Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

A noncholinergic action of acetylcholinesterase (AChE) in the brain: From neuronal secretion to the generation of movement


  1. 1.

    In various brain regions, there is a puzzling disparity between large amounts of acetylcholinesterase and low levels of acetylcholine. One such area is the substantia nigra. Furthermore, within the substantia nigra, a soluble form of acetylcholinesterase is released from the dendrites of dopamine-containing nigrostriatal neurons, independent of cholinergic transmission. These two issues have prompted the hypothesis that acetylcholinesterase released in the substantia nigra has an unexpected noncholinergic function.

  2. 2.

    Electrophysiological studies demonstrate that this dendritic release is a function, not of the excitability of the cell from which the acetylcholinesterase is released, but of the inputs to it. In order to explore this phenomenon at the behavioral level, a novel system has been developed for detecting release of acetylcholinesterase “on-line.” It can be seen that release of this protein within the substantia nigra can reflect, but is not causal to, movement.

  3. 3.

    Once released, the possible actions of acetylcholinesterase can be studied at both the cellular and the behavioral level. Independent of its catalytic site, acetylcholinesterase has a “modulatory” action on nigrostriatal neurons. The functional consequences of this modulation would be to enhance the sensitivity of the cells to synaptic inputs.

  4. 4.

    Many basic questions remain regarding the release and action of acetylcholinesterase within the substantia nigra and, indeed, within other areas of the brain. Nonetheless, tentative conclusions can be formulated that begin, in a new way, to provide a link between cellular mechanisms and the control of movement.

This is a preview of subscription content, log in to check access.


  1. Appleyard, M., and Jahnsen, H. (1989). Non-cholinergic effects of acetylcholinesterase upon the membrane properties of mammalian cerebeller Purkinje cells.Eur. J. Neurosci. Suppl. 129.

  2. Appleyard, M., and Smith, A. D. (1987). Spontaneous and carbachol-evoked in vivo secretion of acetylcholinesterase from the hippocampus of the rat.Neurochem. Int. 11397–406.

  3. Appleyard, M., Green, A. R., and Greenfield, S. A. (1987). Acetylcholinesterase activity rises in rat cerebrospinal fluid postictally; Effect of a substantia nigra lesion on this rise and on seizure threshold.Br. J. Pharmacol. 91149–154.

  4. Appleyard, M., Vercher, J.-L., and Greenfield, S. A. (1988). Release of acetylcholinesterase from the guinea pig cerebellum in vivo.Neuroscience 25133–138.

  5. Ashcroft, F. M. (1988). Adenosine 5′-triphosphate-sensitive potassium channels.Annu. Rev. Neurosci. 1197–118.

  6. Beninato, M., and Spencer, R. F. (1987). A cholinergic projection to the rat substantia nigra from the pedunculopontine tegmental nucleus.Brain Res. 412169–174.

  7. Beninato, M., and Spencer, R. F. (1988). The cholinergic innervation of the rat substantia nigra: A light and electron microscopic immunohistochemical study.Exp. Brain Res. 72178–184.

  8. Birman, S. (1985). Determination of acetylcholinesterase activity by a new chemiluminescent assay with the natural substrate.Biochem. J. 225825–828.

  9. Burgun, C., Greenfield, S. A., Waksman, A., and Weston, J. (1985). Differential effects of cholinergic agonists on acetylcholinesterase release from the rat substantia nigra in vivo.J. Physiol. 369:66P.

  10. Butcher, L. L., Talbot, K., and Bilezikjian, L. (1975). Acetylcholinesterase neurons in dopaminecontaining regions of the brain.J. Neural Trans. 37127–153.

  11. Chatonnet, A., and Lockridge, O. (1989). Comparison of acetylcholinesterase and butyrylcholinesterase.Biochem. J. 260625–634.

  12. Chubb, I. W., and Smith, A. D. (1975a). Isoenzymes of soluble and membrane-bound acetylcholinesterase in bovine splanchnic nerve and adrenal medulla.Proc. R. Soc. Lond. 191B245–261.

