Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors
Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors
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DOI：
10.1124/mol.65.5.1293
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发表时间：
2004-05-01
影响因子：
3.6
通讯作者：
Nabeshima, T
中科院分区：
文献类型：
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作者：
Mizoguchi, H;Yamada, K;Nabeshima, T
与甲基苯丙胺(MAP)的奖赏效应有关的长期神经适应的分子机制知之甚少。在本研究中，我们研究了与MAP诱导的大鼠条件性位置偏爱(CPP)表达相关的细胞内信号。大鼠给予MAP或生理盐水(对照组)进行CPP实验条件反射。CPP试验后立即处死经MAP处理的动物和对照组动物。一些MAP处理的大鼠在没有CPP试验的情况下被处死。在MAP处理的CPP+动物的伏隔核(NAC)和纹状体中发现丝裂原活化蛋白激酶(MAPK)ERK1/2的过度磷酸化，而p38和c-jun氨基末端/应激激活蛋白激酶未见过度磷酸化。在对照组和MAP处理的CPP动物中没有发现这种磷酸化。此外，转录因子Ets-like gene-1(Elk-1)，而不是cAMP反应元件结合蛋白，在MAP处理的CPP+的相同区域也显示出类似的过度磷酸化。酪氨酸激酶受体，包括酪氨酸激酶B，在所有组的任何脑区都没有被激活。多巴胺D1受体拮抗剂R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2，3，4，5-tetrahydro-1H-3-benzazepine(SCH23390)和D2受体拮抗剂拉氯普利均可抑制MAP处理的CPP+动物CPP的表达和ERK1/2的激活。实验前向NAC内微量注射选择性MAPK激酶抑制剂2‘-氨基-3’-甲氧基黄酮酮(PD98059)，可阻断MAP诱导的ERK1/2激活，降低MAP诱导的CPP表达。这些结果提示ERK1/2信号通路在MAP诱导的CPP表达中具有重要作用。
Little is known about molecular mechanisms for long-lasting neuroadaptation related to the rewarding effects of methamphetamine (MAP). In the present study, we examined the intracellular signaling that is associated with the expression of conditioned place preference (CPP) induced by MAP in rats. Rats were given MAP or saline (control group) for conditioning to the CPP test. MAP-treated and control animals were killed immediately after the CPP test [CPP+]. Some of the MAP-treated rats were killed without the CPP test [CPP-]. Hyperphosphorylation of mitogen-activated protein kinase (MAPK) ERK1/2, but not p38 and c-Jun N-terminal kinase/stress-activated protein kinase, was found in the nucleus accumbens (NAc) and striatum but not in other brain areas of MAP-treated CPP+ animals. No such phosphorylation was seen in control and MAP-treated CPP- animals. Moreover, the transcription factor ets-like gene-1 (Elk-1), but not cAMP response element-binding protein, also showed a similar hyperphosphorylation in the same regions of MAP-treated CPP+. Tyrosine kinase receptors, including tyrosine kinase B, were not activated in any brain regions examined in all groups. Both the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) and the D2 receptor antagonist raclopride inhibited the expression of CPP as well as the activation of ERK1/2 in MAP-treated CPP+ animals, when they were injected before the CPP test. The microinjection of 2'-amino-3'-methoxyflavone (PD98059), a selective MAPK kinase inhibitor, into the NAc before the test, abolished the MAP-induced ERK1/2 activation and decreased the expression of MAP-induced CPP. These results suggest the importance of the ERK1/2 signaling pathway through activation of dopamine D1 and D2 receptors in the expression of CPP induced by MAP.