, Volume 120, Issue 3, pp 256–266 | Cite as

Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement

  • J. J. Buccafusco
  • W. J. Jackson
  • A. V. TerryJr
  • K. C. Marsh
  • M. W. Decker
  • S. P. Arneric
Original Investigation


ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular administration of ABT-418 significantly enhanced DMTS performance at low (2–32.4 nmol/kg) doses. In fact, the drug was slightly more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly tested with their individualized “Best Dose”, DMTS performance increased on average by 10.1 ± 3.5 percentage points correct, which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times, i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity.

Key words

Nicotine Nicotinic acetylcholine receptors (nAChRs) Learning and memory Cognition Monkey Delayed-matching 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adem A, Synnergren B, Botros M, Ohman B, Winblad B, Nordberg A (1987) (3H) Acetylcholine nicotinic recognition sites in human brain: characterization of agonist binding. Neurosci Lett 83:298–302CrossRefPubMedGoogle Scholar
  2. Anderson DJ, Williams M, Arneric' SP, Pauly JR, Rotent GA, Suber B, Raszkiewicz JL, Wasicak J, Sullivan JP (1995) Characterization of [3H] ABT-418: a novel cholinergic channel ligand. J Pharmacol Exp Ther (submitted)Google Scholar
  3. Arneric' SP, Sullivan JP, Briggs CA, Donnelly-Roberts D, Anderson DJ, Raszkiewicz JL, Hughes M, Cadman ED, Adams P, Garvey DS, Wasicak J, Williams W (1994) ABT-418: a novel cholinergic ligand with cognition enhancing and anxiolytic activities. I. In vitro characterization. J Pharmacol Exp Ther 270:310–318Google Scholar
  4. Balfour DJK (1982) The effect of nicotine on brain neurotransmitter systems. Pharmacol Ther 16:269–282CrossRefPubMedGoogle Scholar
  5. Beani LC, 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-Schmiedeberg's Arch Pharmacol 331:293–296CrossRefGoogle Scholar
  6. Benowitz NL (1992) Nicotine and coronary heart disease. Trends Cardiovasc Med 1:315–321Google Scholar
  7. Briggs CA, Cooper JR (1982) Cholinergic modulation of the release of (3H) acetylcholine from synaptosomes of the myenteric plexus. J Neurochem 38:501–508PubMedGoogle Scholar
  8. Brioni JD, O'Neill A, Kim DJB, Decker MW, Sullivan JP, Arneric' SP (1994) Anxiolytic like effects of the novel cholinergic channel activator, ABT-418. J Pharmacol Exp Ther 271:353–361PubMedGoogle Scholar
  9. Buccafusco JJ, Jackson WJ (1991) Beneficial effects of nicotine administered prior to a delayed matching-to-sample task in the young and aged monkeys. Neurobiol Aging 12:233–238CrossRefPubMedGoogle Scholar
  10. Butcher LL, Wolf NJ (1986) Central cholinergic systems: synopsis of anatomy and overview of physiology and pathology. In: Scheibel AB, Wechsler AF Substrates of Alzheimer's disease. Academic Press, New York, pp 73–86Google Scholar
  11. Chiou CY (1973) Mechanism of acetylcholine release by drugs and its blockade (1). Arch Int Pharmacodyn 201:170–181PubMedGoogle Scholar
  12. Decker MW, Majchrzak MJ (1992) Effects of systemic and intracerebroventricular administration of mecamylamine, a nicotinic cholinergic antagonist, on spatial memory in rats. Psychopharmacology 107:530–539CrossRefPubMedGoogle Scholar
  13. Decker MW, Majchrzak MJ, Anderson DJ (1992) Effects of nicotine on spatial memory deficits in rats with septal lesions. Brain Res 572:281–285CrossRefPubMedGoogle Scholar
  14. Decker MW, Majchrzak MJ, Arneric' SP (1993) Effects of lobeline, a nicotinic receptor agonist, on learning and memory. Pharmacol Biochem Behav 45:571–576CrossRefPubMedGoogle Scholar
