Skip to main content
SpringerLink
Log in

Effects of Long-Term Antipsychotic Treatment on NMDA Receptor Binding and Gene Expression of Subunits

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Postmortem studies in schizophrenic patients revealed alterations in NMDA receptor binding and gene expression of specific subunits. Because most of the patients had been treated with antipsychotics over long periods, medication effects might have influenced those findings. We treated animals with haloperidol and clozapine in clinical doses to investigate the effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Rats were treated with either haloperidol (1,5 mg/kg/day) or clozapine (45 mg/kg/day) given in drinking water over a period of 6 months. Quantitative receptor autoradiography with [3H]-MK-801 was used to examine NMDA receptor binding. In situ hybridization was performed for additional gene expression studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [3H]-MK-801 binding was found to be increased after haloperidol treatment in the striatum and nucleus accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the nucleus accumbens. There were no alterations in gene expression of NMDA subunits in any of the three regions. However, the NR2A subunit was down-regulated in the hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D subunits did not differ between treatment groups and controls. Both altered NMDA receptor binding and subunit expression strengthen a hyperglutamatergic function after haloperidol treatment and may contribute to some of our postmortem findings in antipsychotically treated schizophrenic patients. Because the effects seen in different brain areas clearly vary between haloperidol and clozapine, they may also be responsible for some of the differences in efficacy and side effects.

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

Similar content being viewed by others

REFERENCES

  1. Jentsch, J. D. and Roth, R.H. 1999.The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.Neuropsychopharmacology 20:201–225.

    PubMed  Google Scholar 

  2. Javitt, D.C. and Zukin, S. R. 1991. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 148: 1301–1308.

    PubMed  Google Scholar 

  3. Olney, J. W. and Farber, N. B. 1995. Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52:998–1007.

    PubMed  Google Scholar 

  4. Farber, N. B., Newcomer, J. W., and Olney, J. W. 1999. Glycine agonists: What can they teach us about schizophrenia?. Arch Gen. Psychiatry 56:13–17.

    PubMed  Google Scholar 

  5. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., and Seeburg, P. H. 1994. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540.

    PubMed  Google Scholar 

  6. Ishii, T., Moriyoshi, K., Sugihara, H., Sakurada, K., Kadotani, H., Yokoi, M., Akazawa, C., Shigemoto, R., Mizuno, N., and Masu, M. 1993. Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. J. Biol. Chem. 268: 2836–2843.

    PubMed  Google Scholar 

  7. Aparicio-Legarza, M. I., Davis, B., Hutson, P. H., and Reynolds, G. P. 1998. Increased density of glutamate/N-methyl-D-aspartate receptors in putamen from schizophrenic patients. Neurosci. Lett. 241:143–146.

    PubMed  Google Scholar 

  8. Kornhuber, J., Mack-Burkhardt, F., Riederer, P., Hebenstreit, G. F., Reynolds, G. P., Andrews, H. B., and Beckmann, H. 1989. [3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients. J. Neural Transm. 77:231–236.

    PubMed  Google Scholar 

  9. Noga, J.T., Hyde, T. M., Herman, M. M., Spurney, C. F., Bigelow, L. B., Weinberger, D. R., and Kleinman, J. E. 1997. Glutamate receptors in the postmortem striatum of schizophrenic, suicide, and control brains. Synapse 27:168–176.

    PubMed  Google Scholar 

  10. Grimwood, S., Slater, P., Deakin, J. F., and Hutson, P. H. 1999. NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia. Neuroreport 10:461–465.

    PubMed  Google Scholar 

  11. Dean, B., Scarr, E., Bradbury, R., and Copolov, D. 1999. Decreased hippocampal (CA3) NMDA receptors in schizophrenia. Synapse 32:67–69.

    PubMed  Google Scholar 

  12. Sokolov, B. P. 1998. Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of "neuroleptic-free" schizophrenics: Evidence on reversible up-regulation by typical neuroleptics. J. Neurochem. 71:2454–2464.

    PubMed  Google Scholar 

  13. Gao, X. M., Sakai, K., Roberts, R. C., Conley, R. R., Dean, B., and Tamminga, C. A. 2000. Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: Effects of schizophrenia. Am. J. Psychiatry 157:1141–1149.

    PubMed  Google Scholar 

  14. Humphries, C., Mortimer, A., Hirsch, S., and de Belleroche, J. 1996. NMDA receptor mRNA correlation with antemortem cognitive impairment in schizophrenia. Neuroreport 7:2051–2055.

    PubMed  Google Scholar 

  15. Akbarian, S., Sucher, N. J., Bradley, D., Tafazzoli, A., Trinh, D., Hetrick, W. P., Potkin, S. G., Sandman, C. A., Bunney, W. E., Jr., and Jones, E. G. 1996. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J. Neurosci. 16:19–30.

    PubMed  Google Scholar 

  16. Giardino, L., Bortolotti, F., Orazzo, C., Pozza, M., Monteleone, P., Calza, L., and Maj, M. 1997. Effect of chronic clozapine administration on [3H]MK801–binding sites in the rat brain: A side-preference action in cortical areas. Brain Res. 762:216–218.