  13. Chubb, I. W., and Smith, A. D. (1975b). Release of acetylcholinesterase into the perfusate from the ox adrenal gland.Proc. R. Soc. Lond. 191B263–269.

  14. Chubb, I. W., Goodman, S., and Smith, A. D. (1976). Is acetylcholinesterase secreted from central neurons into cerebrospinal fluid?Neuroscience 157–62.

  15. Chubb, I. W., Hodgson, A. J., and White, G. H. (1980). Acetylcholinesterase hydrolyses substance P.Neuroscience 52065–2072.

  16. Cole, A. E., and Nicholl, R. A. (1983). Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells.Science 2211299–1301.

  17. Cuello, A. C., and Sofroniew, M. V. (1985). The anatomy of the CNS cholinergic neurons. InNeurotransmitters in Action (D. Bousfield, Ed.), Elsevier, Amsterdam, pp. 309–318.

  18. Ceullo, A. C., Romero, E., and Smith, A. D. (1981). In vitro release of acetylcholinesterase from the rat substantia nigra.J. Physiol. 31214–15.

  19. De Sarno, P., Giacobini, E., and Downen, M. (1987). Release of acetylcholinesterase from the caudate nucleus of the rat.J. Neurosci. Res. 18578–590.

  20. Domesick, V. B., Stinus, L., and Paskevich, P. A. (1983). The cytology of dopaminergic and nondopaminergic neurons in the substantia nigra and ventral tegmental area of the rat—a light-microscopic and electron-microscopic study.Neuroscience 8:743P.

  21. Fossier, P., Baux, G., and Tauc, L. (1983). Possible role of acetylcholinesterase in regulation of post-synaptic receptor efficacy at a central inhibitory synapse of Aplysia.Nature 301710–712.

  22. Gonon, G. G. (1988). Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry.Neuroscience 2419–28.

  23. Gould, E., Woolf, N. J., and Butcher, L. L. (1989). Cholinergic projections to the substantia nigra from the pedunculopontine and laterdorsal tegmental nuclei.Neuroscience 28611–623.

  24. Greenfield, S. A. (1984a). Acetylcholinesterase may have novel functions in the brain.Trends Neurosci. 7364–368.

  25. Greenfield, S. A. (1984b). A novel function for acetylcholinesterase in nigro-striatal neurons. InCholinesterases, Walter de Gruyter, Berlin, New York, pp. 289–303.

  26. Greenfield, S. A. (1984c). Can enzymes released from the nigro-striatal pathway act as neuromodulators? InThe Basal Ganglia Advances in Behavioural Biology 27 (J. S. McKenzie, R. E. Kemm, and L. N. Wilcock, Eds.), Plenum Press, New York, London, pp. 319–332.

  27. Greenfield, S. A. (1985). The significance of dendritic release of transmitter and protein in the substantia nigra.Neurochem. Int. 7887–901.

  28. Greenfield, S. A. (1986). Release of acetylcholinesterase from nigrostriatal neurons. InCellular Biology of Ectoenzymes (G. W. Kreutzberg, M. Roddington, and H. Zimmerman, Eds.), Springer-Verlag, New York.

  29. Greenfield, S. A., and Shaw, S. G. (1982). Release of acetylcholinesterase and aminopeptidase in vivo following infusion of amphetamine into the substantia nigra.Neuroscience 72883–2893.

  30. Greenfield, S. A., and Smith, A. D. (1979). The influence of electrical stimulation of certain brain regions on the concentration of acetylcholinesterase in rabbit cerebrospinal fluid.Brain Res. 177445–459.

  31. Greenfield, S. A., Cheramy, A., Leviel, V., and Glowinski, J. (1980). In vivo release of acetylcholinesterase in the cat substantiae nigrae and caudate nuclei.Nature 284355–357.

  32. Greenfield, S. A., Stein, J. F., Hodgson, A. J., and Chubb, I. W. (1981). Depression of nigral pars compacta cell discharge by exogenous acetylcholinesterase.Neuroscience 62287–2295.

