, Volume 172, Issue 4, pp 375–383

AR-R 17779 improves social recognition in rats by activation of nicotinic α7 receptors

  • Marja van Kampen
  • Karin Selbach
  • Renate Schneider
  • Elleonore Schiegel
  • Frank Boess
  • Rudy Schreiber
Original Investigation



Nicotine and agonists at α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) improve learning and memory. The α7-nAChR subtype is of special interest, since it appears to play no role in the abuse liability of nicotine.

Objectives and methods

To further investigate the role of the α7-nAChR in learning and memory, the effects of the specific α7-nAChR agonist AR-R17779 on cognition were measured in the rat social recognition test (SRT) and the effect of the α7-nAChR antagonist methyllycaconitine (MLA) was studied. The SRT and a scopolamine-induced deficit version were validated with the acetylcholinesterase inhibitor metrifonate. Social memory was measured by the ability of an adult rat to recognize a juvenile rat after a delay. The difference in social interaction time (SIT) was measured between two encounters. The difference in SIT is expressed as percent reduction in social interaction time (%RSIT).


Metrifonate (10 and 30 mg/kg PO) increased %RSIT in a behaviorally specific manner, employing a 24-h interval and reversed the scopolamine-induced deficit at a retention time of 15 min. Likewise, AR-R17779 increased %RSIT in unimpaired animals (1, 3, 10 and 30 mg/kg SC) employing a 24-h retention interval, and reversed the scopolamine-induced deficit (0.3 and 1 mg/kg SC) after a 15-min retention interval. The effects of AR-R17779 (1 mg/kg SC) in unimpaired animals were reversed by MLA (10 µg ICV), which induced a decrease of %RSI at a 15-min retention interval when given alone.


AR-R17779 increased social recognition memory by activation of α7-nAChRs, suggesting that α7-nAChR agonists possess cognitive-enhancing properties.


α7-nicotinic receptors Social memory Cognition Acetylcholinesterase inhibitors Scopolamine 