    PubMed  Google Scholar 

  17. Tarazi, F. I., Florijn, W. J., and Creese, I. 1996. Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics. Psychopharmacology 128:371–379.

    PubMed  Google Scholar 

  18. McCoy, L. and Richfield, E. K. 1996. Chronic antipsychotic treatment alters glycine-stimulated NMDA receptor binding in rat brain. Neurosci. Lett. 213:137–141.

    PubMed  Google Scholar 

  19. Spumey, C. F., Baca, S. M., Murray, A. M., Jaskiw, G. E., Kleinman, J. E., and Hyde, T. M. 1999. Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats. Synapse 34:266–276.

    PubMed  Google Scholar 

  20. Banerjee, S. P., Zuck, L. G., Yablonsky-Alter, E., and Lidsky, T. I. 1995. Glutamate agonist activity: Implications for antipsychotic drug action and schizophrenia. Neuroreport 6:2500–2504.

    PubMed  Google Scholar 

  21. Ossowska, K., Pietraszek, M., Wardas, J., Nowak, G., and Wolfarth, S. 1999. Chronic haloperidol and clozapine administration increases the number of cortical NMDA receptors in rats. Naunyn Schmiedebergs Arch Pharmacol. 359:280–287.

    PubMed  Google Scholar 

  22. Meshul, C. K., Bunker G. L., Mason J. N., Allen C., and Janowsky A. 1996. Effects of subchronic clozapine and haloperidol on striatal glutamatergic synapses. J. Neurochem. 67:1965–1973.

    PubMed  Google Scholar 

  23. Fitzgerald, L. W., Deutch, A. Y., Gasic, G., Heinemann, S. F., and Nestler, E. J. 1995. Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs. J. Neurosci. 15:2453–2461.

    PubMed  Google Scholar 

  24. Riva, M. A., Tascedda, F., Lovati, E., and Racagni, G. 1997. Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to anti-psychotic drugs. Brain Res. Mol. Brain Res. 50:136–142.

    PubMed  Google Scholar 

  25. Tascedda, F., Lovati, E., Blom, J. M., Muzzioli, P., Brunello, N., Racagni, G., and Riva, M. A. 1999. Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic seroquel (quetiapine fumarate). Neu-ropsychopharmacology 21:211–217.

    Google Scholar 

  26. See, R. E. and Ellison, G. 1990. Comparison of chronic administration of haloperidol and the atypical neuroleptics, clozapine and raclopride, in an animal model of tardive dyskinesia. Eur. J. Pharmacol. 181:175–186.

    PubMed  Google Scholar 

  27. Volavka, J., Cooper, T., Czobor, P., Bitter, I., Meisner, M., Laska, E., Gastanaga, P., Krakowski, M., Chou, J. C., and Crowner, M. 1992. Haloperidol blood levels and clinical effects. Arch. Gen. Psychiatry. 49:354–361.

    PubMed  Google Scholar 

  28. Zilles, K. and Schleicher, A. 1995. Correlative imaging of transmitter receptor distributions in human cortex. Pages 277–307, in Stumpf W. E. and Solomon H. F. (eds.), Autoradiography and Correlative Imaging, Academic Press, San Diego.

    Google Scholar 

  29. Zilles, K., Qu, M. S., Kohling, R., and Speckmann, E. J. 1999. Ionotropic glutamate and GABA receptors in human epileptic neocortical tissue: Quantitative in vitro receptor autoradiography. Neuroscience 94:1051–1061.

    PubMed  Google Scholar 

  30. McCoy, L. and Richfield, E. K. 1996. Washable endogenous substances and regional heterogeneity in agonist enhanced [3H]MK-801 binding in rat brain. Brain Res. 710:103–111.

    PubMed  Google Scholar 

  31. Floresco, S. B., Blaha, C. D., Yang, C. R., and Phillips, A. G. 2001. Dopamine D1 and NMDA receptors mediate potentiation of basolateral amygdala-evoked firing of nucleus accumbens neurons. J. Neurosci. 21:6370–6376.

    PubMed  Google Scholar 

  32. Swerdlow, N. R., Hanlon, F. M., Henning, L., Kim, Y. K., Gaudet, I., and Halim, N. D. 2001. Regulation of sensorimotor gating in rats by hippocampal NMDA: Anatomical localization. Brain Res. 898:195–203.

    PubMed  Google Scholar 

  33. Yamamoto, B. K., Pehek, E. A., and Meltzer, H. Y. 1994. Brain region effects of clozapine on amino acid and monoamine transmission. J. Clin. Psychiatry. 55 (Suppl B):8–14.

    PubMed  Google Scholar 

  34. Lipton, S. A. and Kater, S. B. 1989. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci. 12:265–270.

    PubMed  Google Scholar 

  35. Kerns, J. M., Sierens, D. K., Kao, L. C., Klawans, H. L., and Carvey, P. M. 1992. Synaptic plasticity in the rat striatum following chronic haloperidol treatment. Clin. Neuropharmacol. 15:488–500.

