Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia

Abstract

To test the hypothesis that muscarinic receptors are involved in the pathology of schizophrenia, we measured muscarinic1 (M1R) and muscarinic4(M4R) protein and mRNA as well as [3H]pirenzepine binding in Brodmann's areas (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. There was a significant decrease in [3H]pirenzepine binding to BA 9 (mean ± SEM: 151 ± 15 vs 195 ± 10 fmol mg−1 ETE; P< 0.02), but not BA 40 (143 ± 13 vs 166 ± 11 fmol mg−1 ETE), from subjects with schizophrenia. The level of M1R protein (0.11 ± 0.007 vs 0.15 ± 0.008 OD; P < 0.01), but not M4R protein, was decreased in BA9 from schizophrenic subjects with neither receptor protein being altered in BA 40. The level of M1R mRNA was decreased in BA 9 (30 ± 7.0 vs 79 ± 14 dpm × 103 mg−1ETE, P < 0.01) and BA 40 (28 ± 5.9 vs 99 ± 14, P < 0.01) with schizophrenia but M4R mRNA was only decreased in BA 40 (48 ± 6.6 vs 89 ± 9.9, P < 0.005). These data suggest that the M1R, at least in the dorsolateral prefrontal cortex, may have a role in the pathology of schizophrenia.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Tandon R . Cholinergic aspects of schizophrenia Br J Psychiatry Suppl 1999 37: 7–11

    Article  Google Scholar 

  2. Hyde TM, Crook JM . Cholinergic systems and schizophrenia: primary pathology or epiphenomena J Chem Neuroanatomy 2001 22: 53–63

    Article  CAS  Google Scholar 

  3. Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine Neuropsychopharmacology 1996 14: 87–96

    Article  CAS  Google Scholar 

  4. Kane JM, McGlashan TH . Treatment of schizophrenia Lancet 1995 346: 820–825

    Article  CAS  Google Scholar 

  5. Reus VI . Olanzapine: a novel atypical neuroleptic agent Lancet 1997 349: 1264–1265

    Article  CAS  Google Scholar 

  6. Eglen RM, Choppin A, Watson N . Therapeutic opportunities from muscarinic receptor research Trends Pharmacol Sci 2001 22: 409–414

    Article  CAS  Google Scholar 

  7. Dean B . A predicted cortical serotonergic/cholinergic/GABAergic interface as a site of pathology in schizophrenia Clin Exp Pharmacol Physiol 2001 28: 74–78

    Article  CAS  Google Scholar 

  8. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B . Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment Am J Psychiatry 2001 158: 918–925

    Article  CAS  Google Scholar 

  9. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B . Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation Biol Psychiatr 2000 48: 381–388

    Article  CAS  Google Scholar 

  10. Dean B, Crook JM, Opeskin K, Hill C, Keks N, Copolov DL . The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia Mol Psychiatry 1996 1: 54–58

    CAS  Google Scholar 

  11. Hulme EC, Birdsall NJM, Buckley NJ . Muscarinic receptor subtypes Annu Rev Pharmacol Toxicol 2000 30: 633–673

    Article  Google Scholar 

  12. Perry E, Walker M, Grace J, Perry R . Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 1999 22: 273–280

    Article  CAS  Google Scholar 

  13. Kingsbury AE, Foster OJ, Nisbet AP, Cairns N, Bray L, Eve DJ et al. Tissue pH as an indicator of mRNA preservation in human post-mortem brain Mol Brain Res 1995 28: 311–318

    Article  CAS  Google Scholar 

  14. Keks N, Hill C, Opeskin K, Copolov DL, Dean B . Psychiatric diagnosis after death: the problems of accurate diagnosis. In: Dean B, Hyde TM, Kleinman JE (eds) Using CNS Tissue in Psychiatric Research: A Practical Guide J Gordon & Breach Science Publishers: Sydney 1999 19–37

    Google Scholar 

  15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Fourth edition) American Psychiatric Association: Washington, DC 1994

