Journal of Neural Transmission

, Volume 70, Issue 3–4, pp 357–368

Do tetrahydroaminoacridine (THA) and physostigmine restore acetylcholine release in Alzheimer brains via nicotinic receptors?

  • L. Nilsson
  • A. Adem
  • J. Hardy
  • B. Winblad
  • A. Nordberg
Short Note


In the presence of 9-amino-1, 2, 3,4-tetrahydroacridine (THA) 10−4M or physostigmine 10−4 M, the in vitro3H-Acetylcholine (3H-ACh) release from control cortical slices was significantly reduced. In contrast, THA 10−4 M and physostigmine 10−4 M significantly increased the release of3H-ACh in AD/SDAT brain tissue. This facilitating effect on3H-ACh release was partially blocked (50%) in the presence of the nicotinic antagonist d-tubocurarine 10−6 M indicating a possible interaction via nicotinic receptors. The muscarinic antagonist atropine 10−5 M significantly increased the3H-ACh release both in control and AD/SDAT brains, thus indicating preservation of muscarinic autoreceptors in the AD/SDAT cortical tissue. In receptor competition studies with3H-nicotine,3H-ACh and3H-quinuclidinyl benzilate (3H-QNB) as receptor ligands, THA interfered with both nicotinic and muscarinic receptor ligand binding, while physostigmine had much less effect.

Key words

Alzheimer's disease 3H-Acetylcholine release THA physostigmine nicotinic receptors muscarinic receptors receptor subtypes 


