Skip to main content
SpringerLink
Log in

Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625

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

Abstract

Rationale

α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.

Objectives

We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.

Methods

Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.

Results

WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.

Conclusions

These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.

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

Access this article

Log in via an institution

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
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

AChE:

Acetylcholine esterase

AIC:

Apomorphine-induced climbing

CAR:

Conditioned avoidance responding

CIAS:

Cognitive impairment associated with schizophrenia

MED:

Minimum effective dose

nAChR:

Nicotininc acetylcholine receptor

NS:

Non-significant

NOR:

Novel object recognition

SOR:

Social odor recognition

WYE-103914:

1-(6-(4-fluorophenyl)pyridin-3-yl)-3-(4-(piperidin-1-yl)butyl)urea

References

  • Acker BA, Jacobsen EJ, Rogers BN, Wishka DG, Reitz SC, Piotrowski DW, Myers JK, Wolfe ML, Groppi VE, Thornburgh BA, Tinholt PM, Walters RR, Olson BA, Fitzgerald L, Staton BA, Raub TJ, Krause M, Li KS, Hoffmann WE, Hajos M, Hurst RS, Walker DP (2008) Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity. Bioorg Med Chem Lett 18:3611–3615

    Article  PubMed  CAS  Google Scholar 

  • Adler LE, Hoffer LD, Wiser A, Freedman R (1993) Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 150:1856–1861

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Arnt J (1982) Pharmacological specificity of conditioned avoidance response inhibition in rats: inhibition by neuroleptics and correlation to dopamine receptor blockade. Acta Pharmacol Toxicol 51:321–329

    Article  CAS  Google Scholar 

  • Biton B, Bergis OE, Galli F, Nedelec A, Lochead AW, Jegham S, Godet D, Lanneau C, Santamaria R, Chesney F, Leonardon J, Granger P, Debono MW, Bohme GA, Sgard F, Besnard F, Graham D, Coste A, Oblin A, Curet O, Vige X, Voltz C, Rouquier L, Souilhac J, Santucci V, Gueudet C, Francon D, Steinberg R, Griebel G, Oury-Donat F, George P, Avenet P, Scatton B (2007) SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology 32:1–16

    Article  PubMed  CAS  Google Scholar 

  • Boess FG, De Vry J, Erb C, Flessner T, Hendrix M, Luithle J, Methfessel C, Riedl B, Schnizler K, van der Staay FJ, van Kampen M, Wiese WB, Koenig G (2007) The novel alpha7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents. J Pharmacol Exp Ther 321:716–725

    Article  PubMed  CAS  Google Scholar 

  • Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC, Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR (2005) A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 31:5–19

    Article  PubMed  Google Scholar 

  • Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA (2007) Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schiz Bull 33:1120–1130

    Article  Google Scholar 

  • De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL (2004) Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients. Neuropsychopharmacology 29:1522–1526

    Article  PubMed  Google Scholar 

  • Dickinson JA, Kew JN, Wonnacott S (2008) Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Mol Pharmacol 74:348–359

    Article  PubMed  CAS  Google Scholar 

  • Feuerbach D, Nozulak J, Lingenhoehl K, McAllister K, Hoyer D (2007) JN403, in vitro characterization of a novel nicotinic acetylcholine receptor alpha7 selective agonist. Neurosci Lett 416:61–65

    Article  PubMed  CAS  Google Scholar 

  • Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22–33

    Article  PubMed  CAS  Google Scholar 

  • Ghiron C, Haydar SN, Aschmies S, Bothmann H, Castaldo C, Cocconcelli G, Comery TA, Di L, Dunlop J, Lock T, Kramer A, Kowal D, Jow F, Grauer S, Harrison B, La Rosa S, Maccari L, Marquis KL, Micco I, Nencini A, Quinn J, Robichaud A, Roncarati R, Scali C, Terstappen GC (2010) Novel alpha7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625/WYE-103914). J Med Chem 53(11):4379–4389

    Article  PubMed  CAS  Google Scholar 

  • Hajos M, Hurst RS, Hoffmann WE, Krause M, Wall TM, Higdon NR, Groppi VE (2005) The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats. J Pharmacol Exp Ther 312:1213–1222

    Article  PubMed  CAS  Google Scholar 

  • Klein A, Schmidt WJ (2003) Catalepsy intensifies context-dependently irrespective of whether it is induced by intermittent or chronic dopamine deficiency. Behav Pharmacol 14:49–53

