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Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect

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Abstract

Rationale

In a companion study (Carnicella et al., 2005), we showed that the muscarinic antagonist atropine, when administered after extensive training during both conditioning and testing, affected neither cued nor contextual fear memories when both of them did not compete for the control of the overt behaviour. In contrast, atropine altered the degraded contingency effect (DCE), that is, the processes by which contextual fear memory competes with the cued one for the control of the conditioned response. Atropine-induced disruption of the DCE was fully reversed by the administration of the anticholinesterase inhibitor physostigmine, which suggests a direct cholinergic implication.

Objective

The present series of experiments was conducted in order to define more precisely the involvement of the cholinergic system in such an effect.

Methods

Oxotremorine (0.0, 0.0075, 0.015, or 0.03 mg/kg), pilocarpine (0.0, 0.3, 1, or 3 mg/kg), xanomeline (0.0, 2.5, 5.0, 10.0 or 20.0 mg/kg) and nicotine (0.0, 0.1, 0.2, or 0.4 mg/kg) were tested for reversal of the atropine-induced alteration of the DCE.

Results

Oxotremorine and pilocarpine did not reverse the atropine-induced alteration of the DCE. In contrast, xanomeline and nicotine reversed the effect of atropine on the DCE.

Conclusion

The present series of experiments reveals complex pharmacological interactions within the cholinergic system when cued and contextual fear memories interact. Results are discussed in this connection and with regard to the relation between the properties of cholinergic agonists and their therapeutic values.

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References

  • Abood LG, Biel JH (1962) Anticholinergic psychomimetic agents. Int Rev Neurobiol 4:217–273

    Google Scholar 

  • Anagnostaras SG, Maren S, Fanselow MS (1995) Scopolamine selectively disrupts the acquisition of contextual fear conditioning in rats. Neurobiol Learn Mem 64:191–194

    Article  Google Scholar 

  • Anagnostaras SG, Maren S, Sage JR, Goodrich S, Fanselow MS (1999) Scopolamine and Pavlovian fear conditioning in rats: dose-effect analysis. Neuropsychopharmacology 21:731–744

    Article  Google Scholar 

  • Andersen MB, Fink-Jensen A, Peacock L, Gerlach J, Bymaster F, Lundbaek AJ, Werge T (2003) The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus paella monkeys. Neuropsychopharmacology 28:1168–1175

    Google Scholar 

  • Baddeley AD (1982) Domains of recollection. Psychol Rev 89:708–729

    Article  Google Scholar 

  • Bayen UJ, Phelps MP, Spaniol J (2000) Age-related differences in the use of contextual information in recognition memory: a global matching approach. J Gerontol Ser B Psychol Sci Soc Sci 55:P131–P141

    Google Scholar 

  • Bazin N, Perruchet P (1996) Implicit and explicit associative memory in patients with schizophrenia. Schizophr Res 22:241–248

    Article  Google Scholar 

  • Bazin N, Hardy-Bayle MC, Perruchet P, Feline A (2000) Context-dependent information processing in patients with schizophrenia. Schizophr Res 45:93–101

    Article  Google Scholar 

  • Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Hurley DJ, Paul SM (1997) The effects of xanomeline, an M1-selective muscarinic agonist, on cognitive function and behavioural symptoms in Alzheimer’s disease. Arch Neurol 54:465–473

    CAS  PubMed  Google Scholar 

  • Braver TS, Barch DM (2002) A theory of cognitive control, aging cognition, and neuromodulation. Neurosci Biobehav Rev 26:809–817

    Article  Google Scholar 

  • Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, Shipley LA, Buelke-Sam JL, Bodick NC, Farde L, Sheardown MJ, Olesen PH, Hansen KT, Suzdack PD, Swerberg MDB, Sauerberg P, Mitch CH (1997) Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer’s disease. Drug Dev Res 40:158–170

    Google Scholar 

  • Carnicella S, Pain L, Oberling P (2005) Cholinergic effects on fear conditioning I: the degraded contingency effect is disrupted by atropine but reinstated by physostigmine. Psychopharmacology, in press

