Effects of Ca2+ antagonists on motor activity and the dopaminergic system in aged mice

We investigated the effects of the Ca2+ antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca2+ antagonist, amlodipine. Furthermore, we examined the close correlation between the dopaminergic system and motor activity during the aging process. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents were measured in 2-, 4-, 8-, 18- and 36-week-old mice. Behavioral tests (pole and catalepsy test) were performed with 4- and 36-week-old mice. Nilvadipine or amlodipine was administered intraperitoneally twice a day for 3 consecutive days to 30-36-week-old mice. The striatal dopan-tine, DOPAC and HVA contents were examined and behavioral tests were performed 1 h after the last injection of each Ca2+ antagonist. The dopamine, DOPAC and HVA contents in 2-week-old mice were significantly decreased in the striatum, as compared with 4-week-old animals. Thereafter, age-related increases in the dopamine, DOPAC and HVA contents were observed from 4 to 18 weeks old. However, in 36-week-old mice, the dopamine and DOPAC contents were reduced in the striatum, as compared with 18-week-old animals. Age-related decreases in motor function between 5- and 36-week-old mice were observed in both pole test and catalepsy tests. On the other hand, nilvalipine treatment produced a significant and dose-dependent increase in the striatal dopamine and DOPAC contents in 30-36-week-old mice. In contrast, no significant changes were observed in the striatal dopamine content in amlodipine-treated mice, although this drug showed a significant and dose-dependent increase in the striatal DOPAC and HVA content. In our behavioral study, nilvadipine also showed a significant and dose-dependent inhibition against motor deficits in 30-36-week-old mice. In contrast, amlodipine showed no significant effect on motor deficits in 30-36-week-old mice. The present study demonstrated that nilvadipine, has a protective effect against the deficits in both the striatal dopaminergic system and motor activity in aged mice. Our study also suggested that the beneficial effect of nilvadipine against motor abnormalities may be mediated by a protective effect against the reduced activity of the dopaminergic system in aged mice. These results suggested that nilvadipine may offer a new approach for the treatment of hypobulia in aged humans. (C) 2002 Elsevier Science Inc. All rights reserved.