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

用针对CaM I、CaM II、CaM III三种不同钙调蛋白基因的反义寡核苷酸，急性给予4 mg/kg甲基苯丙胺后2 h，纹状体和伏隔核CaM I基因表达减少，6 h后恢复到对照水平；急性给予甲基苯丙胺后0.5、2、6 h，纹状体胞浆和胞膜中CaM I含量均降低。在慢性实验中，大鼠每天服用4 mg/kg冰毒或生理盐水，连续14天。禁欲4周后，大鼠接受冰毒(4 mg/kg)或生理盐水的刺激。慢性冰毒组和冰毒激发组大鼠中脑边缘区、内侧前额叶皮质和海马区细胞膜钙调素含量显著增加。这些结果表明，长期服用冰毒会导致钙调蛋白从胞浆部分移位到膜部分。钙调素-…在一次注射冰毒后，大鼠大脑的五个区域(顶叶皮质、额叶皮质、海马体、纹状体和伏隔核)中更依赖的蛋白激酶II(CaM-Kinase II)活性降低。选择性多巴胺D受体拮抗剂SCH-23390可阻止冰毒引起的大鼠顶叶皮质、纹状体、伏隔核和黑质/腹侧被盖区CaM-Kinase II活性的下降，而N-甲基-D-天冬氨酸受体拮抗剂MK-801可显著恢复冰毒所致的大鼠顶叶皮质、伏隔核和黑质/腹侧被盖区CaM-Kinase II活性的下降。在长期禁食冰毒1周而不是4周后，纹状体CaM-Kinase II活性仍显著低于慢性生理盐水治疗对照组。与长期注射生理盐水的大鼠相比，长期注射冰毒的大鼠在禁欲4周后接受冰毒刺激，导致CaM-Kinase II活性的下降更明显。Western印迹分析显示，与生理盐水处理的对照组相比，单次注射冰毒或长期注射冰毒后，CaM-Kinase II蛋白的数量没有改变。这些结果表明，在较长的戒断期后，长期服用冰毒会增强冰毒降低CaM-Kinase II活性的能力。较少

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