  33. Greenfield, S. A., Grunewald, R. A., Foley, P., and Shaw, S. G. (1983a). Origin of various enzymes released from the substantia nigra and caudate nucleus: Effects of 6-hydroxydopamine lesions of the nigro-striatal pathway.J. Comp. Neurol. 21487–92.

  34. Greenfield, S. A., Cheramy, A., and Glowinski, J. (1983b). Evoked release of proteins from central neurons in vivo.J. Neurochem. 401048–1057.

  35. Greenfield, S. A. Chubb, I. W., Grunewald, R. A., Henderson, Z., May, J., Portnoy, S., Weston, J., and Wright, M. C. (1984). A non-cholinergic function for acetylcholinesterase in the substantia nigra: Behavioural evidence.Exp. Brain Res. 54513–520.

  36. Greenfield, S. A., Appleyard, M. E., and Bloomfield, M. R. (1986). 6-Hydroxydopamine-induced turning behaviour in the rat: The significance of acetylcholinesterase in cerebrospinal fluid.Behav. Brain Res. 2147–54.

  37. Greenfield, S. A., Jack, J. J. B., Last, A. T. J., and French M. (1988). An electrophysiological action of acetylcholinesterase independent of its catalytic site.Exp. Brain Res. 70441–444.

  38. Greenfield S. A., Nedergaard, S., Webb, C., and French, M. (1989). Pressure ejection of acetylcholinesterase within the guinea pig substantia nigra has non-classical actions on the pars compacta cells independent of selective receptor and ion channel blockade.Neuroscience 2921–25.

  39. Harris, N. C., Ramsay, S., Kelion, A., and Greenfield, S. A., (1989). Electrophysiologocal evidence for a dendritic localization of a calcium conductance in guinea pig substantia nigra neurons in vitro.Exp. Brain Res. 74411–416.

  40. Henderson, Z., and Greenfield, S. A. (1984). Ultrastructural localization of acetylcholinesterase in substantia nigra: A comparison between rat and guinea pig.J. Comp. Neurol. 230278–286.

  41. Henderson, Z., and Greenfield S. A. (1987). Does the substantia nigra have a cholinergic innervation?Neurosci. Lett. 73109–113.

  42. Inestrosa, N. C., Roberts, W. L., Marshall, T. L., and Rosenberry, T. L. (1987). Acetylcholinesterase from bovine caudate nucleus is attached to membranes by a novel subunit distinct from those of acetylocholinesterase in other tissues.J. Biol. Chem. 2624441–4444.

  43. Israel, M., and Lesbats, B. (1981). Chemiluminescent determination of acetylcholine, and continuous detection of its release from Torpedo electric organ synapses and synaptosomes.Neurochem. Int. 381–90.

  44. James, T. A., and Starr, M. S. (1979). Effects of substance P injected into the substantia nigra.Br. J. Pharmacol. 65423–429.

  45. Jessen, K. R., Chubb, I. W., and Smith, A. D. (1978). Intracellular localization of acetylcholinesterase in nerve terminals and capillaries of the rat superior cervical ganglion.J. Neurocytol. 7145–154.

  46. Joyce, E. M., and Iversen, S. D. (1984). Dissociable effects of 6-OHDA-induced lesions of neostriatum on anorexia, locomotor activity and stereotyping. The role of behavioural competition.Physchopharmcolog 83363–366.

  47. Juraska, J. M., Wilson, C. J., and Groves, P. M. (1977). The substantia nigra of the rat: A Golgi study.J. Comp. Neurol. 172585–600.

  48. Karczmar, A. G. (1969). Is the central cholinergic nervous system overexploited?Fed. Proc. 28147–157.

  49. Kaufman, K., and Silman, I. (1980). The induction of ion channels through excitable membranes by acetylcholinesterase.Naturwissenschaften 67608–610.

  50. Kreutzberg, G. W., and Kaija, H. (1974). Exogenous acetylcholinesterase as tracer for extracellular pathways in the brain.Histochemistry 42233–237.

  51. Kreutzberg, G. Q., Troth, L., and Kaija, H. (1975). Acetylcholinesterase as a marker of dendritic transport and dendritic secretion.Adv. Neurol. 12269–281.

