, Volume 191, Issue 4, pp 919–929 | Cite as

Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers

  • G. Dunbar
  • P. H. Boeijinga
  • A. Demazières
  • C. Cisterni
  • R. Kuchibhatla
  • K. Wesnes
  • R. Luthringer
Original Investigation



The aim of this study was to get insight into the central effects of TC-1734 (renamed AZD3480), a selective agonist at the neuronal nicotinic receptor of the α4β2 subtype.

Materials and methods

Electroencephalography (EEG) techniques and computerized cognitive tests were performed in young, healthy male volunteers during two double-blind and placebo-controlled studies: a rising single dose crossover study (from 2 to 320 mg) and a rising repeated dose study with a parallel group design (50, 100, and 200 mg).


In contrast to acute administration, administration of AZD3480 over 10 days produced statistically significant enhancement of several cognitive measures (attention and episodic memory) compared to placebo. Regarding EEG data, AZD3480 showed acceleration of the alpha centroid and of the alpha peak in the single-dose study. This EEG profile of the acceleration type was confirmed in the repeated dose study on both day 1 and day 10, with the greatest effect observed with the highest dose. The EEG pattern shown for AZD3480 was consistent with that previously described with other drugs known to improve attention and vigilance (including nicotine). In addition, subjects dosed with AZD3480 showed a statistically significant increase in mismatch negativity (MMN) amplitude at 50 and 200 mg while reducing MMN latency (200 mg only), suggesting an improvement of pre-attentional mechanisms.


These early data in healthy subjects provide encouragement to consider development of AZD3480 as a novel agent for the treatment of cognitive decline in the elderly, including age-associated memory impairment and/or dementia of the Alzheimer’s type.


Electroencephalography Neuronal nicotinic receptors Alzheimer Memory Attention 



This study was funded by Targacept Inc., the manufacturer of TC-1734.


