MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice

  • S. Murai
  • H. Saito
  • E. Abe
  • Y. Masuda
  • J. Odashima
  • T. Itoh
Full Papers


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 3.0mg/kg), whereas Dup 996, at a dose of 1.0mg/kg, significantly improved memory deficits. In chronic experiments, MKC-231 improved memory deficit at all doses tested (0.3, 1.0, or 3.0mg/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 1.0mg/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.


MKC-231 ethylcholine aziridinium ion (AF64A) Dup 996 THA hippocampal acetylcholine delayed non-matching to sample task working memory deficit 


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  1. Abe E (1991) Reversal effect of DM-9384 on scopolamine-induced acetylcholine depletion in certain regions of the mouse brain. Psychopharmacology 105: 310–316PubMedGoogle Scholar
  2. Abe E, Murai S, Masuda Y, Saito H, Itoh T (1992) Reversal by 3,3′, 5-triido-L-thyronine of the working memory deficit, and the decrease in acetylcholine, glutamate and γ-aminobutyric acid induced by ehtylcholine aziridinium ion in mice. Naunyn-Schmie-debergs Arch Pharmacol 346: 238–242Google Scholar
  3. Abe E, Murai S, Masuda Y, Saito H, Itoh T (1993) α-Sialylcholesterol reverses AF64A-induced deficit in passive avoidance response and depletion of hippocampal acetylcholine in mice. Br J Pharmacol 108: 387–392PubMedGoogle Scholar
  4. Åhline A, Nybäck H, Junthe T, Öhman G, Nordgren I (1991) Tetrahydroaminoacridine in Alzheimer's dementia: clinical and biochemical results of a double-blind crossover trial. Human Psychopharm 6: 109–118Google Scholar
  5. Antonelli T, Beani L, Bianchi C, Pedata F, Pepeu G (1981) Changes in synaptosomal high affinity choline uptake following electrical stimulation of guinea-pigs cortical slices. Br J Pharmacol 74: 525–532PubMedGoogle Scholar
  6. Bessho T, Ohshima C, Saito K, Egawa M, Tobe A (1993) Effects of MKC-231, a novel choline uptake enhancer, on AF64A-induced reduction of high affinity choline uptake and impairment of water maze learning in rats. Jpn J Pharmacol 61 [Suppl]: 90PGoogle Scholar
  7. Bessho T, Takashina K, Ohshima C, Egawa M (1994) Increase in acetylcholine release by MKC-231, a novel choline uptake enhancer, in the hippocampus of AF64A-treated rats. Jpn J Pharmacol 64 [Suppl]: 230PGoogle Scholar
  8. Brioni JD, Curzon P, Buckley MJ, Arneric SP, Decker MW (1993) Linopiridine (Dup 996) facilitates the retention of avoidance training and improves performance of septallesioned rats in the water maze. Pharmacol Biochem Behav 44: 37–43PubMedGoogle Scholar
  9. Chrobak JJ, Hanin I, Schmechel DE, Walsh TJ (1988) AF64A-induced working memory impairment: behavioral, neurochemical and histological correlates. Brain Res 463: 107–117PubMedGoogle Scholar
  10. Chrobak JJ, Walsh TJ (1991) Dose- and delay-dependent working/episodic memory impairments following intraventricular administration of ethylcholine aziridinium ion (AF64). Behav Neural Biol 56: 200–212PubMedGoogle Scholar
  11. DeNoble VJ, Repetti SJ, Gelpke LW, Wood LM, Keim KL (1986) Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats. Pharmacol Biochem Behav 24: 1123–1128PubMedGoogle Scholar
  12. DeNoble VJ, DeNoble KF, Spencer KR, Johnson LC, Cook L, Mayers MJ, Schribner RM (1990) Comparison of Dup 996 with physostigmine, THA and 3,4-DAP on hypoxia-induced amnesia in rats. Pharmacol Biochem Behav 36: 957–961PubMedGoogle Scholar
  13. Fisher A, Mantione RC, Abraham JD, Hanin I (1982) Long term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo. J Pharmacol Exp Ther 222: 140–145PubMedGoogle Scholar
  14. Freeman AE, Dawson PM (1991) Tacrine: a pharmacological review. Prog Neurobiol 36: 257–277PubMedGoogle Scholar
  15. Gottfries CG (1985) Alzheimer's disease and senile dementia: biochemical characteristics and aspects of treatment. Psychopharmacology 86: 245–252PubMedGoogle Scholar
  16. Hock FJ, McGaugh JL (1985) Enhancing effects of Hoe 175 on memory in mice. Psychopharmacology 86: 114–117PubMedGoogle Scholar
