Skip to main content

Advertisement

Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

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).

Results

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.

Conclusions

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • 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 113:131–141

    Article  CAS  PubMed  Google Scholar 

  • 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 674:252–259

    Article  CAS  PubMed  Google Scholar 

  • Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529

    Article  PubMed  Google Scholar 

  • 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 70:467–474

    Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    CAS  PubMed  Google Scholar 

  • Blokland A (1996) Acetylcholine: a neurotransmitter for learning and memory? Brain Res Brain Res Rev 21:285–300

    Google Scholar 

  • 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 57:231–241

    CAS  PubMed  Google Scholar 

  • Brioni JD, Kim DJ, O’Neill AB (1996) Nicotine cue: lack of effect of the alpha 7 nicotinic receptor antagonist methyllycaconitine. Eur J Pharmacol 301:1–5

    CAS  PubMed  Google Scholar 

  • 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 120:256–266

    CAS  PubMed  Google Scholar 

  • 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 26:420.3

    Google Scholar 

  • Dachir S, Schmidt B, Levy A (1997) Effects of metrifonate on radial arm maze acquisition in middle-aged rats. Brain Res 777:251–254

    Article  CAS  PubMed  Google Scholar 

  • Dantzer R, Bluthe RM, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368

    Google Scholar 

  • 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 47:164–171

    PubMed  Google Scholar 

  • 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 98:3501–3506

    Article  CAS  PubMed  Google Scholar 

  • Everts HG, Koolhaas JM (1997) Lateral septal vasopressin in rats: role in social and object recognition? Brain Res 760:1–7

    Article  CAS  PubMed  Google Scholar 

  • Felix R, Levin ED (1997) Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats. Neuroscience 81:1009–1017

    Article  CAS  PubMed  Google Scholar 

  • 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 286:134–138

    Article  CAS  PubMed  Google Scholar 

  • 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 894:347–353

    Article  CAS  PubMed  Google Scholar 

  • Gheusi G, Bluthe RM, Goodall G, Dantzer R (1994) Ethological study of the effects of tetrahydroaminoacridine (THA) on social recognition in rats. Psychopharmacology 114:644–650

    CAS  PubMed  Google Scholar 

  • 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 24:331.9

    Google Scholar 

  • 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 117:197–208

    CAS  PubMed  Google Scholar 

  • Hahn B, Shoaib M, Stolerman IP (2001) Attentional effects of nicotinic agonists in rats. Soc Neurosci Abstr 27:313.18

    Google Scholar 

  • 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 168:130–134

    Article  CAS  PubMed  Google Scholar 

  • 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 83:165–167

    Article  CAS  PubMed  Google Scholar 

  • 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 322:11–19

    Article  CAS  PubMed  Google Scholar 

  • 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 113:169–181

    CAS  PubMed  Google Scholar 

  • 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 28:542–551

    Article  PubMed  Google Scholar 

  • Kogan JH, Frankland PW, Silva AJ (2000) Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10:47–56

    CAS  PubMed  Google Scholar 

  • 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 56:103–110

    Article  CAS  PubMed  Google Scholar 

  • Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138:217–230

    Article  CAS  PubMed  Google Scholar 

  • Levin ED, Bettegowda C, Blosser J, Gordon J (1999) AR-R17779, an alpha7 nicotinic agonist, improves learning and memory in rats. Behav Pharmacol 10:675–680

    CAS  PubMed  Google Scholar 

  • 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 31:127–134

    CAS  Google Scholar 

  • 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 287:918–925

    CAS  PubMed  Google Scholar 

  • 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):79–86

    Google Scholar 

  • Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, New York

  • 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 97:262–268

    Google Scholar 

  • 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 391:173–177

    CAS  PubMed  Google Scholar 

  • Popik P, van Ree JM (1998) Neurohypophyseal peptides and social recognition in rats. Prog Brain Res 119:415–436

    CAS  PubMed  Google Scholar 

  • 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 380:61–65

    Article  CAS  PubMed  Google Scholar 

  • 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 322:1–9

    Article  CAS  PubMed  Google Scholar 

  • 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 323:11–19

    Article  CAS  PubMed  Google Scholar 

  • 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 325:173–180

    CAS  PubMed  Google Scholar 

  • 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 159:248–257

    Article  CAS  PubMed  Google Scholar 

  • 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 5:90–98

    PubMed  Google Scholar 

  • Terry AV Jr, Buccafusco JJ, Decker MW (1997) Cholinergic channel activator, ABT-418, enhances delayed-response accuracy in rats. Drug Dev Res 40:304–312

    Article  CAS  Google Scholar 

  • Thor DH, Holloway WR (1982) Social memory of the male laboratory rat. J Comp Physiol Psychol 96:1000–1006

    Google Scholar 

  • van der Staay FJ, Hinz VC, Schmidt BH (1996) Effects of metrifonate on escape and avoidance learning in young and aged rats. Behav Pharmacol 7:56–64

    PubMed  Google Scholar 

  • Winslow JT, Camacho F (1995) Cholinergic modulation of a decrement in social investigation following repeated contacts between mice. Psychopharmacology 121:164–172

    CAS  PubMed  Google Scholar 

  • 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 645:309–317

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Dr. Jordan Mechanic is thanked for his critical review of the manuscript and helpful comments. Dr. van der Staay is thanked for the helpful discussions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rudy Schreiber.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Kampen, M., Selbach, K., Schneider, R. et al. AR-R 17779 improves social recognition in rats by activation of nicotinic α7 receptors. Psychopharmacology 172, 375–383 (2004). https://doi.org/10.1007/s00213-003-1668-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1668-7

Keywords

Navigation