  16. Foster P . Neuroleptic equivalence Pharmaceut J 1998 243: 431–432

    Google Scholar 

  17. Dean B, Crook JM, Pavey G, Opeskin K, Copolov DL . Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia Mol Psychiatry 2000 5: 203–207

    Article  CAS  Google Scholar 

  18. Loiacono RE, Gundlach AL . In situ hybridisation histochemistry: application to human brain tissue. In: Dean B, Hyde TM, Kleinman JE (eds) Using CNS Tissue in Psychiatric Research: A Practical Guide Harwood Academic Press: Sydney 1999 85–106

    Google Scholar 

  19. Ndoye A, Buchli R, Greenberg B, Nguyen VT, Zia S, Rodriguez JG et al. Identification and mapping of keratinocyte muscarinic acetylcholine receptor subtypes in human epidermis J Invest Dermatol 1998 111: 410–416

    Article  CAS  Google Scholar 

  20. Buchli R, Ndoye A, Rodriguez JG, Zia S, Webber RJ, Grando SA . Human skin fibroblasts express m2, m4, and m5 subtypes of muscarinic acetylcholine receptors J Cell Biochem 1999 74: 264–277

    Article  CAS  Google Scholar 

  21. Vogt BA, Plager MD, Crino PB, Bird ED . Laminar distributions of muscarinic acetylcholine, serotonin, GABA and opioid receptors in human posterior cingulate cortex Neuroscience 1990 36: 165–174

    Article  CAS  Google Scholar 

  22. Watanabe S, Nishikawa T, Takashima M, Toru M . Increased muscarinic cholinergic receptors in prefrontal cortices of medicated schizophrenics Life Sci 1983 33: 2187–2196

    Article  CAS  Google Scholar 

  23. Flynn DD, Ferrari-DiLeo G, Mash DC, Levey AI . Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer's disease J Neurochem 1995 64: 1888–1891

    Article  CAS  Google Scholar 

  24. Burnet PW, Eastwood SL, Harrison PJ . 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia Neuropsychopharmacology 1996 15: 442–455

    Article  CAS  Google Scholar 

  25. Hamilton SE, Loose MD, Qi M, Levey AI, Hille B, McKnight GS et al. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice Proc Natl Acad Sci U S A 1997 94: 13311–13316

    Article  CAS  Google Scholar 

  26. Gillette MU, Buchanan GF, Artinian L, Hamilton SE, Nathanson NM, Liu C . Role of the M1 receptor in regulating circadian rhythms Life Sci 2001 68: 2467–2472

    Article  CAS  Google Scholar 

  27. Heinrichs RW, Zakzanis KK . Neurocognitive deficit in schizophrenia: a quantitative review of the evidence Neuropsychology 1998 12: 426–445

    Article  CAS  Google Scholar 

  28. Keshavan MS, Reynolds CF III, Miewald MJ, Montrose DM, Sweeney JA, Vasko RC Jr et al. Delta sleep deficits in schizophrenia: evidence from automated analyses of sleep data Arch Gen Psychiatry 1998 55: 443–448

    Article  CAS  Google Scholar 

  29. Felder CC, Porter AC, Skillman TL, Zhang L, Bymaster FP, Nathanson NM et al. Elucidating the role of muscarinic receptors in psychosis Life Sci 2001 68: 2605–2613

    Article  CAS  Google Scholar 

  30. Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD et al. Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice Schizophr Res 2000 42: 249–259

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Dr Ken Opeskin and the Staff at the Victorian Institute of Forensic Medicine for their assistance with the collection of tissue, Professor Nicholas Keks and Ms Christine Hill for providing diagnostic confirmation and Mr Geoffrey Pavey for his efforts in curating the tissue collection at the Mental Health Research Institute. This work was financed in part by Grants-in-Aid from the Rebecca L Cooper Research Laboratories, the Stanley Foundation and the Wood's Family Trust and NH&MRC Project (grant 209046).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B Dean.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dean, B., McLeod, M., Keriakous, D. et al. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 7, 1083–1091 (2002). https://doi.org/10.1038/sj.mp.4001199

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001199

Keywords

This article is cited by

Search

Quick links