  15. Decker MW, Brioni J, Sullivan JP, Buckley M, Radek R, Raszkiewicz JL, Hughes M, Giardina W, Wasicak JT, Garvey DS, Williams M, Arneric SP (1994a) ABT418: a novel cholinergic ligand with cognition enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther 270:319–328PubMedGoogle Scholar
  16. Decker MW, Brioni JD, Buckley MJ, Curzon P, Arneric' SP (1994b) Preclinical cognitive effects of cholinergic channel ligands. Neuropsychopharmacology 10:4365Google Scholar
  17. Elrod K, Buccafusco JJ, Jackson WJ (1988) Nicotine enhances delayed matching-to-sample performance in primates. Life Sci 43:277–287CrossRefPubMedGoogle Scholar
  18. Etienne P, Robitaille Y, Wood P, Gauthier S, Nair NPV, Quirion R (1986) Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease. Neuroscience 19:1279–1291CrossRefPubMedGoogle Scholar
  19. Flynn DD, Mash DC (1986) Characterization of 1-[3H] nicotine binding in human cerebral cortex: comparison between Alzheimer's disease and the normal. J Neurochem 47:1948–1954PubMedGoogle Scholar
  20. Garvey DS, Wasicak J, Decker MW, Brioni JD, Sullivan JP, Carrera GM, Holladay MH, Arneric SP, Williams M (1994) Novel isoxazoles which interact with brain cholinergic channel receptors that have intrinsic cognitive enhancing and anxiolytic activities. J Med Chem 37:1055–1059PubMedGoogle Scholar
  21. Gellerman LW (1933) Chance order of alternating stimuli in visual discrimination experiments. J Genet Psychol 42:207–208Google Scholar
  22. Hodges H, Sinden J, Turner JJ, Netto CA, Sowinski P, Gray JA (1992) Nicotine as a tool to characterize the role of the basal forebrain cholinergic projections system in cognition. In: Lippiello PM, Collins AC, Gray JA, Robinson JH (eds) The biology of nicotine: current research issues. Raven Press, New York, pp 157–182Google Scholar
  23. Jackson WJ, Elrod K, Buccafusco JJ (1989) Delayed matching-to-sample in monkeys as a model for learning and memory deficits: role of brain nicotinic receptors. In: Meyer EM, Simpkinsn JW, Yamamoto J (eds) Novel approaches to the treatment of Alzheimer's disease Plenum, New York, pp 39–52Google Scholar
  24. Levin ED (1992) Nicotinic systems in cognitive function. Psychopharmacology 108:417–431CrossRefPubMedGoogle Scholar
  25. Levin ED, Castonguay M, Ellison GD (1987) Effects of the nicotinic receptor blocker, mecamylamine, on radial-arm maze performance in rats. Behav Neural Biol 48:206–212PubMedGoogle Scholar
  26. Levin ED, Lee C, Rose JE, Reyes A, Ellison G, Jaravik M, Gritz E (1990) Chronic nicotine and withdrawal effects on radial-arm performance in rats. Behav Neurol Biol 53:269–276Google Scholar
  27. Linville DG, Arneric SP (1991) Cortical cerebral blood flow governed by the basal forebrain: age-related impairments. Neurobiol Aging 12:503–510CrossRefPubMedGoogle Scholar
  28. Linville DG, Williams S, Raskiewicz JL, Arneric SP (1993) Nicotinic agonists modulate basal forebrain (BF) control of cortical cerebral blood flow in anesthetized rats. J Pharmacol Exp Ther 267:440–448PubMedGoogle Scholar
  29. McCormick DA (1990) Cellular mechanism of cholinergic neocortical and thalamic neuronal excitability. In: Sterade M, Biesold D (eds) Brain cholinergic systems, Oxford University Press. pp 236–264Google Scholar
  30. Meyer EM, de Fiebre CM, Hunter BE, Simkins CE, Frauworth N, de Fiebre NEC (1994) Effects of anabaseine-related analogs on rat brain nicotinic receptor binding and on avoidance behaviors. Drug Dev Res 31 (in press)Google Scholar
