Abstract
The neuronal nicotinic acetylcholine receptors (nAChRs) show rich abundance in human brain. Three nAChR binding sites with super-high, high and low affinities have been identified using nicotinic agonists with different receptor affinity (Nordberg et al. 1988, Warpman and Nordberg 1995). Molecular biology studies have identified eight nAChR subunits (β2-a9, β2-β4) in rodent brain and seven nAChR subunits (a3-a5, a7, β2-β4) in human brain (Sargent et al. 1993). Different combinations of a and β subunits can form different nAChR subtypes in pentaineric structures which upon activation elicit varying physiological and pharmacological effects (McGee and Role 1995, Zhang and Nordberg 1995). The a4β2 nAChR subtype is considered to be the most common in rodent brain (Flores et al. 1992). Whether this is also the case in human brain has to be proven. It has recently been suggested that the presynaptic modulation of transmitter release may represent a major function of the nAChRs (McGee et al. 1995, Wonnacott 1997). The nAChRs may play a modulatory role for several neurotransmitters in brain (Figure 1). It is quite possible that the nAChRs can be tuned regarding channel opening time, agonists sensitivity and densitization properties to fulfil the requirements for a certain neurotransmitter and brain region. Figure 1 shows some examples of transmitters that appear to be regulated by presynaptic nAChRs. The nAChR subunits may differ between different regions of the brain as well as transmitter systems. Thus the presynaptic nAChR regulating dopamine release appears to contain the <x4 subunit (Wonnacott 1997), while the a7 nAChR subunit seem to facilitate the release of glutamate (Gray et al. 1996) (Figure 1). The occurence of more than one nAChR subtype presynaptically might be possible and is therefore an important issue to explore when focusing on drug development.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Akaike, A., Tamura, Y., Yokota, T., Shimohama, S., and Kimura, J., 1994, Nicotine-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Res. 644:181–187.
Albuquerque, E.X., Manickavasagom, A., Pereira, E.F.R., Castro, N.G., Schrattenholz, A., Barbosa, C.T.F., Bon-fante-Carbarcas, R., Aracava, Y., Eisenberg, H.M., and Maelicke A., 1997, Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synpatic function. J. Pharmacol. Exp. Then 280:1117–1136.
Corder, E.H., Jelic, V., Basun, H., Lannfelt, L., Valind, S., Winblad, B., and Nordberg, A., 1997, No difference in cerebral glucose metabolism in Alzheimer patients with differing apolipoprotein E genotype. Arch. Neurol. 54:273–277.
Corder, E.H., Saunders A.M., and Strittmatter W.J. et al., 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923.
Donnelly-Roberts, D.L., Xue, I.C., Arneric, S.P., and Sullivan, J.P., 1996, In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418. Brain Res. 719:36–44.
Flores, C.M., Rogers, S.W., Pabreza L.A., Wolfe B.B., and Keller, K.J., 1992, A subtype of nicotinic cholinergic receptor in brain is composed of a4 and β2 subunits and is upregulated by chronic nicotine treatment. Mol. Pharmacol. 41:31–37.
Gray S., Rajan A.S., Radcliffe K.A., Yakehiro M., and Dani J.A., 1996, Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383:713–716.
Hellström-Lindahl E., Zhang X., and Nordberg A., Expression of nicotinic receptor subunit mRNAs in lymhocytes from normal and Alzheimer patients. Alzheimer’s Research, in press.
McGehee, D.S., Heath M.J.S., Gelber S., Deway P., and Role L.W., 1995, Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269:1692–1696.
McGehee, D.S., and Role, L.W., 1995, Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Ann. Rev. Physiol. 57:521–546.
Newhouse, P.A., Potter, A., Corwin, J., and Lenox, R., 1994, Modeling of the nicotinic receptor loss in dementia using the nicotinic antagonist mecamylamine: Effects on human cognitive functioning. Drug Dev. Res. 31:71–79.
Nordberg, A., Adem, A., Hardy J. and Winblad B., 1988, Change in nicotinic receptor subtypes in temporal cortex of Alzheimer brains. Neurosci. Lett. 86:317–321.
Nordberg, A., Lilja, A., Lundqvist, H., Hartvig, P., Amberia, K., Viitanen, M., Warpman, U., Johansson, M., Hell-ström-Lindahl, E., Bjurling, P., Fasth, K.J., Långström, B., and Winblad, B., 1992, Tacrine restores cholin-ergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography. Neurobiol. Aging 13:747–758.
Nordberg, A., Lundqvist, H., Hartvig, P., Andersson, J., Johansson, M., Hellström-Lindahl, E. and Långström, B., 1997, Imaging of nicotinic and muscarinic receptors in Alzheimer’s diseasexffect of tacrine treatment. Dement. Geriatr. Cogn. Disord. 8:78–84.