  1. Albuquerque EX, Pereira EF, Mike A, Eisenberg HM, Maelicke A, Alkondon M (2000) Neuronal nicotinic receptors in synaptic functions in humans and rats: physiological and clinical relevance. Behav Brain Res 113:131–141CrossRefPubMedGoogle Scholar
  2. Arendash GW, Sengstock GJ, Sanberg PR, Kem WR (1995) Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21. Brain Res 674:252–259CrossRefPubMedGoogle Scholar
  3. Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529CrossRefPubMedGoogle Scholar
  4. Bettany JH, Levin ED (2001) Ventral hippocampal alpha 7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze. Pharmacol Biochem Behav 70:467–474Google Scholar
  5. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedGoogle Scholar
  6. Blokland A (1996) Acetylcholine: a neurotransmitter for learning and memory? Brain Res Brain Res Rev 21:285–300Google Scholar
  7. Briggs CA, Anderson DJ, Brioni JD, Buccafusco JJ, Buckley MJ, Campbell JE, Decker MW, Donnelly-Roberts D, Elliott RL, Gopalakrishnan M, Holladay MW, Hui YH, Jackson WJ, Kim DJ, Marsh KC, O’Neill A, Prendergast MA, Ryther KB, Sullivan JP, Arneric SP (1997) Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav 57:231–241PubMedGoogle Scholar
  8. Brioni JD, Kim DJ, O’Neill AB (1996) Nicotine cue: lack of effect of the alpha 7 nicotinic receptor antagonist methyllycaconitine. Eur J Pharmacol 301:1–5PubMedGoogle Scholar
  9. Buccafusco JJ, Jackson WJ, Terry AV Jr, Marsh KC, Decker MW, Arneric SP (1995) Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement. Psychopharmacology 120:256–266PubMedGoogle Scholar
  10. Chen Y, Cecinato V, McPhie G, De Filippi G, Sher E (2000) Nicotine and an alpha7 selective nicotinic agonist AR-R17779 facilitate the induction of long-term potentiation induced by a short tetanus. Soc Neurosci Abstr 26:420.3Google Scholar
  11. Dachir S, Schmidt B, Levy A (1997) Effects of metrifonate on radial arm maze acquisition in middle-aged rats. Brain Res 777:251–254CrossRefPubMedGoogle Scholar
  12. Dantzer R, Bluthe RM, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368Google Scholar
  13. de Fiebre CM, Meyer EM, Henry JC, Muraskin SI, Kem WR, Papke RL (1995) Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethyl-aminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha7/125I-alpha-bungarotoxin receptor subtypes. Mol Pharmacol 47:164–171PubMedGoogle Scholar
  14. Elgoyhen AB, Vetter DE, Katz E, Rothlin CV, Heinemann SF, Boulter J (2001) Alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and mechanosensory hair cells. Proc Natl Acad Sci USA 98:3501–3506CrossRefPubMedGoogle Scholar
  15. Everts HG, Koolhaas JM (1997) Lateral septal vasopressin in rats: role in social and object recognition? Brain Res 760:1–7CrossRefPubMedGoogle Scholar
  16. Felix R, Levin ED (1997) Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats. Neuroscience 81:1009–1017CrossRefPubMedGoogle Scholar
  17. Fujii S, Ji Z, Sumikawa K (2000) Inactivation of alpha7 ACh receptors and activation of non-alpha7 ACh receptors both contribute to long term potentiation induction in the hippocampal CA1 region. Neurosci Lett 286:134–138CrossRefPubMedGoogle Scholar
  18. Fujii S, Ji Z, Sumikawa K (2001) Acute and chronic nicotine exposure reverse age-related declines in the induction of long-term potentiation in the rat hippocampus. Brain Res 894:347–353CrossRefPubMedGoogle Scholar
  19. Gheusi G, Bluthe RM, Goodall G, Dantzer R (1994) Ethological study of the effects of tetrahydroaminoacridine (THA) on social recognition in rats. Psychopharmacology 114:644–650PubMedGoogle Scholar
  20. Gordon J, Gurley DA, Tran O, Machulskis A, Zongrone J, Luhowskyi S, Ryan T, Mack A, Loch J, III, Balestra M, DeCory T, Sampognaro A, Wright N, Verhoest P, Macor J, Kover A, Wu E, Griffith R, Mullen G, Murray R, Blosser J (1998) AR-R 17779: the first high affintiy, subtype-selective full agonist at the rodent alpha 7 nicotinic acetylcholine receptor. Soc Neurosci Abstr 24:331.9Google Scholar
  21. Grottick AJ, Higgins GA (2000) Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res 117:197–208PubMedGoogle Scholar
  22. Hahn B, Shoaib M, Stolerman IP (2001) Attentional effects of nicotinic agonists in rats. Soc Neurosci Abstr 27:313.18Google Scholar
  23. Hunter BE, de Fiebre CM, Papke RL, Kem WR, Meyer EM (1994) A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus. Neurosci Lett 168:130–134CrossRefPubMedGoogle Scholar
  24. Itoh A, Nitta A, Hirose M, Hasegawa T, Nabeshima T (1997a) Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats. Behav Brain Res 83:165–167CrossRefPubMedGoogle Scholar
  25. Itoh A, Nitta A, Katono Y, Usui M, Naruhashi K, Iida R, Hasegawa T, Nabeshima T (1997b) Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. Eur J Pharmacol 322:11–19CrossRefPubMedGoogle Scholar
