Journal of Pharmacology and Experimental Therapeutics, 258, 496-501 (1991)
Abstract
The purpose of this study was to investigate whether the muscarinic modulation
of neostriatal acetylcholine release changes with senescence. Neostriatal
slices from Fisher 344 rats aged 3, 10, and 28 months were prepared and
incubated in Krebs-Ringer bicarbonate buffer oxygenated with 95% O2/5%
CO2. Acetylcholine release from slices of each age group was
monitored in the presence or absence of muscarinic agents, and the release in
the presence of the drug was compared to the release from slices of age-matched
controls in the absence of drug. The muscarinic agonist, oxotremorine, and two
muscarinic antagonists, atropine and pirenzepine, were tested for their effects
on acetylcholine release. Pirenzepine is selective in its interaction with the
M1 muscarinic receptor subtype; atropine and oxotremorine are
nonselective in their actions. Of the three drugs tested, pirenzepine displayed
a significant age-related difference in its effects on acetylcholine release.
Whereas the effects of pirenzepine (50 mM) on acetylcholine
release modulation in slices from the 3-month rats were negligible, the M1-selective
antagonist increased the release of acetylcholine from slices of 10- and
28-month rats by another 42 and 192% (P < 0.05), respectively. Atropine (1 mM) was also tested, and an increase in acetylcholine release by another
64, 104, and 218% (all P < 0.05) was observed in slices from the 3-, 10-,
and 28-month rats, respectively. In the presence of oxotremorine (50 mM), acetylcholine release decreased in slices from the 3-month rats by
35% (P < 0.1), but changed by only 7 and 15% in the 10- and 28-month slices,
respectively. Pirenzepine was also tested for its dose-related effects in
slices from the three age groups. In concentrations ranging from 5 to 100 mM, pirenzepine induced a dose-related increase in acetylcholine release
from slices of the 28-month rats, but had no dose-related effects on release
from slices of the 10-month rats. In slices from the 3-month rats, the lowest
concentration of pirenzepine (5 mM) tended to
increase acetylcholine release (not significant). Pirenzepine, at
concentrations that significantly increased acetylcholine release from the
28-month slices, had little effect on acetylcholine release from the 3-month
slices. Receptor binding analysis of pirenzepine to neostriatal membranes
fractions from 3- and 28-month rats indicate an 18.3% decrease (P < 0.05) in
the density of pirenzepine binding sites in the neostriatum of the 28-month
animals. These results indicate that with senescence there is an increase in
the muscarinic modulation of acetylcholine release in the neostriatum. The
different effects of pirenzepine in the three age groups suggest that the
change in the muscarinic modulation of acetylcholine release might involve
different muscarinic receptor subtypes as the animal ages.
© 1991 The American Society for Pharmacology and Experimental Therapeutics
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