    Article  PubMed  CAS  Google Scholar 

  • Leiser SC, Bowlby MR, Comery TA, Dunlop J (2009) A cog in cognition: how the [alpha]7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol Ther 122:302–311

    Article  PubMed  CAS  Google Scholar 

  • Leonard S, Breese C, Adams C, Benhammou K, Gault J, Stevens K, Lee M, Adler L, Olincy A, Ross R, Freedman R (2000) Smoking and schizophrenia: abnormal nicotinic receptor expression. Eur J Pharmacol 393:237–242

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Hernandez G, Placzek AN, Thinschmidt JS, Lestage P, Trocme-Thibierge C, Morain P, Papke RL (2007) Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons. Neuropharmacology 53:134–144

    Article  PubMed  CAS  Google Scholar 

  • Marder SR (2006) Initiatives to promote the discovery of drugs to improve cognitive function in severe mental illness. J Clin Psychiatry 67:e03

    Article  PubMed  Google Scholar 

  • Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63:630–638

    Article  PubMed  CAS  Google Scholar 

  • Roncarati R, Scali C, Comery TA, Grauer SM, Aschmi S, Bothmann H, Jow B, Kowal D, Gianfriddo M, Kelley C, Zanelli U, Ghiron C, Haydar S, Dunlop J, Terstappen GC (2009) Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders. J Pharmacol Exp Ther 329:459–468

    Article  PubMed  CAS  Google Scholar 

  • Shin-Ichi I, Kanji I, Takao S, Takeo F (1989) Effects of repeated testing on the incidence of haloperidol-induced catalepsy in mice. Pharmacol Biochem Behav 33:705–707

    Article  Google Scholar 

  • Taly A, Corringer PJ, Guedin D, Lestage P, Changeux JP (2009) Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov 8:733–750

    Article  PubMed  CAS  Google Scholar 

  • Tietje KR, Anderson DJ, Bitner RS, Blomme EA, Brackemeyer PJ, Briggs CA, Browman KE, Bury D, Curzon P, Drescher KU, Frost JM, Fryer RM, Fox GB, Gronlien JH, Hakerud M, Gubbins EJ, Halm S, Harris R, Helfrich RJ, Kohlhaas KL, Law D, Malysz J, Marsh KC, Martin RL, Meyer MD, Molesky AL, Nikkel AL, Otte S, Pan L, Puttfarcken PS, Radek RJ, Robb HM, Spies E, Thorin-Hagene K, Waring JF, Ween H, Xu H, Gopalakrishnan M, Bunnelle WH (2008) Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties. CNS Neurosci Ther 14:65–82

    Article  PubMed  CAS  Google Scholar 

  • Wadenberg ML, Kapur S, Soliman A, Jones C, Vaccarino F (2000) Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology 150:422–429

    Article  PubMed  CAS  Google Scholar 

  • Wadenberg ML, Soliman A, VanderSpek SC, Kapur S (2001) Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 25:633–641

    Article  PubMed  CAS  Google Scholar 

  • Wiker C, Schilstrom B, Sandback C, Wadenberg ML, Svensson TH (2008) Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats. Int J Neuropsychopharmacol 11:845–850

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are very grateful for the expert technical assistance of A. Adedoyin, P. Paul, J. Graul, P. Liu, and H. Majchrowski in conducting and analyzing the pharmacokinetic studies. The authors would also like to thank Dr. Sharon Rosenzweig-Lipson for helpful discussions in preparation of the manuscript.

Conflicts of interest

All authors were employees of Wyeth (now Pfizer) or Sienabiotech at the time of these studies.

Author information

Authors and Affiliations

  1. Neuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, MS8220-4220, Groton, CT, 06340, USA

    Karen L. Marquis, Thomas A. Comery, Flora Jow, Rachel L. Navarra, Steven M. Grauer, Claudine Pulicicchio, Cody Kelley, Julie A. Brennan, Simon Haydar & John Dunlop

  2. Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100, Siena, Italy

    Renza Roncarati, Carla Scali, Chiara Ghiron & Georg C. Terstappen

Authors
  1. Karen L. Marquis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas A. Comery
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Flora Jow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rachel L. Navarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven M. Grauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudine Pulicicchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cody Kelley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julie A. Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renza Roncarati
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carla Scali
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Simon Haydar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chiara Ghiron
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Georg C. Terstappen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John Dunlop
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Dunlop.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marquis, K.L., Comery, T.A., Jow, F. et al. Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625. Psychopharmacology 218, 635–647 (2011). https://doi.org/10.1007/s00213-011-2357-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2357-6

Keywords

Search

Navigation