Neuronal Nicotinic acetylcholine Receptors: Novel targets for cns Therapeutics

Michael W. Decker*, James P. Sullivan, Stephen P. Arneric, and Michael Williams
Dept. 4N5; Bldg. AP-9A
Abbott Laboratories
100 Abbott Park Rd.
Abbott Park, IL 60064
Phone: 847-937-2422
FAX: 847-938-0072


Due to a limit on the number of references allowed, the authors have made extensive use of review articles in the reference list and have largely cited papers appearing since the original publication of this chapter in 1995. Additional references can be obtained by consulting these sources.

1.         Albuquerque EX, Alkondon M, Pereira EFR, Castro NG, Schrattenholz A, Barbosa CTF, Bonfante-Cabarcas R, Aracava Y, Eisenberg HM, Maelicke A.  Properties of neuronal nicotinic acetylcholine receptors:  Pharmacological characterization and modulation of synaptic function. J Pharmacol Exp Ther 1997; 280: 1117-1136.

2.         Arneric SP, Sullivan JP, Decker MW, Brioni JD, Bannon AW, Briggs CA, Donnelly-Roberts D, Radek RJ, Marsh KC, Kyncl J, Williams M, Buccafusco JJ.  Potential treatment of Alzheimer disease using cholinergic channel Activators (ChCAs) with cognitive enhancement, anxiolytic-like, and cytoprotective properties. Alz Dis Assoc Disorders 1995; 9: suppl. 2, 50-61.

3.         Badio B, Daly JW.  Epibatidine, a potent analgetic and nicotinic agonist. Mol Pharmacol 1994; 45: 563-569.

4.         Balfour DJK, Fagerström KO.  Pharmacology of nicotine and its therapeutic use in smoking cessation and neurodegernative disorders. Pharacol Ther 1996; 72: 51-81.

5.         Bencherif M, Byrd G, Caldwell WS, Hayes JR, Lippiello PM.  Pharmacological characterization of RJR-2403:  A nicotinic agonist with potential therapeutic benefit in the treatment of Alzheimer's disease. CNS Drug Rev 1997; 3: 325-345.

6.         Bitner RS, Nikkel AL, Curzon P, Arneric SP, Bannon AW, Decker MW.  Role of the nucleus raphe magnus in antinociception produced by ABT-594:  Immediate early gene responses possibly linked to neuronal nicotinic acetylcholine receptors on serotonergic neurons. J Neurosci 1998; 18: 5426-5432.

7.         Boyd RT.  The molecular biology of neuronal nicotinic acetylcholine receptors. Crit Rev Toxicol 1997; 27: 299-318.

8.         Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart M, Sullivan B, Demasters BK, Freedman R, Leonard S.  Comparison of the regional expression of nicotinic acetylcholine receptor a7 mRNA and [125I]-a-bungarotoxin binding in human postmortem brain. J Comp Neurol 1997; 387: 385-398.

9.         Breslau N.  Psychiatric comorbidity of smoking and nicotine dependence. Behav Genet 1995; 25: 95-101.

10.       Brioni JD, Decker MW, Sullivan JP, Arneric SP.  The pharmcology of (-)-nicotine and novel cholinergic channel modulators. Adv Pharmacol 1997; 37: 153-214.

11.       Brioni JD, O'Neill AB, Kim DJB, Buckley MJ, Decker MW, Arneric SP.  Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. J Pharmacol Exp Ther 1994; 271: 353-361.

12.       Buisson B, Bertrand D.  Allosteric modulation of neuronal nicotinic acetylcholine-receptors. J Physiol (Paris) 1998; 92: 89-100.

13.       Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM.  A new a-conotoxin which targets a3b2 nicotinic acetylcholine receptors. J Biol Chem 1996; 271: 7522-7528.

14.       Changeux JP, Bertrand D, Corringer PJ, Dehaene S, Edelstein S, Lena C, Le Novere N, Marubio L, Picciotto M, Zoli M.  Brain nicotinic receptors: structure and regulation, role in learning and reinforcement. Brain Res Rev 1998; 26: 198-216.