  17. Kuhar MJ, Murrin LC (1978) Sodium-dependent, high affinity choline uptake. J Neurochem 30: 15–21PubMedGoogle Scholar
  18. Leventer SM, McKeag D, Clancy M, Wulfert E, Hanin I (1985) Intracerebroventricular administration of ethylcholine mustard aziridinium ion (AF64A) reduces release of acetylcholine from rat hippocampal slices. Neuropharmacology 24: 453–459PubMedGoogle Scholar
  19. Leventer SM, Wülfert E, Hanin I (1987) Time course of ethylcholine aziridinium ion (AF64A)-induced cholinotoxicity in vivo. Neuropharmacology 26: 361–365PubMedGoogle Scholar
  20. Masuda Y, Murai S, Saito H, Abe E, Itoh T (1992) A simple T-maze method for estimating working memory in mice, effect of ethylcholine mustard aziridinium ion (AF64A). J Pharmacol Toxicol Methods 28: 45–48PubMedGoogle Scholar
  21. Murai S, Miyate H, Saito H, Nagahama H, Masuda Y, Itoh T (1989) Simple determination of acetylcholine and choline within 4 minutes by HPLC-ECD and immobilized enzyme column in mice brain areas. J Pharmacol Methods 21: 255–262PubMedGoogle Scholar
  22. Murray TK, Cross AJ, Green AR (1991) Reversal by tetrahydroaminoacridine of scopolamine-induced memory and performance deficits in rats. Psychopharmacology 105: 134–136PubMedGoogle Scholar
  23. Murrin LC, DeHaven RN, Kuhar MJ (1977) On the relationship between [3H]choline uptake activation and [3H]acetylcholine release. J Neurochem 29: 681–687PubMedGoogle Scholar
  24. Nakahara H, Iga Y, Mizuno F, Kawanishi G (1988) Effects of intracerebroventricular injection of AF64A on learning behaviors in rats. Jpn J Pharmacol 48: 121–130PubMedGoogle Scholar
  25. Nickolson V, Tamm SW, Myers MJ, Cook L (1990) Dup 996 (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) enhances the stimulus-induced release of acetylcholine from rat brain in vitro and in vivo. Drug Dev Res 19: 285–300Google Scholar
  26. Nordgren I, Karlen B, Kimland M (1992) Metrifonate and tacrine: a comparative study on their effect on acetylcholine dynamics in mouse brain. Pharmacol Toxicol 71: 236–240PubMedGoogle Scholar
  27. Olton DS (1979) Maze, maps, and memory. Am Psychol 34: 583–596PubMedGoogle Scholar
  28. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in dementia. Br Med J 2: 1457–1459PubMedGoogle Scholar
  29. Price DL (1987) New perspectives on Alzheimer's disease. Annu Rev Neurosci 9: 489–512Google Scholar
  30. Plotkin DA, Jarvik LF (1986) Cholinergic dysfunction in Alzheimer's disease: cause or effect? Prog Brain Res 65: 91–103PubMedGoogle Scholar
  31. Riekkinen PJ, Sirvio J, Riekkinen P (1989) The effects of THA on medial septal lesion-induced memory deficits. Pharmacol Biochem Behav 36: 237–241Google Scholar
  32. Sarter M, Hagan J, Dudchenko P (1992) Behavioral screening for cognition enhancers: from indiscriminate to valid testing, part I. Psyhopharmacology 107: 144–159Google Scholar
  33. Smith G (1988) Animal models of Alzheimer's disease: experimental cholinergic denervation. Brain Res Rev 13: 103–118Google Scholar
  34. Spignoli G, Pepeu G (1987) Interactions between oxiracetam, aniracetam and scopolamine behavior and brain acetylcholine. Pharmacol Biochem Behav 27: 491–495PubMedGoogle Scholar
  35. Vickroy TW (1993) Presynaptic cholinergic actions by the putative cognitive enhancing agent Dup 996. J Pharmacol Exp Ther 264: 910–917PubMedGoogle Scholar
  36. Whitehouse PJ, Struble RB, Hedreen JC, Clark AW, Price D (1985) Alzheimer's disease and related dementias: selective involvement of specific neuronal systems. Neurobiology 1: 319–339Google Scholar
  37. Whitehouse PJ, Vale WW, Zweig RM, Singer HS, Mayeux R, Price DL, De Souza EB (1987) Reductions in corticotropine-releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease and Progressive Supranuclear Palsy. Neurology 37: 905–909PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • S. Murai
    • 1
  • H. Saito
    • 1
  • E. Abe
    • 1
  • Y. Masuda
    • 1
  • J. Odashima
    • 1
  • T. Itoh
    • 1
  1. 1.Department of Pharmacology, School of DentistryIwate Medical UniversityMoriokaJapan

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