The effects of acute and chronic administration of
MKC-231, a new
choline uptake enhancer, and two other
nootropic agents, linopiridine (
Dup 996) and
tetrahydroaminoacridine (THA) on working memory deficits and decreased hippocampal
acetylcholine (ACh) content were studied in a delayed non-matching to sample task, using a T-maze, in
ethylcholine aziridinium ion (AF64A)-treated mice. Treatment with
AF64A (3.5 nmol, i.c.v.) produced
memory deficits and decreased hippocampal ACh content. In acute behavioral experiments,
MKC-231 and THA had no significant effect on AF64A-induced
memory deficits at any doses tested (0.3, 1.0 and 3.0 mg/kg), whereas
Dup 996, at a dose of 1.0 mg/kg, significantly improved
memory deficits. In chronic experiments,
MKC-231 improved
memory deficit at all doses tested (0.3, 1.0, or 3.0 mg/kg p.o., once daily for 11 days) and
Dup 996 did so only at a dose of 3.0 mg/kg, whereas THA did not improve
memory deficit at any doses tested. In acute neurochemical experiments,
MKC-231 and THA did not reverse the AF64A-induced hippocampal ACh depletion.
Dup 996, however, further decreased hippocampal ACh content compared to that in the AF64A-treated group. In chronic experiments,
MKC-231 significantly reversed hippocampal ACh depletion at doses of 0.3 and 1.0 mg/kg, whereas neither
Dup 996 nor THA reversed hippocampal ACh depletion at any doses tested. These results indicate that
MKC-231 improved the AF64A-induced working memory deficit and hippocampal ACh depletion, probably by recovering reduced high-affinity
choline uptake and ACh release.