15.       Chavez-Noriega LE, Crona JH, Washburn MS, Urrutia A, Elliott KJ, Johnson EC.  Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors ha2b2, ha2b4, ha3b2, ha3b4, ha4b2, ha4b4 and ha7 expressed in xenopus oocytes. J Pharmacol Exp Ther 1997; 280: 346-356.

16.       Clarke PBS, Reuben M.  Release of [3H]-noradrenaline from rat hippocampal synaptosomes by nicotine:  mediation by different nicotinic receptor subtypes from striatal [3H]-dopamine release. Br J Pharmacol 1996; 117: 595-606.

17.       Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A.  Nicotinic binding in rat brain:  Autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-a-bungarotoxin. J Neurosci 1985; 5: 1307-1315.

18.       Colquhoun LM, Patrick JW.  a3, b2, and b4 form heterotrimeric neuronal nicotinic acetylcholine receptors in xenopus oocytes. J Neurochem 1997; 69: 2355-2362.

19.       Corringer PJ, Bertrand S, Bohler S, Edelstein SJ, Changeux JP, Bertrand D.  Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors. J Neurosci 1998; 18: 648-657.

20.       Damaj MI, Feiyin M, Dukat M, Glassco W, Glennon RA, Martin BR.  Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in mice. J Pharmacol Exp Ther 1998; 284: 1058-1065.

21.       Decker MW, Anderson DJ, Brioni JD, Donnelly-Roberts DL, Kang CH, O'Neill AB, Piattoni-Kaplan M, Swanson S, Sullivan JP.  Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors. Eur J Pharmacol 1995; 280: 79-89.

22.       Decker MW, Brioni JD, Neuronal nicotinic receptors:  Potential treatment of Alzheimer's disease with novel cholinergic channel modulators. In Brioni JD, Decker MW (Eds.), Pharmacological Treatment of Alzheimer's Disease:  Molecular and Neurobiological Foundations, Wiley-Liss, New York, 1997, pp. 433-459.

23.       Decker MW, Curzon P, Holladay MW, Nikkel AL, Bitner RS, Bannon AW, Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Williams M, Arneric SP.  The role of neuronal nicotinic acetylcholine receptors in antinociception: effects of ABT-594. J Physiol (Paris) 1998; 92: 221-224.

24.       Diwan A, Castine M, Pomerleau CS, Meadorwoodruff JH, Dalack GW.  Differential prevalence of cigarette-smoking in patients with schizophrenic vs mood disorders. Schizophrenia Research 1998; 33: 113-118.

25.       Donnelly-Roberts DL, Brioni JD, Preclinical evidence on the neuroprotective effects of nicotinic ligands. In Arneric SP, Brioni JD (Eds.), Neuronal Nicotinic Receptors:  Pharmacology and Therapeutic Opportunities, John Wiley & Sons, New York, 1999, pp. 337-322.

26.       Elgoyhen A, Johnson D, Boulter J, Vetter D, Heinemann S.  a9:  An acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 1994; 79: 709-715.

27.       Epping-Jordan MP, Watkins SS, Koob GF, Markou A.  Dramatic decreases in brain reward function during nicotine withdrawal. Nature 1998; 393: 76-79.

28.       Flores CM, DeCamp RM, Kilo S, Rogers SW, Hargreaves KM.  Neuronal nicotinic receptor expression in sensory neurons of the rat trigeminal ganglion:  Demonstration of a3b4, a novel subtype in the mammalian nervous system. J Neurosci 1996; 16: 7892-7901.

29.       Frazier CJ, Rollins YD, Breese CR, Leonard S, Freedman R, Dunwiddie TV.  Acetylcholine activates an a-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J Neurosci 1998; 18: 1187-95.

30.       Ghelardini C, Galeotti N, Barlocco D, Bartolini A.  Antinociceptive profile of the new nicotinic agonist DBO-83. Drug Devel Res 1997; 40: 251-258.

31.       Glover ED, Leischow SJ, Rennard SI, Glover PN, Daughton D, Quiring J, Schneider FH, Mione PJ.  A smoking cessation trial with lobeline sulfate:  a pilot study. Am J Health Behav 1998; 22: 62-75.