  31. Newhouse PA, Potter A, Corwin J, Lenox R (1992) Acute nicotinic blockade produces cognitive impairment in normal humans. Psychopharmacology 108:480–484CrossRefPubMedGoogle Scholar
  32. Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL (1988) Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology 95:71–175CrossRefGoogle Scholar
  33. Nordberg A, Winblad B (1986) Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci Lett 72:115–119CrossRefPubMedGoogle Scholar
  34. Oliverio A (1966) Effects of mecamylamine on avoidance conditioning and maze learning of mice. J Pharmacol Exp Ther 154:350–356PubMedGoogle Scholar
  35. Quirion R, Martel JC, Robitaille Y, Etienne P, Wood P, Nair NPV, Gauthier S (1986) Neurotransmitter and receptor deficits in senile dementia of the Alzheimer type. Can J Neurol Sci 13:503–510PubMedGoogle Scholar
  36. Riekkinen P, Jr, Sirvi J, Aaltonen M, Riekkinen P (1990) The effects of concurrent manipulations of nicotinic and muscarinic receptors on spatial and passive avoidance learning. Pharmacol Biochem Behav 37:405–410CrossRefPubMedGoogle Scholar
  37. Sahakian B, Jones G, Levy R, Gray J, Warburton D (1989) The effects of nicotine on attention, information procesing, and short-term memory in patients with dementia of the Alzheimer's type. Br J Psychiatry 154:797–800PubMedGoogle Scholar
  38. Schroder H, Giacobini E, Struble RG, Zilles K, Maelicke A (1991) Nicotinic cholinoceptive neurons of the frontl cortex are reduced in Alzheimer's disease. Neurobiol Aging 12:259–262CrossRefPubMedGoogle Scholar
  39. Shimohama S, Taniguchi T, Fujiwara M, Kameyama M (1985) Biochemical characterization of the nicotinic cholinergic receptors in human brain: binding of (−)-(3H) nicotine. J Neurochem 445:604–610Google Scholar
  40. Terry AV, Buccafusco JJ, Jackson WJ (1993) Scopolamine reversal of nicotine enhanced delayed matching-to-sample performance by monkeys. Pharmacol Biochem Behav 45:925–929CrossRefPubMedGoogle Scholar
  41. Tilson HA, McLamb RL, Shaw S, Rodgers BC, Pediaditakis P, Cook L (1988) Radial-arm maze deficits produced by colchicine administered into the area of the nucleus basalis are ameliorated by cholinergic agents. Brain Res 438:83–94CrossRefPubMedGoogle Scholar
  42. Wessler I, Kilbinger H (1986) Release of (3H) acetylcholine from a modified rat phrenic nerve-hemidiaphragm preparation. Naunyn-Schmiedeberg's Arch. Pharmacol 334:357–364Google Scholar
  43. Wessler I, Halank M, Rasbach J, Kilbinger H (1986) Presynaptic nicotine receptors mediating a positive feed-back on transmitter release from the rat phrenic nerve. Naunyn-Schmiedeberg's Arch Pharmacol 334:365–372Google Scholar
  44. Whitehouse PJ, Price DL, Clark AW, Coyle AW, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126CrossRefPubMedGoogle Scholar
  45. 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 371:146–151CrossRefPubMedGoogle Scholar
  46. Younkin SG, Goodridge B, Katz J, Lockett G, Nafziger D, Usiak MF, Younkin, LH (1986) Molecular forms of acetylcholinesterase in Alzheimer's disease. Fed Prod 45:2982–2988Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • J. J. Buccafusco
    • 1
    • 3
  • W. J. Jackson
    • 1
    • 2
  • A. V. TerryJr
    • 1
  • K. C. Marsh
    • 4
  • M. W. Decker
    • 4
  • S. P. Arneric
    • 4
  1. 1.Department of Pharmacology and Toxicology, Alzheimer's Research CenterMedical College of GeorgiaAugustaUSA
  2. 2.Department of Physiology and EndocrinologyMedical College of GeorgiaAugustaUSA
  3. 3.Medical Research ServiceDepartment of Veterans Affairs Medical CenterAugustaUSA
  4. 4.Pharmaceutical Products DivisionAbbott LaboratoriesAbbott ParkUSA

Personalised recommendations