  1. Arthur D, Levin ED (2002) Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response. Psychopharmacology 160:140–145PubMedCrossRefGoogle Scholar
  2. Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68:209–245PubMedCrossRefGoogle Scholar
  3. Besthorn C, Zerfass R, Geiger-Kabisch C, Sattel H, Daniel S, Schreiter-Gasser U, Forstl H (1997) Discrimination of Alzheimer’s disease and normal aging by EEG data. Electroencephalogr Clin Neurophysiol 103(2):241–248PubMedCrossRefGoogle Scholar
  4. Brassen S, Adler G (2003) Short-term effects of acetylcholinesterase inhibitor treatment on EEG and memory performance in Alzheimer patients: an open, controlled trial. Pharmacopsychiatry 36(6):304–308PubMedCrossRefGoogle Scholar
  5. Buccafusco JJ, Letchworth SR, Bencherif M, Lippiello PM (2005) Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance. Trends Pharmacol Sci 26:352–360PubMedCrossRefGoogle Scholar
  6. Dago KT, Luthringer R, Lengelle R, Rinaudo G, Macher JP (1994) Statistical decision tree: a tool for studying pharmaco-EEG effects of CNS active drugs. Neuropsychobiology 29:91–96PubMedCrossRefGoogle Scholar
  7. Dierks T, Frölich L, Ihl R, Maurer K (1994) Event-related potentials and psychopharmacology: cholinergic modulation of P300. Pharmacopsychiatry 27:72–74PubMedGoogle Scholar
  8. Dunbar G, Kuchibhatla R (2006) Cognitive enhancement in man with ispronicline, a nicotinic partial agonist. J Mol Neurosci 30:169–172PubMedCrossRefGoogle Scholar
  9. Dunbar G, Demazieres A, Monreal A, Cisterni C, Kuchibhatla R, Luthringer R (2006a) Pharmacokinetics and safety profile of ispronicline (TC-1734) a new neuronal nicotinic receptor partial agonist, in healthy young male volunters. J Clin Pharmacol 46(7):715–726PubMedCrossRefGoogle Scholar
  10. Dunbar G, Inglis F, Kuchibhatla R, Sharma T, Tomlinson M, Wamsley JR (2006b) Effect of ispronicline (TC-1734) a neuronal nicotinic receptor partial agonist, in subjects with age associated memory impairment (AAMI). J Psychopharmacol (in press, August 4)Google Scholar
  11. Edwards J, Wesnes K, Warburton DM, Gale A (1985) Evidence of more rapid stimulus evaluation following cigarette smoking. Addict Behav 10:113–126PubMedCrossRefGoogle Scholar
  12. Engeland C, Mahoney C, Mohr E, Ilivitsky V, Knott VJ (2002) Acute nicotine effects on auditory sensory memory in tacrine treated and nontreated patients with Alzheimer’s disease: an event-related potential study. Pharmacol Biochem Behav 72(1–2):457–464PubMedCrossRefGoogle Scholar
  13. Forstl H, Sattel H, Besthorn C, Daniel S, Geiger-Kabisch C, Hentschel F, Sarochan M, Zerfass R (1996) Longitudinal cognitive, electroencephalographic and morphological brain changes in ageing and Alzheimer’s disease. Br J Psychiatry 168(3):280–286PubMedCrossRefGoogle Scholar
  14. Foulds J, McSorley K, Sneddon J, Feyerabend C, Jarvis MJ, Russel MA (1994) Effect of subcutaneous nicotine injections on EEG alpha frequency in non-smokers: a placebo-controlled pilot study. Psychopharmacology 115(1–2):163–166PubMedCrossRefGoogle Scholar
  15. Gotti C, Clementi F (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–936PubMedCrossRefGoogle Scholar
  16. Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, Laville M, Reibaud M, Pradier L, Dunbar G, Bencherif M (2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev 10(2):147–166PubMedCrossRefGoogle Scholar
  17. Hogg RC, Raggenbass M, Bertrand D (2003) Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol 147:1–46PubMedCrossRefGoogle Scholar
  18. Houlihan ME, Pritchard WS, Robinson JH (1996) Faster P300 latency after smoking in visual but not auditory oddball tasks. Psychopharmacology 123:231–238PubMedCrossRefGoogle Scholar
  19. Jelic V, Dierks T, Amberla K, Almkvist O, Winblad B, Nordberg A (1998) Longitudinal changes in quantitative EEG during long-term tacrine treatment of patients with Alzheimer’s disease. Neurosci Lett 254:85–88PubMedCrossRefGoogle Scholar
  20. Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, Burnett AL (2003) Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy male volunteers. Neuropsychopharmacology 28:542–551PubMedCrossRefGoogle Scholar
  21. Knott V, Bosman M, Mahoney C, Ilivitsky V, Quirt K (1999) Transdermal nicotine: single dose effects on mood, EEG, performance, and event-related potentials. Pharmacol Biochem Behav 63(2):253–261PubMedCrossRefGoogle Scholar
  22. Knott V, Engeland C, Mohr E, Mahoney C, Llivitsky V (2000) Acute nicotine administration in Alzheimer’s disease: an exploratory EEG study. Neuropsychobiology 41:210–220PubMedCrossRefGoogle Scholar
  23. Kowalski JW, Gawel M, Pfeffer A, Barcikowska M (2001) The diagnosis value of EEG in Alzheimer disease. J Clin Neurophysiol 18(6):570–575PubMedCrossRefGoogle Scholar
  24. Lindgren M, Molander L, Verbaan C, Lunell E, Rosén I (1999) Electroencephalograhic effects of intravenous nicotine—a dose-response study. Psychopharmacology 145:335–342CrossRefGoogle Scholar