32.       Goldner FM, Dineley KT, Patrick JW.  Immunohistochemical localization of the nicotinic acetylcholine-receptor subunit a6 to dopaminergic-neurons in the substantia nigra and ventral tegmental area. Neuroreport 1997; 8: 2739-2742.

33.       Gopalakrishnan M, Monteggia LM, Anderson DJ, Arneric SP, Sullivan JP.  Stable expression, pharmcologic properties and regulation of the human nicotinic acetylcholine a2b4 receptor. J Pharmacol Exp Ther 1996; 276: 289-297.

34.       Gotti C, Fornasari D, Clementi F.  Human neuronal nicotinic receptors. Prog Neurobiol 1997; 53: 199-237.

35.       Holladay MW, Dart MJ, Lynch JK.  Neuronal nicotinic acetylcholine receptors as targets for drug discovery. J Med Chem 1997; 40: 4169-4194.

36.       Iwamoto ET, Marion L.  Adrenergic, serotonergic and cholinergic components of nicotinic antinociception in rats. J Pharmacol Exp Ther 1993; 265: 777-89.

37.       Kaiser SA, Wonnacott S, Nicotinic receptor modulation of neurotransmitter release. In Arneric SP, Brioni JD (Eds.), Neuronal Nicotinic Receptors:  Pharmacology and Therapeutic Opportunities, John Wiley & Sons, New York, 1999, pp. 141-159.

38.       Khan IM, Yaksh TL, Taylor P.  Epibatidine binding sites and activity in the spinal cord. Brain Res 1997; 753: 269-282.

39.       Kulak JM, Nguyen TA, Olivera BM, McIntosh JM.  a-conotoxin MII blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J Neurosci 1997; 17: 5263-70.

40.       Le Houezec J.  Nicotine: abused substance and therapeutic agent. Journal of Psychiatry & Neuroscience 1998; 23: 95-108.

41.       Le Novere N, Zoli M, Changeux JP.  Neuronal nicotinic receptor a6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. Eur J Neurosci 1996; 8: 2428-2439.

42.       Lee PN.  Smoking and Alzheimer's disease:  A review of the epidemiological evidence. Neuroepidemiology 1994; 13: 131-144.

43.       Lena C, Changeux JP.  Allosteric modulations of the nicotinic acetylcholine receptor. Trends Neurosci 1993; 16: 181-186.

44.       Lena C, Changeux JP.  Pathological mutations of nicotinic receptors and nicotine-based therapies for brain disorders. Curr Opin Neurobiol 1997; 7: 674-682.

45.       Lena C, Changeux JP.  Role of Ca2+ ions in nicotinic facilitation of GABA release in mouse thalamus. J Neurosci 1997; 17: 576-585.

46.       Leonard S, Adler LE, Olincy A, Breese CR, Gault J, Ross RG, Lee M, Cawthra E, Nagamoto HT, Freedman R, The role of neuronal nicotinic receptors in psychopathology. In Arneric SP, Brioni JD (Eds.), Neuronal Nicotinic Receptors:  Pharmacology and Therapeutic Opportunities, John Wiley & Sons, New York, 1999, pp. 307-322.

47.       Levin ED.  Nicotinic systems and cognitive function. Psychopharmacology 1992; 108: 417-431.

48.       Levin ED, Simon BB.  Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 1998; 138: 217-230.

49.       Lindstrom J.  Nicotinic acetylcholine receptors in health and disease. Molecular Neurobiology 1997; 15: 193-222.

50.       Listerud M, Brussard AB, Devay P, Colman DR, Role LW.  Functional contribution of neuronal AChR subunits revealed by antisense oligonucleotides. Science 1991; 254: 1518-1521.

51.       Lopez MG, Fonteriz RI, Gandia L, de la Fuente M, Villarroya M, Garcia-Sancho J, Garcia AG.  The nicotinic acetylcholine receptor of the bovine chromaffin cell, a new target for dihydropyridines. Eur J Pharmacol 1993; 247: 199-207.

