Calcium-dependent mechanisms underlying methamphetamine-induced behavioral sensitization - an animal model of schizophrenia

利用反义寡核苷酸对三种不同的大鼠钙调素基因甲基苯丙胺（methamphetamine，METH）4 mg/kg急性给药后2 h内，纹状体和中脑核内CaM Ⅰ、CaM Ⅱ、CaM Ⅲ、CaM Ⅰ mRNA均降低，6 h后恢复到对照水平。METH急性给药后6 h。在慢性实验中，每天一次用4 mg/kg METH或盐水处理大鼠，持续14天。在4周的禁欲期后，用METH（4 mg/kg）或盐水攻击大鼠。钙调素的含量在膜馏分中的中脑边缘区，内侧前额叶皮层和海马的大鼠，经历了慢性METH管理和挑战与METH显着增加。这些结果表明，慢性METH给药导致钙调素从胞质组分移位到膜组分。 ...更多信息 在单次注射METH后，大鼠脑的五个区域（顶叶皮质、额叶皮质、海马、纹状体和丘脑核）中依赖性蛋白激酶II（CaM-激酶II）活性降低。预处理的选择性多巴胺D1受体拮抗剂SCH 23390防止急性甲基苯丙胺诱导的减少，在顶叶皮层，纹状体，核丘脑和黑质/腹侧被盖区的钙调蛋白激酶II活性。(SN用N-甲基-D-天冬氨酸受体拮抗剂MK-801预处理可显著恢复急性MET引起的顶叶皮质、丘脑核和SN/VTA中CaM激酶II活性的降低。纹状体钙调蛋白激酶II活性仍然显着低于慢性盐水治疗的对照组后，1周，但不是4周，从长期管理的甲基禁欲。一个METH的挑战后，4周的禁欲期诱导钙调蛋白激酶II活性在大鼠慢性注射METH比在大鼠慢性注射生理盐水更明显的下降。Western印迹分析显示，与盐水处理的对照组相比，单次注射METH或慢性注射METH后，CaM-激酶II蛋白的量没有改变。这些结果表明，长期治疗与METH导致的能力增强METH降低钙调蛋白激酶II活性后，延长停药期。少

Using antisense oligonucleotides to three distinct rat calmodulin 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 methamphetamine (METH), but returned to the control level by 6 h, The calmodulin contentin 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. Following a 4-week abstinence period, rats were challenged with either METH (4mg/kg) or saline. The calmodulin content in the membrane fraction was significantly increased in the mesolimbic area, medial prefrontal cortex and hippocampus of the rats that underwent the chronic METH administration and a challenge with METH. These results suggest that chronic METH administration leads to a translocation of calmodulin from the cytosolic to membrane fractions.Ca^<2+>/calmodulin- … More dependent protein kinase II (CaM-kinase II) activity was decreased in five regions of the rat brain (parietal cortex, frontal cortex, hippocampus, striatum and nucleus accumbens) after a single injection of METH. Pretreatment with the selective dopamine D1 receptor antagonist SCH 23390 prevented the acute METH-induced decrease in CaM-kinase II activity in the parietal cortex, striatum, nucleus accumbens and substantia nigra/ventral tegmental area.(SN/VTA) Pretreatment with the N-methyl-D-aspartate receptor antagonist MK-801 significantly restored the acute METH-induced decrease in CaM-kinase II activity in the parietal cortex, nucleus accumbens and SN/VTA. Striatal CaM-kinase II activity was still significantly lower than that of the chronic saline-treated controls after a 1-week, but not a 4-week, abstinence from chronic administration of METH. A METH challenge after a 4-week abstinence period induced a more pronounced decrease in CaM-kinase II activity in rats chronically injected with METH than in rats chronically injected with saline. Western blot analysis revealed that the amount of CaM-kinase II protein was not altered after a single METH injection or after chronic METH injections, compared with saline-treated controls. These results suggest that chronic treatment with METH leads to an enhanced capacity of METH to decrease CaM-kinase II activity after an extended withdrawal period. Less