Nikaido T, Akiyama M, Moriya T, Shibata S
Department of Pharmacology and Brain Science, School of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan.
Mol Pharmacol. 2001 Apr;59(4):894-900. doi: 10.1124/mol.59.4.894.
Methamphetamine (MAP) causes the sensitization phenomena not only in MAP-induced locomotor activity, dopamine release, and Fos expression, but also in MAP-induced circadian rhythm. Cocaine-induced sensitization is reportedly impaired in Drosophila melanogaster mutant for the Period (Per) gene. Thus, sensitization may be related to induction of the Per gene. A rapid induction of mPer1 and/or mPer2 in the suprachiasmatic nucleus after light exposure is believed to be necessary for light-induced behavioral phase shifting. Although the caudate/putamen (CPu) expresses mPer1 and/or mPer2 mRNA, the function of these genes in this nucleus has not yet been elucidated. Therefore, we examined whether MAP affects the expression of mPer1 and/or mPer2 mRNA in the mouse CPu. Injection of MAP augmented the expression of mPer1 but not mPer2 or mPer3 in the CPu, and this MAP-induced increase in mPer1 expression lasted for 2 h. Also, the MAP-induced increase of mPer1 mRNA was strongly antagonized by pretreatment with a dopamine D1 receptor and N-methyl-D-aspartate (NMDA) receptor antagonist, but not by a D2 receptor antagonist. Interestingly, application of either the D1 or the D2 agonist alone did not cause mPer1 expression. The present results demonstrate that activation of both NMDA and D1 receptors is necessary to produce MAP-induced mPer1 expression in the CPu. Repeated injection of MAP caused a sensitization in not only the locomotor activity but also mPer1 expression in the CPu without affecting the level of mPer2, mPer3, or mTim mRNA. Thus, these results suggest that MAP-induced mPer1 gene expression may be related to the mechanism for MAP-induced sensitization in the mouse.
甲基苯丙胺（MAP）不仅会在MAP诱导的运动活动、多巴胺释放和Fos表达中引发敏化现象，还会在MAP诱导的昼夜节律中引发该现象。据报道，在果蝇Period（Per）基因突变体中，可卡因诱导的敏化受到损害。因此，敏化可能与Per基因的诱导有关。光照后，视交叉上核中mPer1和/或mPer2的快速诱导被认为是光诱导行为相位转移所必需的。虽然尾状核/壳核（CPu）表达mPer1和/或mPer2 mRNA，但这些基因在该核中的功能尚未阐明。因此，我们研究了MAP是否会影响小鼠CPu中mPer1和/或mPer2 mRNA的表达。注射MAP可增强CPu中mPer1的表达，但不会增强mPer2或mPer3的表达，且这种MAP诱导的mPer1表达增加持续2小时。此外，多巴胺D1受体和N-甲基-D-天冬氨酸（NMDA）受体拮抗剂预处理可强烈拮抗MAP诱导的mPer1 mRNA增加，但D2受体拮抗剂则不能。有趣的是，单独应用D1或D2激动剂均不会导致mPer1表达。目前的结果表明，NMDA和D1受体的激活对于在CPu中产生MAP诱导的mPer1表达是必要的。重复注射MAP不仅会导致运动活动敏化，还会导致CPu中mPer1表达敏化，而不会影响mPer2、mPer3或mTim mRNA的水平。因此，这些结果表明，MAP诱导的mPer1基因表达可能与小鼠中MAP诱导的敏化机制有关。