52.       Luetje CW, Wada K, Rogers S, etc.  Neurotoxins distinguish between different neuronal nicotinic acetylcholine receptor subunit combinations. J Neurochem 1990; 55: 632-640.

53.       Luo S, Kulak JM, Cartier GE, Jacobsen RB, Yoshikami D, Olivera BM, McIntosh JM.  a-conotoxin AuIB selectively blocks a3b4 nicotinic acetylcholine receptors and nicotine-evoked norepinephrine release. J Neurosci 1998; 18: 8571-8579.

54.       Marks MJ, Garnham DA, Grady SR, Collins AC.  Nicotinic receptor function determined by stimulation of rubidium efflux from mouse brain synaptosomes. J Pharmacol Exp Ther 1993; 264: 542-552.

55.       Matta SG, Fu YT, Valentine JD, Sharp BM.  Response of the hypothalamo-pituitary-adrenal axis to nicotine. Psychoneuroendocrinology 1998; 23: 103-113.

56.       Menzaghi F, McClure DE, Lloyd GK, Subtype-selective nAChR agonists for the treatment of neurological disorders:  SIB-1508Y and SIB-1553A. In Arneric SP, Brioni JD (Eds.), Neuronal Nicotinic Receptors:  Pharmacology and Therapeutic Opportunities, John Wiley & Sons, New York, 1999, pp. 379-394.

57.       Meyer EM, Tay ET, Papke RL, Meyers C, Huang GL, de Fiebre CM.  3-[2,4-dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat a7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner. Brain Res 1997; 768: 49-56.

58.       Meyer EM, Tay ET, Zoltewicz JA, Meyers C, King MA, Papke RL, De Fiebre CM.  Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties. J Pharmacol Exp Ther 1998; 284: 1026-1032.

59.       Morley BJ, Li HS, Hiel H, Drescher DG, Elgoyhen AB.  Identification of the subunits of the nicotinic cholinergic receptors in the rat cochlea using RT-PCR and in situ hybridization. Mol Brain Res 1998; 53: 78-87.

60.       Newhouse P, Potter A, Corwin J.  Effects of nicotinic cholinergic agents on cognitive functioning in Alzheimer's and Parkinson's disease. Drug Devel Res 1996; 38: 278-289.

61.       Orr-Urtreger A, Goldner FM, Saeki M, Lorenzo I, Goldberg L, DeBiasi M, Dani JA, Patrick JW, Beaudet AL.  Mice deficient in the a7 neuronal nicotinic acetylcholine-receptor lack a-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci 1997; 17: 9165-9171.

62.       Papke RI.  The kinetic properties of neuronal nicotinic acetylcholine receptors:  Genetic basis of functional diversity. Prog Neurobiol 1993; 41: 509-531.

63.       Pauly JR, Grun EU, Collins AC, Glucocorticoid regulation of sensitivity to nicotine. In Lippiello PM, Collins AC, Gray JA, Robinson JH (Eds.), The biology of nicotine:  current research issues, Raven Press, New York, 1992, pp. 121-139.

64.       Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP.  Acetylcholine-receptors containing the b2 subunit are involved in the reinforcing properties of nicotine. Nature 1998; 391: 173-177.

65.       Pidoplichko VI, Debiasi M, Williams JT, Dani JA.  Nicotine activates and desensitizes midbrain dopamine neurons. Nature 1997; 390: 401-404.

66.       Pontieri FE, Tanda G, Orzi F, Di Chiara G.  Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 1996; 382: 255-257.

67.       Radcliffe KA, Dani JA.  Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission. J Neurosci 1998; 18: 7075-7083.

68.       Rao TS, Correa LD, Reid RT, Lloyd GK.  Evaluation of anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands in the rat tail-flick assay. Neuropharmacology 1996; 35: 393-405.

69.       Rogers DT, Iwamoto ET.  Multiple spinal mediators in parenteral nicotine-induced antinociception. J Pharmacol Exp Ther 1993; 267: 341-349.

70.       Role LW, Berg DK.  Nicotinic receptors in the development and modulation of CNS synapses. Neuron 1996; 16: 1077-1085.