  25. Matejcek M (1980) Cortical correlates of vigilance regulation and their use in evaluating the effects of treatment. Adv Biochem Psychopharmacol 23:339–348PubMedGoogle Scholar
  26. Meador KJ, Loring DW, Davis HC, Sethi KD, Patel BR, Adams RJ et al (1989) Cholinergic and serotonergic effects on the P3 potential and recent memory. J Clin Exp Neuropsychol 11(Suppl 2):252–260PubMedCrossRefGoogle Scholar
  27. Moore TL, Killiany RJ, Herndon JG, Rosene DL, Moss MB (2006) Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol Aging 27(10):1484–1493PubMedCrossRefGoogle Scholar
  28. Moretti DV, Babiloni C, Binetti G, Cassetta E, Dal Forno G, Ferreric F, Ferri R, Lanuzza B, Miniussi C, Nobili F, Rodriguez G, Salinari S, Rossini PM (2004) Individual analysis of EEG frequency and band power in mild Alzheimer’s disease. Clin Neurophysiol 115:299–308PubMedCrossRefGoogle Scholar
  29. Münte TF, Heinze HJ, Scholz M, Künkel H (1988) Effects of a cholinergic nootropic (WEB 1881 FU) on event-related potentials recorded in incidental and intentional memory tasks. Neuropsychobiology 19:158–168PubMedCrossRefGoogle Scholar
  30. Münte TF, Heinze HJ, Scholz MB, Bartusch SM, Dietrich DE (1989) Event-related potentials and visual spatial attention: influence of a cholinergic drug. Neuropsychobiology 21:94–99PubMedCrossRefGoogle Scholar
  31. Näätänen R, Paavilainen P, Alho K, Reinikainen K, Sams M (1989) Do event-related potentials reveal the mechanism of the auditory sensory memory in the human brain? Neurosci Lett 98:217–221PubMedCrossRefGoogle Scholar
  32. Newhouse PA, Potter A, Kelton M, Corwin J (2001) Nicotinic treatment of Alzheimer’s disease. Biol Psychiatry 49:268–278PubMedCrossRefGoogle Scholar
  33. Nordberg A (2001) Nicotinic receptor in Alzheimer’s disease: therapeutic implications. Biol Psychiatry 49:200–210PubMedCrossRefGoogle Scholar
  34. Obinu MC, Reibaud M, Miquet JM, Pasquet M, Rooney T (2002) Brain-selective stimulation of nicotinic receptors by TC-1734 enhances ACh transmission from frontoparietal cortex and memory in rodents. Prog Neuropsychopharmacol Biol Psychiatry 26:913–918PubMedCrossRefGoogle Scholar
  35. Pekkonen E, Jaaskelainen IP, Hietanen M, Huotilainen M, Kaakkola S, Näätänen R, Ilmoniemi RJ, Erkinjuntti T (2000) Mismatch negativity in aging and in Alzheimer’s and Parkinson’s diseases. Audiol Neurootol 5:216–224PubMedCrossRefGoogle Scholar
  36. Pekkonen E, Hirvonen J, Jaaskelainen IP, Kaakkola S, Huttunen J (2001) Auditory sensory memory and the cholinergic system: implications for Alzheimer’s disease. Neuroimage 14(2):376–382PubMedCrossRefGoogle Scholar
  37. Perry EK, Martin-Ruiz CM, Court JA (2001) Nicotinic receptor subtypes in human brain related to aging and dementia. Alcohol 24:63–68PubMedCrossRefGoogle Scholar
  38. Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA (1999) Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzhiemer’s disease. Psychopharmacology 142:334–342PubMedCrossRefGoogle Scholar
  39. Prichep LS, John ER, Ferris SH, Reisberg B, Almas M, Alper K, Cancro R (1994) Quantitative EEG correlates of cognitive deterioration in the elderly. Neurobiol Aging 15(1):85–90PubMedCrossRefGoogle Scholar
  40. Rodriguez G, Vitali P, De Leo C, De Carli F, Girtler N, Nobili F (2002) Quantitative EEG changes in Alzheimer patients during long-term donepezil therapy. Neuropsychobiology 46(1):49–56PubMedCrossRefGoogle Scholar
  41. Saletu B (1996) Pharmacodynamics and EEG. In: Krijzer F, Hermann WM (eds) Advances in pharmaco-EEG. Practical and theoretical considerations in preclinical and clinical studies. Berlin Zentrale Universitätsdruckerer, pp 187–204Google Scholar
  42. Saletu B, Anderer P, Saletu-Zylharz GM, Arnold O, Pascual-Marqui RD (2002) Classification and evaluation of the pharmacodynamics of psychotropic drugs by single-lead pharmaco-EEG, EEG mapping and tomography (LORETA). Methods Find Exp Clin Pharmacol 24(suppl C):97–120Google Scholar
  43. Wesnes KA, Simpson PM, Thompson S (1994) Cognition enhancement with physostigmine in young volunteers. J Psychopharmacol 8(suppl):A19Google Scholar
  44. Wesnes KA, Ward T, McGinty A, Petrini O (2000) The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology 152:353–361PubMedCrossRefGoogle Scholar
  45. Zoli M, Picciotto MR, Ferrari R, Cocchi D, Changeux JP (1999) Increased neurodegeneration during aging in mice lacking high-affinity nicotine receptors. EMBO J 18(5):1235–1244PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • G. Dunbar
    • 2
  • P. H. Boeijinga
    • 1
  • A. Demazières
    • 1
  • C. Cisterni
    • 1
  • R. Kuchibhatla
    • 2
  • K. Wesnes
    • 3
  • R. Luthringer
    • 1
  1. 1.FORENAPRouffachFrance
  2. 2.TARGACEPT Inc.Winston-SalemUSA
  3. 3.Cognitive Drug Research Ltd.Goring-on-ThamesUK

Personalised recommendations