    Google Scholar 

  • Christopoulos A, Parsons AM, El-Fakahany EE (1999) Pharmacological analysis of the novel mode of interaction between xanomeline and the M1 muscarinic acetylcholine receptor. J Pharmacol Exp Ther 289:1220–1228

    Google Scholar 

  • Cohen JD, Servan-Schreiber D (1992) Context, cortex, and dopamine: a connectionist approach to behavior and biology in schizophrenia. Psychol Rev 99:45–77

    Article  CAS  PubMed  Google Scholar 

  • Cohen JD, Barch DM, Carter C, Servan-Schreiber D (1999) Context-processing deficits in schizophrenia: converging evidence from three theoretically motivated cognitive tasks. J Abnorm Psychol 108:120–133

    Article  Google Scholar 

  • Cummings JL, Gorman DG, Shapira J (1993) Physostigmine ameliorates the delusions of Alzheimer’s disease. Biol Psychiatry 33:536–541

    Article  Google Scholar 

  • Davis KL, Hollander E, Davidson M, Davis BM, Mohs RC, Horvath TB (1987) Induction of depression with oxotremorine in patients with Alzheimer’s disease. Am J Psychiatry 144:468–471

    Google Scholar 

  • De Sarno P, Giacobini E (1989) Modulation of acetylcholine release by nicotinic receptors in the rat brain. J Neurosci Res 22:194–200

    Article  Google Scholar 

  • Disterhoft JF, Oh MM (2003) Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals. Neurobiol Learn Mem 80:223–233

    Article  Google Scholar 

  • Disterhoft JF, Kronforst-Collins M, Oh MM, Power JM, Preston AR, Weiss C (1999) Cholinergic facilitation of trace eyeblink conditioning in aging rabbits. Life Sci 64:541–548

    Article  Google Scholar 

  • Dixon WJ (1988) BMDP statistical manual. University of California Press, Berkeley

    Google Scholar 

  • Elgoyhen AB, Johnson DS, Boulter J, Vetter DE, Heinemann S (1994) Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79:705–715

    CAS  PubMed  Google Scholar 

  • Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684

    Article  CAS  PubMed  Google Scholar 

  • Gallagher R (1998) Nicotine withdrawal as an etiologic factor in delirium. J Pain Symptom Manage 16:76–77

    Article  Google Scholar 

  • Gerzanich V, Anand R, Lindstrom J (1994) Homomers of alpha 8 and alpha 7 subunits of nicotinic receptors exhibit similar channel but contrasting binding site properties. Mol Pharmacol 45:212–220

    Google Scholar 

  • Greene LT (1971) Physostigmine treatment of anticholinergic–drug depression in postoperative patients. Anesth Analg 50:222–226

    Google Scholar 

  • Jakubík J, Tuček S, El-Fakahany EE (2004) Role of receptor protein and membrane lipids in xanomeline wash-resistant binding to muscarinic M1 receptors. J Pharmacol Exp Ther 308:105–110

    Article  Google Scholar 

  • Kasprow WJ, Schachtman TR, Miller RR (1987) The comparator hypothesis of conditioned response generation: manifest conditioned excitation and inhibition as a function of relative excitatory strengths of CS and conditioning context at the time of testing. J Exp Psychol Anim Behav Process 13:395–406

    Article  Google Scholar 

  • Keppel G (1982) Design and analysis: a researcher handbook, 2nd edn. Prentice-Hall, Englewood Cliffs

    Google Scholar 

  • Ketchum JS, Sidell FR, Crowell EB Jr, Aghajanian GK, Hayes AH Jr (1973) Atropine, scopolamine, and ditran: comparative pharmacology and antagonists in man. Psychopharmacologia 28:121–145

    Article  Google Scholar 

  • Krajnik M, Zylicz Z (1995) Terminal restlessness and nicotine withdrawal. Lancet 346:1044