Nordberg, A., Lundqvist, H., Hartvig, P., Lilja, A., and Långström, B., 1995, Kinetic analysis of regional (S)(−)11 c-nicotine binding in normal and Alzheimer brains-in vivo assessment using positron emission tomography. Alzheimer Dis. Assoc. Disord. 9:21–27.
Nordberg, A., and Winblad, B., 1986, Reduced number of 3H-nicotine and 3H-acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci. Lett. 72:115–119.
Ohm, T.G., Kirca, M., Bohl, J., Scharnagl, H., Gross, W., and März, W., 1995, Apolipoprotein E polymorphism influences not only cerebral plaque load but also Alzheimer-type neuroflbrillary tangle formation. Neuroscience 66:583–587.
Poirier, J., Delisle, M.C., Quirion, R., Aubert, I., Farlow, M., Lahiri, D., Hui, S., Bertrand, P., Nalbantoglu, J., Gil-fix, B.M., and Gauthier, S., 1995, Apolipoprotein E4 allele as a predictor of cholinergic deficit and treatment outcome in Alzheimer disease. Proc. Natl. Acad. Sci. 92:12260–12264.
Peng, X., Gerzanich, V., Anand, R., Whiting, P., and Lindstrom, J., 1994, Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol. Pharmacol. 46:523–530.
Polvikoski, T., Sulkava, R., Haltia, M., Kainulainen, K., Vourio, A., Verkkoniemi, A., Niinisto, L., Halonen, P., and Kontula, K., 1995, Apolipoprotein E, dementia and cortical deposition of β-amyloid protein. N. Engl. J. Med. 333:1242–1247.
Sargent, P.B., 1993, The diversity of neuronal nicotinic acetylcholine receptors. Ann. Rev. Neurosci. 16:403–433.
Sahakian, B., Jones, G., Levy, R., Gray, J., and Warburton, D., 1989, The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of Alzheimer’s type. Br. J. Psychiatry 154:797–800.
Salmon, A.R., Marcinowski, K.J., Friedland, R.P., and Zagorski, M.G., 1996, Nicotine inhibits amyloid formation by the β-peptide. Biochemistry 35:13568–13578.
Soininen, H., Kosunen, O., Helisalmi, S., Mannermaa, A., Paljärvi, L., Talasniemi, S., Ryynänen M., and Riekkinen, Sr. P., 1995, A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein e4 allele. Neurosci. Lett. 187:79–82.
Svensson, A-L., and Nordberg, A., 1997, Interaction of tacrine, galanthamine, NXX-066 and E2020 with neuronal α4β2 nicotinic receptors expressed in fibroblast cells. In: Alzheimer’s Disease: Biology, Diagnosis and Therapeutics, K. Iqbal, B. Winblad, T. Nishimura, M. Takeda, H.M. Wisniewski, eds., John Wiley & Sons, Chichester, pp. 751–756.
Svensson, A-L., and Nordberg, A., 1996, Tacrine interacts with an allosteric activator site on α4β2 nAChRs in MIO cells. NeuroReport 7:2201–2205.
Warburton, D.M., Rusted, J.M., and Fowler, J., 1992, A comparison of the attentional and consolidation hypotheses for the facilitation of memory by nicotine. Psychopharmacology 108:443–447.
Warpman, U., and Nordberg, A., 1995, Epibatidine and ABT 418 reveal selective losses of α4β2 nicotinic receptors in Alzheimer brains. NeuroReport 6:2419–2423.
Wickelgren, I., 1997, Estrogen stakes claim to cognition. Science 276:675–678.
Wonnacott, S., 1997, Presynaptic nicotinic ACh receptors. TINS 20:92–98.
Zhang, X., Gong, Z-H., Hellström-Lindahl, E., and Nordberg, A., 1994, Regulation of α4β2 nicotinic acetylcholine receptors in M10 cells following treatment with nicotinic agents. NeuroReport 6:313–317.
Zhang, X., and Nordberg, A., Characterization of nicotinic acetylcholine receptors in brain. In: Brain Imaging of Nicotine and Tobacco Smoking, E.F. Domino, ed., NPP Books, Ann Arbor, pp. 59–71.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media New York
About this chapter
Cite this chapter
Nordberg, A. et al. (1998). Nicotinic Receptors as a new Target for Treatment of Alzheimer’s Disease. In: Fisher, A., Hanin, I., Yoshida, M. (eds) Progress in Alzheimer’s and Parkinson’s Diseases. Advances in Behavioral Biology, vol 49. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5337-3_66
Download citation
DOI: https://doi.org/10.1007/978-1-4615-5337-3_66
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7435-0
Online ISBN: 978-1-4615-5337-3
eBook Packages: Springer Book Archive