Ca. Barnes et al., Chronic treatment of old rats with donepezil or galantamine: Effects on memory, hippocampal plasticity and nicotinic receptors, NEUROSCIENC, 99(1), 2000, pp. 17-23
The function of the cholinergic system is known to change during normal agi
ng and in pathological conditions such as Alzheimer's disease. The present
study was designed to assess, within the same group of old animals, the beh
avioral, electrophysiological and neurochemical effects of chronic treatmen
t with agents that increase the function of the cholinergic system through
both muscarinic and nicotinic mechanisms. Doses were determined that produc
ed 60% cholinesterase inhibition by donepezil and galantamine for the old r
ats. This was chosen to be analogous to therapeutic levels achieved for tre
atment of human Alzheimer's disease patients with these agents. Because of
the well-known age-related changes in spatial memory and hippocampal synapt
ic plasticity, spatial working memory in the radial eight-arm maze and hipp
ocampal long-term potentiation induction and decay as well as nicotinic rec
eptor density and affinity, were measured in old rats implanted with minipu
mps that delivered donepezil, galantamine or saline. There was no effect of
drug treatment on baseline synaptic transmission or on the threshold or ma
gnitude of long-term potentiation induction. Both drug treatment groups, ho
wever, showed significantly extended long-term potentiation decay times at
the perforant path-granule cell synapse over the saline control animals, as
measured during the week following induction. Both drugs also elevated the
number of nicotinic receptors within the hippocampus and neocortex. This i
s the first demonstration of cholinergic modulation of synaptic plasticity
over the time-course of days. Furthermore, the durability of long-term pote
ntiation was significantly, positively correlated with nicotinic receptor b
inding in the hippocampus. Chronic treatment with donepezil or galantamine
had no significant effect on a well-learned spatial working memory task on
the radial maze.
These data suggest that the therapeutic doses of cholinesterase inhibitors
used to treat patients with Alzheimer's disease may have effects on neuroph
ysiology and neurochemistry that are close to the threshold for producing d
etectable behavioral improvements. (C) 2000 IBRO, Published by Elsevier Sci
ence Ltd. All rights reserved.