Nimodipine, a 1,4-dihydropyridine calcium antagonist related to nifedipine, is reportedly clinically beneficial in the treatment of dementias and experimentally effective in memory and performance paradigms in aging animals. These observations suggest that changes in voltage-gated calcium channels may contribute to the aging performance. This work will use aging rodents, the Fischer 344 rat, and will study changes in channels as a function of age from 3 to 30 months. Changes in the number of L- and N-type voltage-gated calcium channels will be measured by radioligand binding with a 1,4-dihydropyridine and w-conotoxin respectively. Functional measurements of calcium channels will include 45calcium uptake into brain synaptosomes and K+ depolarization-induced PI turnover. Several discrete brain regions will be studied including brain stem, cortex, caudate, olfactory bulb, striatum and cerebellum. Radial maze studies will be employed to correlate behavioral and channel changes. To define the action of nimodipine animals will be chronically treated with drug and measurements of channel number and function made. Chronic treatment may yield, in common with other receptor systems, an up-regulation of calcium channels. This may underlie the reported therapeutic effects of nimodipine. Together with these measurements of calcium channel number and-function we will assess the numbers of a variety of neurotransmitter receptors, including acetylcholine [muscarinic] and adrenergic [beta-receptor] together with ATP-dependent K+ channels. These data will permit literature comparisons and provide a broader assessment of membrane protein changes with aging. The calcium channel changes will be the major focus of attention and this work will provide the first systematic examination of these changes during the aging process.
| Bangalore, R; Triggle, D J (1995) Age-dependent changes in voltage-gated calcium channels and ATP-dependent potassium channels in Fischer 344 rats. Gen Pharmacol 26:1237-42 |
| Liu, J; Rutledge, A; Triggle, D J (1995) Short-term regulation of neuronal calcium channels by depolarization. Ann N Y Acad Sci 765:119-33;discussion 160-2 |