  52. Lacey, M. G., Mercuri, N. B., and North, R. A. (1987). Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta.J. Physiol. 392397–416.

  53. Last, A. T. J., and Greenfield, S. A. (1987). Acetylcholinesterase has a non-cholinergic neuromodulatory action on the guinea-pig substantia nigra.Exp. Brain Res. 67445–448.

  54. Lehmann, J., and Fibiger, H. C. (1978). Acetylcholinesterase in the substantia nigra and caudateputamen of the rat: Properties and localization in dopaminergic neurons.J. Neurochem. 30615–624.

  55. Levey, A. I., Wainer, B. H., Mufson, E. J., and Mesulam, M.-M. (1983). Colocalization of acetylcholinesterase and choline acetyltransferase in the rat cerebrum.Neuroscience 99–22.

  56. Liesli, P., Panuala, P., and Rechardt, L. (1980). Ultrastructural localization of acetylcholinesterase activity in primary cultures of rat substantia nigra.Histochemistry 707–18.

  57. Llinas, R. R., and Greenfield, S. A. (1987). On-line visualization of dendritic release of acetylcholinesterase from mammalian substantia nigra neurons.Proc. Natl. Acad. Sci. USA 843047–3050.

  58. Llinas, R., Greenfield, S. A., and Jahnsen, H. J. (1984). Electrophysiology of pars compacta cells in the in vitro substantia nigra—a possible mechanism for dendritic release.Brain Res. 294127–132.

  59. Martinez-Murillo, R., Villalba, R., Montero-Caballero, M. I., and Rodrigo, J. (1989a). Cholinergic somata and terminals in the rat substantia nigra: An immunocytochemical study with optical and electron microscopic techniques.J. Comp. Neurol. 281397–415.

  60. Martinez-Murillo, R., Villalba, R. M., and Rodrigo, J. (1989b). Electron microscopic localization of cholinergic terminals in the rat substantia nigra: An immunocytochemical study.Neurosci. Lett. 96121–126.

  61. Mercer, L., del Fiacco, M., and Cuello, A. C. (1978). The smooth endoplasmic reticulum as a possible storage site for dendritic dopamine in substantial nigra neurones.Experientia 35101–103.

  62. Mercer, L., Del Fiacco, M., and Cuello, A. C. (1979). The smooth endoplasmic recticulum as a possible storage site for dendritic dopamine in substantia nigra neurones.Experientia 35101–103.

  63. Mourre, C., Yehezkel, B. A., Bernardi, H., Fosset, M., and Lazdunski, M. (1989). Antidiabetic sulfonylureas: Localization of binding sites in the brain and effects on the hyperpolarization induced by anoxia in hippocampal slices.Brain Res. 486159–164.

  64. Nedergaard, S., Bolam, J. P., and Greenfield, S. A. (1988a). Facilitation of a dendritic calcium conductance by 5-HT in the substantia nigra.Nature 333174–177.

  65. Nedergaard, S., Hopkins, C., and Greenfield, S. A. (1988b). Do nigrostriata neurons possess a discrete dendritic modulatory mechanism? Electrophysiological evidence from guinea-pig brain slices.Exp. Brain Res. 69444–448.

  66. Nedergaard, S., Webb, C., and Greenfield, S. A. (1989). A possible ionic basis for dendritic release of dopamine in the guinea pig substantia nigra.Acta Physiol. Scand. 13567–68.

  67. Nieoullon, A., Cheramy, A., and Glowinski, J. (1977). Release of dopamine in vivo from cat substantia nigra.Nature 266375–377.

  68. Olpe, H. R., and Koella, W. P. (1977). Rotatory behaviour in rats by intranigral application of substance P and an eledoisin fragment.Brain Res. 126576–579.

  69. Pycock, C. J. (1980). Turning behavior in animals.Neuroscience 5461–514.

  70. Rinvik, E., and Grofova, I. (1970). Observations on the fine structure of the substantia nigra in the cat.Exp. Brain Res. 11229–248.

