate putamen

et al. 2021

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“…Furthermore, the Akt/mammalian target of rapamycin (mTOR) signaling pathway in the NAc is critically involved in the bidirectional synaptic plasticity after acute or chronic cocaine administration 10 . Methamphetamine‐induced behavioral sensitization required increased levels of the NMDA Receptor 2B (GluN2B)‐PP2A‐Akt cascade in the dorsal striatum 11 . Nicotine exposure during adolescence induces the profound upregulation of the Akt‐ glycogen synthase kinase 3(GSK‐3) signaling pathways directly within the NAc 12 .…”

Section: Introductionmentioning

confidence: 99%

“… 10 Methamphetamine‐induced behavioral sensitization required increased levels of the NMDA Receptor 2B (GluN2B)‐PP2A‐Akt cascade in the dorsal striatum. 11 Nicotine exposure during adolescence induces the profound upregulation of the Akt‐ glycogen synthase kinase 3(GSK‐3) signaling pathways directly within the NAc. 12 Furthermore, the p‐Akt level in the NAc is reduced when rats are re‐exposed to the cues associated cocaine memories in conditioned place preference model.…”

Section: Introductionmentioning

confidence: 99%

Akt and its phosphorylation in nucleus accumbens mediate heroin‐seeking behavior induced by cues in rats

et al. 2021

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Akt is initially identified as one of the downstream targets of phosphatidylinositol‐3 kinase (PI3K) and is involved in morphine reward and tolerance. However, whether phospholyration of Akt (p‐Akt) mediates heroin relapse remains unclear. Here, we aimed to explore the role of p‐Akt in the nucleus accumbens (NAc) in cue‐induced heroin‐seeking behaviors after withdrawal. First, rats were trained to self‐administer heroin for 14 days, after which we assessed heroin‐seeking behaviors induced by a context cue (CC) or by discrete conditioned cues (CS) after 1 day or 14 days of withdrawal. We found that the active responses induced by CC or CS after 14 days of withdrawal were higher than those after 1 day of withdrawal. Meanwhile, the expression of p‐Akt in the NAc was also greatest when rats were exposed to the CS after 14 days of withdrawal. Additionally, a microinjection of LY294002, an inhibitor of PI3K, into the NAc inhibited the CS‐induced heroin‐seeking behaviors after 14 days of withdrawal, paralleling the decreased levels of p‐Akt in the NAc. Finally, Akt1 or β‐arrestin 2 was downregulated via a lentiviral injection to assess the effect on heroin seeking after 14 days of withdrawal. CS‐induced heroin‐seeking behavior was inhibited by downregulation of Akt1, but not β‐arrestin 2, in the NAc. These data demonstrate that Akt phosphorylation in the NAc may play an important role in the incubation of heroin‐seeking behavior, suggesting that the PI3K/Akt pathways may be involved in the process of heroin relapse and addiction.

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“…We further analyzed common DMCs annotated genes and found that they were enriched in pathways such as axon guidance, circadian rhythm, oocyte meiosis, dopaminergic synapse, and adrenergic signaling in cardiomyocytes (top 5). Interestingly, we found that the gene Ppp2r2b (protein phosphatase two regulatory subunit B, beta isoform) was a conserved serine/threonine protein phosphatase involved in the dopaminergic pathway, which has been found implicated in neurological disorders ( Rampino et al, 2019 ; Wang et al, 2019 ), as well as METH-induced behavioral sensitization in our previous report ( Chen et al, 2020 ). This suggests that methylation changes of neurodevelopmental processes-related genes may contribute to enhanced sensitization effects in prenatal and postnatal METH-exposed males.…”

Section: Discussionmentioning

confidence: 81%

Maternal Methamphetamine Exposure Influences Behavioral Sensitization and Nucleus Accumbens DNA Methylation in Subsequent Generation

et al. 2022

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The deleterious effects of methamphetamine (METH) exposure extend beyond abusers, and may potentially impact the vulnerability of their offspring in developing addictive behaviors. Epigenetic signatures have been implicated in addiction, yet the characteristics to identify prenatal METH abuse to offspring addiction risk remains elusive. Here, we used escalating doses of METH-exposed mouse model in F0 female mice before and during pregnancy to simulate the human pattern of drug abuse and generated METH-induced behavioral sensitization to investigate the addictive behavior in offspring mice. We then utilized whole genome-bisulfite sequencing (WGBS) to investigate the methylation signature of nucleus accumbens (NAc) in male METH-sensitized mice. Interestingly, male but not female offspring exhibited an enhanced response to METH-induced behavioral sensitization. Additionally, the METH-exposed group of male mice underwent a more comprehensive wave of epigenome remodeling over all genomic elements compared with unexposed groups due to drug exposure history. 104,219 DMCs (METH-SAL vs. SAL-SAL) induced by prenatal METH-exposure were positively correlated with that of postnatal METH-exposure (38,570, SAL-METH vs. SAL-SAL). Moreover, 4,983 DMCs induced by pre- and postnatal METH exposure (METH-METH vs. SAL-METH) were negatively correlated with that of postnatal METH exposure, and 371 commonly changed DMCs between the two comparison groups also showed a significantly negative correlation and 86 annotated genes functionally enriched in the pathways of neurodevelopment and addiction. Key annotated genes included Kirrel3, Lrpprc, and Peg3, implicated in neurodevelopmental processes, were down-regulated in METH-METH group mice compared with the SAL-METH group. Taken together, we render novel insights into the epigenetic correlation of drug exposure and provide evidence for epigenetic characteristics that link maternal METH exposure to the intensity of the same drug-induced behavioral sensitization in adult offspring.

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Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization Through the GluN2B-PP2A-AKT Cascade in the Dorsal Striatum of Mice

Cited by 16 publications

References 50 publications

LB100 attenuates methamphetamine-induced behavioral sensitization by inhibiting the Raf1-ERK 1/2 cascade in the caudate putamen

LB100 attenuates methamphetamine-induced behavioral sensitization by inhibiting the Raf1-ERK 1/2 cascade in the caudate putamen

Akt and its phosphorylation in nucleus accumbens mediate heroin‐seeking behavior induced by cues in rats

Maternal Methamphetamine Exposure Influences Behavioral Sensitization and Nucleus Accumbens DNA Methylation in Subsequent Generation

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