    Article  Google Scholar 

  • Levin ED, Rose JE (1991) Nicotinic and muscarinic interactions and choice accuracy in the radial-arm maze. Brain Res Bull 27:125–128

    Article  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, McGurk SR, South D, Butcher LL (1989) Effects of combined muscarinic and nicotinic blockade on choice accuracy in the radial-arm maze. Behav Neural Biol 51:270–277

    Article  Google Scholar 

  • Mayer SA, Chong JY, Ridgway E, Min KC, Commichau C, Bernardini GL (2001) Delirium from nicotine withdrawal in neuro-ICU patients. Neurology 57:551–553

    Google Scholar 

  • McGehee DS, Heath MJ, Gelber S, Devay P, Role LW (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269:1692–1696

    CAS  PubMed  Google Scholar 

  • Messer WS Jr (2002) The utility of muscarinic agonists in the treatment of Alzheimer’s disease. J Mol Neurosci 19:187–193

    Google Scholar 

  • Miller RR, Matzel LD (1989) Contingency and relative associative strength. In: Klein SB, Mowrer RR (eds) Contemporary learning theories: Pavlovian conditioning and the status of traditional learning theory. Laurence Erlbaum Associates, Hillsdale, NJ, pp 61–84

    Google Scholar 

  • Mirza NR, Peters D, Sparks RG (2003) Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev 9:159–186

    CAS  PubMed  Google Scholar 

  • Mouradian MM, Mohr E, Williams JA, Chase TN (1988) No response to high-dose muscarinic therapy in Alzheimer’s disease. Neurol 38:606–608

    Google Scholar 

  • Mutter SA, Williams TW (2004) Aging and the detection of contingency in causal learning. Psychol Aging 19:13–26

    Article  Google Scholar 

  • Oberling P, Bristol AS, Matute H, Miller RR (2000) Biological significance attenuates overshadowing, relative validity, and degraded contingency effects. Anim Learn Behav 28:172–186

    Google Scholar 

  • Perry EK, Perry RH (1995) Acetylcholine and hallucinations: disease-related compared to drug-induced alterations in human consciousness. Brain Cogn 28:240–258

    Article  Google Scholar 

  • Quirion R, Richard J, Wilson A (1994) Muscarinic and nicotinic modulation of cortical acetylcholine release monitored by in vivo microdialysis in freely moving adult rats. Synapse 17:92–100

    Article  Google Scholar 

  • Rescorla RA, Wagner AR (1972) A theory of Pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement. In: Black AH, Prokasy WF (eds) Classical conditioning. II. Current theory and research. Appleton-Century-Crofts, New York, pp 64–99

    Google Scholar 

  • Richards MH, van Giersbergen PLM (1995) Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists. Br J Pharmacol 114:1241–1249

    Google Scholar 

  • Rizzo L, Danion J-M, Van der Linden M, Grange D (1996a) Patients with schizophrenia remember that an event has occurred, but not when. Br J Psychiatry 168:427–431

    Google Scholar 

  • Rizzo L, Danion J-M, Grange D, Van der Linden M, Rohmer J-G (1996b) Impairment of memory for spatial context in schizophrenia. Neuropsychology 10:376–384

    Article  Google Scholar 

  • Schwarz RD, Davis RE, Jean JC, Spencer CJ, Tecle H, Thomas AJ (1993) Characterization of muscarinic agonists in recombinant cell lines. Life Sci 52:465–472

    Article  Google Scholar 

  • Sedman AJ, Bockbrader H, Schwarz RD (1995) Preclinical and phase I clinical characterization of CI979/RU35926, a novel muscarinic agonist fort he treatment of Alzheimer’s disease. Life Sci 56:877–882

    Article  Google Scholar 

  • Shannon HE, Bymaster FP, Calligaro DO, Greenwood B, Mitch CH, Sawyer BD, Ward JS, Wong DT, Olesen PH, Sheardown MJ, Swedberg MDB, Suzdack PD, Sauerberg P (1994) Xanomeline: a novel muscarinic agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther 269:271–281

