MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice.
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.
Murai
S
S
Department of Pharmacology, School of Dentistry, Iwate Medical University, Morioka, Japan.
Saito
H
H
Abe
E
E
Masuda
Y
Y
Odashima
J
J
Itoh
T
T
D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000647:Amnesia; D000818:Animals; D001388:Aziridines; D002794:Choline / Q000031:analogs & derivatives; D002796:Choline Deficiency; D003627:Data Interpretation, Statistical; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage*; D009435:Synaptic Transmission; D013619:Tacrine / Q000494:pharmacology
D001388:Aziridines; D007211:Indoles; D011725:Pyridines; D011804:Quinolines; D013619:Tacrine; C044894:ethylcholine aziridinium; D000110:Acetylcholinesterase; C061017:linopirdine; D002794:Choline; D000109:Acetylcholine; C092988:MKC 231