71.       Rose JE.  Nicotine addiction and treatment. Ann Rev Med 1996; 47: 493-507.

72.       Rose JE, Corrigall WA.  Nicotine self-administration in animals and humans: Similarities and differences. Psychopharmacology 1997; 130: 28-40.

73.       Salin-Pascual RJ, Drucker-Colin R.  A novel effect of nicotine on mood and sleep in major depression. Neuroreport 1998; 9: 57-60.

74.       Sanberg PR, Silver AA, Shytle RD, Philipp MK, Cahill DW, Fogelson HM, McConville BJ.  Nicotine for the treatment of Tourette's syndrome. Pharmacology & Therapeutics 1997; 74: 21-25.

75.       Sanberg PRK, Shytle RD, Silver AA.  Treatment of Tourettes syndrome with mecamylamine. Lancet 1998; 352: 705-706.

76.       Schilström B, Nomikos GG, Nisell M, Hertel P, Svensson TH.  N-methyl-d-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens. Neuroscience 1998; 82: 781-789.

77.       Smith CJ, Giacobini E.  Nicotine, Parkinson's and Alzheimer's disease. Reviews in the Neurosciences 1992; 3: 25-43.

78.       Stauderman KA, Mahaffy LS, Akong M, Velicelebi G, Chavez-Noriega LE, Crona JH, Johnson EC, Elliott KJ, Gillespie A, Reid RT, Adams P, Harpold MM, Corey-Naeve J.  Characterization of human recombinant neuronal nicotinic acetylcholine-receptor subunit combinations a2b4, a3b4 and a4b4 stably expressed in HEK293 cells. J Pharmacol Exp Ther 1998; 284: 777-789.

79.       Stevens KE, Wear KD.  Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models. Pharmacol Biochem Behav 1997; 57: 869-874.

80.       Stolerman IP, Jarvis MJ.  The scientific case that nicotine is addictive. Psychopharmacology 1995; 117: 2-10.

81.       Sullivan JP, Donnelly-Roberts D, Briggs CA, Anderson DJ, Gopalakrishnan M, Piattoni-Kaplan M, Campbell JE, McKenna DG, Molinari E, Hettinger AM, Garvey DS, Wasicak JT, Holladay MW, Williams M, Arneric SP.  A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand. Neuropharmacology 1996; 35: 725-34.

82.       Tani Y, Saito K, Imoto M, Ohno T.  Pharmacological characterization of nicotinic receptor-mediated acetylcholine-release in rat brain - an in vivo microdialysis study. Eur J Pharmacol 1998; 351: 181-188.

83.       Taylor P, Agents acting at the neuromuscular junction and autonomic ganglia. In Hardman JG, Gilman AG, Limbird LE (Eds.), Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, 1996, pp. 177-197.

84.       Vernallis AB, Conroy WG, Berg DK.  Neurons assemble acetylcholine receptors with as many as three kinds of subunits while maintaining subunit segregation among receptor subtypes. Neuron 1993; 10: 451-464.

85.       Viseshakul N, Figl A, Lytle C, Cohen BN.  The a4 subunit of rat a4b2 nicotinic receptors is phosphorylated in vivo. Mol Brain Res 1998; 59: 100-104.

86.       Wang F, Gerzanich V, Wells GB, Anand R, Peng X, Keyser K, Lindstrom J.  Assembly of human neuronal nicotinic receptor a5 subunits with a3, b2 and b4 subunits. J Biol Chem 1996; 271: 17656-17665.

87.       Winzer-Serhan UH, Leslie FM.  Codistribution of nicotinic acetylcholine receptor subunit a3 and b4 mRNAs during rat brain development. J Comp Neurol 1997; 386: 540-554.

88.       Wonnacott S, Albuquerque EX, Bertrand D.  Methyllycaconitine: a new probe that discriminates between nicotinic acetylcholine receptor subclasses. Meth Neurosci 1993; 12: 263-275.

89.       Zoli M, Lena C, Picciotto MR, Changeux JP.  Identification of four classes of brain nicotinic receptors using b2 mutant mice. J Neurosci 1998; 18: 4461-4472.

Return to Chapter

published 2000