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  1. Adem A (1987) Characterization of muscarinic and nicotinic receptors in neural and non-neural tissue: Changes in Alzheimer's disease. Acta Universitas Upsaliensis 32: 4–61Google Scholar
  2. Beani L, Bianchi C, Siniscalchi A, Sivilotti L, Tanganelli S, Veratti E (1984) Different approaches to study acetylcholine release: endogenous ACh versus tritium efflux. Naunyn Schmiedebergs Arch Pharmacol 328: 119–126PubMedGoogle Scholar
  3. Beani L, Bianchi C, Nilsson L, Nordberg A, Romanelli L, Sivilotti L (1985) The effect of nicotine and cytisine on3H-acetylcholine release from cortical slices of guinea pig brain. Naunyn Schmiedebergs Arch Pharmacol 331: 293–296PubMedGoogle Scholar
  4. Corkin S (1981) Acetylcholine, aging and Alzheimer's disease. Trends Neuro Sci 12: 287–290Google Scholar
  5. Caulfield MP, Straughan DW, Cross AJ, Cron T, Birdsall NJM (1982) Cortical muscarinic receptor subtypes and Alzheimer's disease. Lancet 11: 1277Google Scholar
  6. Gottfries CG (1985) Alzheimer's disease and senile dementia: biochemical characteristics and aspects of treatment. Psychopharmacology 86: 245–252PubMedGoogle Scholar
  7. Hadházy P, Szerb JC (1977) The effect of cholinergic drugs on3H-acetylcholine release from slices of rat hippocampus, striatum and cortex. Brain Res 123: 311–322PubMedGoogle Scholar
  8. Hardy JA, Dodd PR, Okley AE, Perry RH, Edwardson JA, Kidd AM (1983) Metabolically active synaptosomes can be prepared from frozen rat and human brain. J Neurochem 40: 608–614PubMedGoogle Scholar
  9. Hardy JA, Adolfsson R, Alafuzoff I, Bucht S, Marcusson J, Nyberg P, Perdahl E, Wester P, Winblad B (1985) Transmitter deficits in Alzheimer's disease. Neurochem Int 7: 545–563Google Scholar
  10. Heilbronn E (1961) Inhibition of cholinesterases by tetrahydroaminacrin. Acta Chem Scand 15: 1386–1390Google Scholar
  11. Hollander E, Mohs RC, Davies KL (1986) Cholinergic approaches to the treatment of Alzheimer's disease. Br Med Bull 42: 97–100PubMedGoogle Scholar
  12. Marchi M, Paudice P, Raiteri M (1981) Autoregulation of acetylcholine release in isolated hippocampal nerve endings. Eur J Pharmacol 73: 75–79PubMedGoogle Scholar
  13. Mash DC, Flynn DD, Potter LT (1985) Loss of M2 muscarinic receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. Science 228: 1115–1117PubMedGoogle Scholar
  14. Mohs RC, Davies BM, Mathé AA, Rosen WG, Johns CA, Greenwald BS, Horvath TB, Davies KL (1985) Intravenous and oral physostigmine in Alzheimer's disease. Interdiscipl Top Gerontol 20: 140–152Google Scholar
  15. Nilsson L, Nordberg A, Hardy J, Wester P, Winblad B (1986) Physostigmine restores3H-acetylcholine efflux from Alzheimer brain slices to normal level. J Neural Transm 67: 275–285PubMedGoogle Scholar
  16. Nordberg A, Winblad B (1986a) Brain nicotinic and muscarinic receptors in normal aging and dementia. In: Fisher A, Hanin I, Lachman C (eds) Alzheimer's and Parkinson's disease: strategies in research and development. Plenum Press, New York, pp 95–108 (Advances in behavioral biology, vol 29)Google Scholar
  17. Nordberg A, Winblad B (1986b) Reduced number of3H-nicotine and3H-acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci Lett 72: 115–119PubMedGoogle Scholar
  18. Nordberg A, Alafuzoff I, Winblad B (1986) Muscarinic subtypes in hippocampus in Alzheimer's disease and mixed dementia type. Neurosci Lett 70: 160–164PubMedGoogle Scholar
  19. Nordberg A, Adem A, Nilsson L, Winblad B (1987a) Cholinergic deficits in CNS and peripheral non-neyrolan tissue in Alzheimer dementia. In: Dowdall M, Hawthorne J (eds) Cellular and molecular basis of cholinergic function. Ellis Horwood, Chichester, Sussex, pp 858–868Google Scholar
  20. Nordberg A, Adem A, Nilsson L, Winblad B (1987b) Nicotinic and muscarinic cholinergic receptor heterogeneity in human brain at normal aging and dementia of Alzheimer type. In: Pepeu G, Tomlinson B, Wischik CM (eds) Proc int symp “New trends in aging research”. Fidia Research series, Liviano Press (in press)Google Scholar
  21. Nordström ö, Westlind A, Undén A, Meyersson B, Sachs C, Bartfai T (1982) Pre- and postsynaptic muscarinic receptors in surgical samples from human cerebral cortex. Brain Res 234: 287–297PubMedGoogle Scholar
  22. Perry EK (1986) The cholinergic hypothesis: ten years on. Br Med Bull 42: 63–69PubMedGoogle Scholar
  23. Sims NR, Smith CCT, Davison AN, Bowen DM, Flack RHA, Snowden JS (1980) Glucose metabolism and acetylcholine synthesis in relation to neuronal activity in Alzheimer's disease. Lancet i: 333–336Google Scholar
  24. Summers WK, Majovski LV, Marsh GM, Tachiki K, Kling A (1986) Oral tetrahydroaminoacridine in long-term treatment of senil dementia, Alzheimer type. New Engl J Med 315: 1241–1245PubMedGoogle Scholar
  25. Szerb JC, Somogyi GT (1973) Depression of acetylcholine release from cortical slices by cholinesterase inhibition and by oxotremorine. Nature (New Biol) 241: 121–122Google Scholar
  26. Vizi ES, Somogyi GT, Nagashima H, Duncalf D, Chaudhry IA, Kobayashi O, Goldiner PL, Foldes FF (1987) Tubocararine and Pancuronium inhibit evoked release of acetylcholine from the mouse hemidiaphragm preparation. Br J Anaesth 59: 226–231PubMedGoogle Scholar
  27. Wessler I, Halank M, Rasbach J, Kilbinger H (1986) Presynaptic nicotine receptors mediating a positive feedback on transmitter release from the rat phrenic nerve. Naunyn Schmiedebergs Arch Pharmacol 334: 365–372PubMedGoogle Scholar
  28. Whitehouse PJ, Martino AM, Antuono PG, Lowenstein PR, Coyle JT, Price DL, Kellar KJ (1986) Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Res 371: 146–151PubMedGoogle Scholar
  29. Zhang X, Stjernlöf P, Adem A, Nordberg A (1987) Anatoxin-a a potent ligand for nicotinic cholinergic receptors in rat brain. Eur J Pharmacol 135: 457–458PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • L. Nilsson
    • 1
  • A. Adem
    • 1
  • J. Hardy
    • 2
  • B. Winblad
    • 3
  • A. Nordberg
    • 1
  1. 1.Department of PharmacologyUniversity of UppsalaUppsalaSweden
  2. 2.Department of BiochemistrySt. Mary's Hospital Medical SchoolLondonUK
  3. 3.Department of Geriatric Medicine, Karolinska InstituteHuddinge HospitalSweden

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