Effects of Ca2+ antagonists on motor activity and the dopaminergic system in aged mice.
We investigated the effects of the Ca(2+) antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca(2+) 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 dopamine, DOPAC and HVA contents were examined and behavioral tests were performed 1h after the last injection of each Ca(2+) 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.
Kurosaki
Rumiko
R
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.
Akasaka
Megumi
M
Michimata
Mari
M
Matsubara
Mitsunobu
M
Imai
Yutaka
Y
Araki
Tsutomu
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D002121:Calcium Channel Blockers; C035100:nilvadipine; D015102:3,4-Dihydroxyphenylacetic Acid; D017311:Amlodipine; D009543:Nifedipine; D004298:Dopamine; D006719:Homovanillic Acid