The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice
The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice
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DOI：
10.1523/jneurosci.1120-18.2019
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发表时间：
2019-08-07
影响因子：
5.3
通讯作者：
Spanagel, Rainer
中科院分区：
文献类型：
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作者：
Bernardi, Rick F.;Olevska, Anastasia;Spanagel, Rainer
Ras/Raf/MEK/ERK（Ras - ERK）信号通路与滥用药物的效应有关。MEK1/2（ERK1/2上游的激酶）抑制剂对于确定Ras - ERK级联在药物依赖的行为可塑性改变中的作用至关重要，但小GTP酶的Ras家族在药物相关行为中尚未得到广泛研究。我们研究了Ras鸟嘌呤核苷酸释放因子1（RasGRF1）和2（RasGRF2）（Ras - ERK信号级联的上游调节因子）在雄性小鼠可卡因自我给药（SA）中的作用。我们首先确定了Ras - ERK信号在可卡因SA中的作用，证明在C57BL/6N小鼠纹状体中，SA后pERK1/2上调。然后我们比较了RasGRF1和RasGRF2基因敲除（KO）小鼠品系，结果表明RasGRF2 KO小鼠的可卡因SA相对于野生型（WT）对照增加，而RasGRF1 KO和WT小鼠无差异。RasGRF2小鼠中的这种效应可能由Ras - ERK信号通路介导，因为在RasGRF2 KO小鼠中可卡因SA后pERK1/2未上调。有趣的是，在伏隔核（NAc）中通过慢病毒敲低RasGRF2产生了与RasGRF2 KO小鼠相反的效果，即减少了可卡因SA。随后我们证明，在可卡因SA前外周给予MEK抑制剂PD325901增加了可卡因摄入量，重现了RasGRF2 KO小鼠中观察到的增加现象，而将PD325901给予NAc则减少了可卡因摄入量，类似于慢病毒敲低RasGRF2后的效果。这些数据表明RasGRF2在小鼠可卡因SA中具有依赖ERK的作用，并提示全身性与位点特异性RasGRF2抑制具有不同的效应。
Ras/Raf/MEK/ERK (Ras-ERK) signaling has been implicated in the effects of drugs of abuse. Inhibitors of MEK1/2, the kinases upstream of ERK1/2, have been critical in defining the role of the Ras-ERK cascade in drug-dependent alterations in behavioral plasticity, but the Ras family of small GTPases has not been extensively examined in drug-related behaviors. We examined the role of Ras Guanine Nucleotide Releasing Factor 1 (RasGRF1) and 2 (RasGRF2), upstream regulators of the Ras-ERK signaling cascade, on cocaine self-administration (SA) in male mice. We first established a role for Ras-ERK signaling in cocaine SA, demonstrating that pERK1/2 is upregulated following SA in C57BL/6N mice in striatum. We then compared RasGRF1 and RasGRF2 KO mouse lines, demonstrating that cocaine SA in RasGRF2 KO mice was increased relative to WT controls, whereas RasGRF1 KO and WT mice did not differ. This effect in RasGRF2 mice is likely mediated by the Ras-ERK signaling pathway, as pERK1/2 upregulation following cocaine SA was absent in RasGRF2 KO mice. Interestingly, the lentiviral knockdown of RasGRF2 in the NAc had the opposite effect to that in RasGRF2 KO mice, reducing cocaine SA. We subsequently demonstrated that the MEK inhibitor PD325901 administered peripherally prior to cocaine SA increased cocaine intake, replicating the increase seen in RasGRF2 KO mice, whereas PD325901 administered into the NAc decreased cocaine intake, similar to the effect seen following lentiviral knockdown of RasGRF2. These data indicate a role for RasGRF2 in cocaine SA in mice that is ERK-dependent, and suggest a differential effect of global versus site-specific RasGRF2 inhibition.