| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
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-
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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
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