    CAS  PubMed  Google Scholar 

  • Shannon HE, Hart JC, Bymaster FP, Calligaro DO, Delapp NW, Mitch CH, Ward JS, Fink-Jensen A, Sauerberg P, Jeppesen L, Sheardown MJ, Swedberg MD (1999) Muscarinic receptor agonists like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats. J Pharmacol Exp Ther 290:901–907

    Google Scholar 

  • Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swerberg MD, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen (2000) Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 42:249–259

    Article  CAS  PubMed  Google Scholar 

  • Simon BB, Knuckley B, Powell DA (2004) Galantamine facilitates acquisition of a trace-conditioned eyeblink response in healthy, young rabbits. Learn Mem 11:116–122

    Article  Google Scholar 

  • Stanhope KJ, Mirza NR, Bickerdike MJ, Bright JL, Harrington NR, Hesselink MB, Kennett GA, Lightowler S, Sheardown MJ, Syed R, Upton RL, Wadsworth G, Weiss SM, Wyatt A (2001) The muscarinic agonist xanomeline has an antipsychotic-like profile in rats. J Pharmacol Exp Ther 299:782–792

    Google Scholar 

  • Terry AV Jr, Buccafuso JJ (2003) The cholinergic hypothesis of age and alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827

    Article  Google Scholar 

  • Terry AV Jr, Buccafusco JJ, Jackson WJ (1993) Scopolamine reversal of nicotine enhanced delayed matching-to-sample performance in monkeys. Pharmacol Biochem Behav 45:925–929

    Article  Google Scholar 

  • Weiss C, Preston AR, Oh MM, Disterhoft JF, Schwarz RD, Welty D (2000) The M1 muscarinic agonist CI-1017 facilitates trace eyeblink conditioning in aging rabbits and increases the excitability of CA1 pyramidal neurons. J Neurosci 20:783–790

    Google Scholar 

  • White KE, Cummings JL (1996) Schizophrenia and Alzheimer’s disease: clinical and pathophysiologic analogies. Compr Psychiatry 37:188–195

    Article  Google Scholar 

  • Wood MD, Murkitt KL, Ho M, Brown F, Hunter AJ, Middlemiss DN (1999) Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4, hM5 using microphysiometry. Br J Pharmacol 126:1620–1624

    Google Scholar 

  • Woodruff-Pak DS, Santos IS (2000) Nicotinic modulation in an animal model of a form of associative learning impaired in Alzheimer’s disease. Behav Brain Res 113:11–19

    Article  Google Scholar 

  • Yeomans JS (1995) Role of tegmental cholinergic neurons in dopaminergic activation, antimuscarinic psychosis and schizophrenia. Neuropsychopharmacology 12:3–16

    Article  Google Scholar 

  • Zwart R, Vijverberg HP (1997) Potentiation and inhibition of neuronal nicotinic receptors by atropine: competitive and noncompetitive effects. Mol Pharmacol 52:886–895

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Prof. J.C. Stoclet for the time he devoted to this study. This study was supported by MENRT “Action Concertée Incitative Cognitique” grant 1A019F and Fondation NRJ-Institut de France. Sebastien Carnicella was supported by a French predoctoral fellowship from the MNERT. Xanomeline was generously provided by Lilly Research Company, Indianapolis, USA. We would like to thank Raymond Willhelm for the care he lavished on the rats. Thanks are also due to Andrew Wright for his help with the English language.

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  1. ULP-CNRS UMR7521, 12 rue Goethe, 67000, Strasbourg, France

    Philippe Oberling

  2. InsermU405, Strasbourg, France

    Sebastien Carnicella & Laure Pain

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  1. Sebastien Carnicella
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  2. Laure Pain
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Correspondence to Philippe Oberling.

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Carnicella, S., Pain, L. & Oberling, P. Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect. Psychopharmacology 178, 533–541 (2005). https://doi.org/10.1007/s00213-004-2101-6

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