  26. Kem WR (2000) The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: studies with DMXBA (GTS-21). Behav Brain Res 113:169–181PubMedGoogle Scholar
  27. Kitagawa H, Takenouchi T, Azumas R, Wesnes KA; Kramers WG, Clody DE, Burnett AL (2003) Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28:542–551CrossRefPubMedGoogle Scholar
  28. Kogan JH, Frankland PW, Silva AJ (2000) Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10:47–56PubMedGoogle Scholar
  29. Kronforst-Collins MA, Moriearty PL, Ralph M, Becker RE, Schmidt B, Thompson LT, Disterhoft JF (1997) Metrifonate treatment enhances acquisition of eyeblink conditioning in aging rabbits. Pharmacol Biochem Behav 56:103–110CrossRefPubMedGoogle Scholar
  30. Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138:217–230CrossRefPubMedGoogle Scholar
  31. Levin ED, Bettegowda C, Blosser J, Gordon J (1999) AR-R17779, an alpha7 nicotinic agonist, improves learning and memory in rats. Behav Pharmacol 10:675–680PubMedGoogle Scholar
  32. Meyer EM, de Fiebre CM, Hunter BE, Simpkins 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 31:127–134Google Scholar
  33. Meyer EM, Kuryatov A, Gerzanich V, Lindstrom J, Papke RL (1998) Analysis of 3-(4-hydroxy, 2-methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors. J Pharmacol Exp Ther 287:918–925PubMedGoogle Scholar
  34. Nordgren I, Bengtsson E, Holmstedt B, Pettersson BM (1981) Levels of metrifonate and dichlorvos in plasma and erythrocytes during treatment of schistosomiasis with Bilarcil. Acta Pharmacol Toxicol (Copenh) 49 (Suppl 5):79–86Google Scholar
  35. Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111PubMedGoogle Scholar
  36. Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, New YorkGoogle Scholar
  37. Perio A, Terranova JP, Worms P, Bluthe RM, Dantzer R, Biziere K (1989) Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psychostimulants. Psychopharmacology 97:262–268Google Scholar
  38. Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177PubMedGoogle Scholar
  39. Popik P, van Ree JM (1998) Neurohypophyseal peptides and social recognition in rats. Prog Brain Res 119:415–436PubMedGoogle Scholar
  40. Prickaerts J, Honig W, Schmidt BH, Blokland A (1999) Metrifonate improves working but not reference memory performance in a spatial cone field task. Eur J Pharmacol 380:61–65CrossRefPubMedGoogle Scholar
  41. Riekkinen M, Schmidt B, Kuitunen J, Riekkinen P Jr (1997a) Effects of combined chronic nimodipine and acute metrifonate treatment on spatial and avoidance behavior. Eur J Pharmacol 322:1–9CrossRefPubMedGoogle Scholar
  42. Riekkinen P Jr, Schmidt B, Riekkinen M (1997b) Behavioral characterization of metrifonate-improved acquisition of spatial information in medial septum-lesioned rats. Eur J Pharmacol 323:11–19CrossRefPubMedGoogle Scholar
  43. Scali C, Giovannini MG, Bartolini L, Prosperi C, Hinz V, Schmidt B, Pepeu G (1997) Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats. Eur J Pharmacol 325:173–180PubMedGoogle Scholar
  44. Schreiber R, Dalmus M, De Vry J (2002) Effects of alpha 4/beta 2- and alpha 7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice. Psychopharmacology 159:248–257CrossRefPubMedGoogle Scholar
  45. Terranova JP, Perio A, Worms P, Le Fur G, Soubrie P (1994) Social olfactory recognition in rodents: deterioration with age, cerebral ischaemia and septal lesion. Behav Pharmacol 5:90–98PubMedGoogle Scholar
  46. Terry AV Jr, Buccafusco JJ, Decker MW (1997) Cholinergic channel activator, ABT-418, enhances delayed-response accuracy in rats. Drug Dev Res 40:304–312CrossRefGoogle Scholar
  47. Thor DH, Holloway WR (1982) Social memory of the male laboratory rat. J Comp Physiol Psychol 96:1000–1006Google Scholar
  48. van der Staay FJ, Hinz VC, Schmidt BH (1996) Effects of metrifonate on escape and avoidance learning in young and aged rats. Behav Pharmacol 7:56–64PubMedGoogle Scholar
  49. Winslow JT, Camacho F (1995) Cholinergic modulation of a decrement in social investigation following repeated contacts between mice. Psychopharmacology 121:164–172PubMedGoogle Scholar
  50. Woodruff-Pak DS, Li YT, Kem WR (1994) A nicotinic agonist (GTS-21), eyeblink classical conditioning, and nicotinic receptor binding in rabbit brain. Brain Res 645:309–317PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Marja van Kampen
    • 1
    • 3
  • Karin Selbach
    • 1
  • Renate Schneider
    • 1
  • Elleonore Schiegel
    • 1
  • Frank Boess
    • 1
  • Rudy Schreiber
    • 1
    • 2
  1. 1.CNS ResearchBayer AGWuppertalGermany
  2. 2.CNS NeurobehaviorRoche PharmaceuticalsPalo AltoUSA
  3. 3.ICON Clinical Research GmbHHeinrich-Hertz-Strasse 26LangenGermany

Personalised recommendations