  71. Robbins, T. W. (1977). A critique of the methods available for the measurement of spontaneous locomotor activity. InHandbook of Psychopharmacology (L. L. Iversen, S. D. Iversen, and S. H. Snyder, Eds.), Plenum Press, New York, Vol. 7, pp. 37–82.

  72. Romero, E., and Smith, A. D. (1980). Release of acetylcholinesterase from superfused slices of rat hypothalamus.J. physiol. 301:52P.

  73. Rotundo, R. (1984). Synthesis, assembly and processing of the AChE in tissue cultured muscle. InCholinesterases: Fundamental and Applied Aspects (M. Brzin, T. Kiauta, and E. A. Barnard, Eds.), Walter de Gruyter, The Hague, pp. 203–218.

  74. Schmid-Antomarchi, H., De Weille, J. R., Fosset, M., and Lazdunski, M. (1987). The receptor for antidiabetic sulfonylureas controls the activity of the ATP-modulated K channel in insulinsecreting cells.J. Biol. Chem. 26215840–15844.

  75. Silver, A. (1974).The Biology of the Cholinesterases, Elsevier, Amsterdam, pp. 117–303, 428–431.

  76. Small, D. H. (1989). Acetylcholinesterase: Zymogens or neuropeptide processing enzymes?Neuroscience 29241–249.

  77. Steinbusch, H. W. M., Nieuwenhuys, R., Verhofstad, A. A. K., and Van der Kooy, D. (1981). The nucleus raphe dorsalis of the rat and its projections upon the caudate putamen. A combined cytotectonic immunohistochemical and retrograde transport study.J. Physiol. (Paris)77157–174.

  78. Taguchi, R., and Ikezwa, H. (1987). Properties of bovine erythrocyte acetylcholinesterase solubilized by phosphatidylinositol-specific phospholiphase.J. Biochem. 102803–811.

  79. Taylor, S. J., and Greenfield, S. A. (1989a). Pulsatile release of acetylcholinesterase following electrical stimulation of the striatum.Brain Res. 505153–156.

  80. Taylor, S. J., and Greenfield, S. A. (1989b). Release of acetylcholinesterase from the guinea-pig substantia nigra during peripheral nerve stimulation.Brain Res. 482356–358.

  81. Taylor, S. J., Haggblad, J., and Greenfield, S. A. (1989). Measurement of cholinesterase activity released from the brain “on-line” and in vivo.Neurochem. Int. 15199–205.

  82. Taylor, S. J., Bartlett, M. J., and Greenfield, S. A. (1988). Release of acetylcholinesterase within the guinea-pig substantia nigra: Effects of 5-hydroxytryptamine and amphetamine.Neuropharmacology 27507–514.

  83. Toutant, J. P., Roberts, W. L., Murray, N. R., and Rosenberry, T. L. (1989). Conversion of human erythrocyte acetylcholinesterase from an amphiphilic to a hydrophilic form by phosphatidylinositol-specific phospholiphase-C and serum phospholipase-D.Eur. J. Biochem. 180503–508.

  84. Ungerdstedt, U. (1971). Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system.Acta Physiol. Scand. Suppl. 36769–93.

  85. Wassef, M., Berod, A., and Sotelo, C. (1981). Dopaminergic dendrites in the pars reticulata of the rat substantia nigra and their striatal input. Combined immunocytochemical localization of tyrosine hydroxylase and anterograde degeneration.Neuroscience 62125–2139.

  86. Weston, J., and Greenfield, S. A. (1985). Application of acetylcholinesterase to the substantia nigra induces stereotypy in rats.Behav. Brain Res. 1871–74.)

  87. Weston, J., and Greenfield, S. A. (1986). Release of acetylcholinesterase in the rat nigrostriatal pathway: relation to receptor activation and firing rate.Neuroscience 171079–1088.

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Greenfield, S.A. A noncholinergic action of acetylcholinesterase (AChE) in the brain: From neuronal secretion to the generation of movement. Cell Mol Neurobiol 11, 55–77 (1991).

Download citation

Key words

  • acetylcholinesterase
  • substantia nigra
  • dendrites
  • calcium conductances
  • release
  • neuromodulation
  • movement