    PubMed  Google Scholar 

  36. Meshul, C. K., Buckman, J. F., Allen, C., Riggan, J. P., and Feller, D. J. 1996. Activation of corticostriatal pathway leads to similar morphological changes observed following haloperidol treatment. Synapse 22:350–361.

    PubMed  Google Scholar 

  37. Meshul, C. K., Stallbaumer, R. K., Taylor, B., and Janowsky, A. 1994. Haloperidol-induced morphological changes in stria-tum are associated with glutamate synapses. Brain Res. 648: 181–195.

    PubMed  Google Scholar 

  38. See, R. E. and Chapman, M. A. 1994. Chronic haloperidol, but not clozapine, produces altered oral movements and increased extracellular glutamate in rats. Eur. J. Pharmacol. 263:269–276.

    PubMed  Google Scholar 

  39. Oretti, R. G., Spurlock, G., Buckland, P. R., and McGuffin, P. 1994. Lack of effect of antipsychotic and antidepressant drugs on glutamate receptor mRNA levels in rat brains. Neurosci. Lett. 177:39–43.

    PubMed  Google Scholar 

  40. Chen, A. C., McDonald, B., Moss, S. J., and Gurling, H. M. 1998. Gene expression studies of mRNAs encoding the NMDA receptor subunits NMDAR1, NMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D following long-term treatment with cis-and trans-flupenthixol as a model for understanding the mode of action of schizophrenia drug treatment. Brain Res. Mol. Brain Res. 54:92–100.

    PubMed  Google Scholar 

  41. Morikawa, E., Mori, H., Kiyama, Y., Mishina, M., Asano, T., and Kirino, T. 1998. Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (NR2A) subunit of NMDA receptor. J. Neurosci. 18:9727–9732.

    PubMed  Google Scholar 

  42. Tang, Y. P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A.,Zhuo, M., Liu, G., and Tsien, J. Z. 1999. Genetic enhancement of learning and memory in mice. Nature 401:63–69.

    PubMed  Google Scholar 

  43. Greene, R. 2001. Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 11:569–577.

    PubMed  Google Scholar 

  44. Yamamoto, B. K. and Cooperman, M. A. 1994. Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J. Neurosci. 14:4159–4166.

    PubMed  Google Scholar 

  45. Chen, L. and Yang, C. R. 2002. Interaction of dopamine D1 and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex. J. Neurophysiol. 87: 2324–2336.

    PubMed  Google Scholar 

  46. Korpi, E. R., Wong, G., and Luddens, H. 1995. Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. Naunyn Schmiedebergs Arch. Pharmacol. 352: 365–373.

    Google Scholar 

  47. Ding, D.C., Gabbott, P. L., and Totterdell, S. 2001. Differences in the laminar origin of projections from the medial prefrontal cortex to the nucleus accumbens shell and core regions in the rat. Brain Res. 917:81–89.

    PubMed  Google Scholar 

  48. Buchsbaum, M. S., Hazlett, E. A., Haznedar, M. M., Spiegel-Cohen, J., and Wei, T. C. 1999. Visualizing fronto-striatal circuitry and neuroleptic effects in schizophrenia. Acta Psychiatr. Scand. Suppl. 395:129–137.

    PubMed  Google Scholar 

  49. Filloux, F., Liu, T. H., Hsu, C. Y., Hunt, M. A., and Wamsley, J. K. 1988. Selective cortical infarction reduces [3H]sulpiride binding in rat caudate-putamen: Autoradiographic evidence for presynaptic D2 receptors on corticostriate terminals. Synapse 2:521–531.

    PubMed  Google Scholar 

  50. Fletcher, E. J. and MacDonald, J. F. 1993. Haloperidol interacts with the strychnine-insensitive glycine site at the NMDA receptor in cultured mouse hippocampal neurones. Eur. J. Pharmacol. 235:291–295.

    PubMed  Google Scholar 

  51. Carlsson, A., Hansson L.O., Waters, N., and Carlsson, M.L. 1997. Neurotransmitter aberrations in schizophrenia, new perspectives and therapeutic implications. Life Sci; 61:75–94.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Central Institute of Mental Health, P.O. Box 12 21 20, D-68072, Mannheim, Germany

    Andrea Schmitt, Mathias Zink, Bettina Müller, Brigitte May, Alexander Jatzko, Dieter F. Braus & Fritz A. Henn

  2. Department of Clinical Neurobiology, University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany

    Anne Herb

Authors
  1. Andrea Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mathias Zink
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bettina Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brigitte May
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Herb
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexander Jatzko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dieter F. Braus
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fritz A. Henn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Schmitt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmitt, A., Zink, M., Müller, B. et al. Effects of Long-Term Antipsychotic Treatment on NMDA Receptor Binding and Gene Expression of Subunits. Neurochem Res 28, 235–241 (2003). https://doi.org/10.1023/A:1022325116309

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022325116309

Search

Navigation