Shimizu Y, Akiyama K, Kodama M, Ishihara T, Hamamura T, Kuroda S
Department of Neuropsychiatry, Okayama University Medical School, Japan.
Brain Res. 1997 Aug 15;765(2):247-58. doi: 10.1016/s0006-8993(97)00435-6.
The effect of acute and chronic administration of methamphetamine (METH) on the levels of calmodulin (CaM) and its mRNAs has been investigated in rat brain using antisense oligonucleotides to three distinct rat CaM genes (CaM I, CaM II, CaM III). CaM I mRNA was reduced in the striatum and nucleus accumbens within 2 h of acute administration of 4 mg/kg METH, but returned to the control level by 6 h. The CaM content in both the cytosolic and membrane fractions of the striatum was reduced 0.5, 2, and 6 h after acute administration of METH. In the chronic experiments, rats were treated with either 4 mg/kg METH or saline once daily for 14 days. This was followed by a withdrawal period of 28 days, and thereafter, the animals were challenged with either METH (4 mg/kg, i.p.) or saline. All the animals were decapitated 6 h after this injection. There were four treatment groups: METH-METH (MM); METH-saline (MS); saline-METH (SM); and saline-saline (SS). There was a significant decrease in the mRNA for CaM I and CaM II in the striatum, and CaM II and CaM III in the nucleus accumbens in the MS group and the MS and MM groups, respectively, when compared to the SS group. The CaM content in the striatal membrane fraction decreased in both the SM and MS groups but not in the MM group. In contrast, the CaM content in the membrane fraction of the mesolimbic area showed a significant increase in the MM group. The CaM content in the cytosolic fraction of these brain areas decreased in both the SM and MM groups. The total CaM decreased significantly in the SM and MM groups of the striatum, but increased significantly in the MM group of the mesolimbic area. The mRNA for CaM I and CaM III decreased significantly in the MM group, and in the SM and MM groups, in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA), respectively. The CaM content in both the cytosolic and membrane fractions and total CaM content of the SN/VTA decreased significantly in the SM, MS and MM group as compared with the SS group. In the medial prefrontal cortex and hippocampus the significant increase of CaM content in the membrane fraction of the MM group was also found, but neither the CaM content in the cytosol fraction nor total CaM content changed. These results suggest that chronic METH administration leads to a translocation of CaM from the cytosolic to membrane fractions; these may underlie METH-induced behavioral sensitization.
利用针对大鼠三个不同钙调蛋白基因（钙调蛋白I、钙调蛋白II、钙调蛋白III）的反义寡核苷酸，研究了急性和慢性给予甲基苯丙胺（METH）对大鼠脑内钙调蛋白（CaM）水平及其mRNA的影响。急性给予4mg/kg METH后2小时内，纹状体和伏隔核中的钙调蛋白I mRNA减少，但6小时后恢复到对照水平。急性给予METH后0.5、2和6小时，纹状体胞质和膜部分中的CaM含量均降低。在慢性实验中，大鼠每天一次给予4mg/kg METH或生理盐水，持续14天。随后是28天的戒断期，此后，动物接受METH（4mg/kg，腹腔注射）或生理盐水刺激。注射后6小时将所有动物断头。有四个治疗组：METH-METH（MM）；METH-生理盐水（MS）；生理盐水-METH（SM）；生理盐水-生理盐水（SS）。与SS组相比，MS组纹状体中钙调蛋白I和钙调蛋白II的mRNA以及MS组和MM组伏隔核中钙调蛋白II和钙调蛋白III的mRNA均显著降低。SM组和MS组纹状体膜部分中的CaM含量降低，但MM组未降低。相反，中脑边缘区膜部分中的CaM含量在MM组中显著增加。这些脑区胞质部分中的CaM含量在SM组和MM组中均降低。纹状体的SM组和MM组中总CaM显著降低，但中脑边缘区的MM组中显著增加。钙调蛋白I和钙调蛋白III的mRNA在MM组中显著降低，在黑质致密部（SNC）和腹侧被盖区（VTA）中，分别在SM组和MM组中显著降低。与SS组相比，SM、MS和MM组中SN/VTA的胞质和膜部分中的CaM含量以及总CaM含量均显著降低。在内侧前额叶皮质和海马中，也发现MM组膜部分中的CaM含量显著增加，但胞质部分中的CaM含量和总CaM含量均未改变。这些结果表明，慢性给予METH导致CaM从胞质部分转运到膜部分；这些可能是METH诱导的行为敏化的基础。
