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Subchronic Effects of Phencyclidine on Dopamine and Serotonin Receptors: Implications for Schizophrenia

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Abstract

Changes in representative dopamine (D1, D2, and D4) and serotonin (5-HT1A and 5-HT2A) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D1 receptors in the medial and lateral caudate–putamen (22% and 23%, respectively) and increased 5HT1A receptor binding in the medial–prefrontal (26%) and dorsolateral–frontal cortex (30%). No changes in D1 or 5HT1A receptors were detected in other brain regions. These findings suggest that downregulation of striatal D1 receptors and upregulation of cortical 5HT1A receptors may contribute to PCP-induced impairment of cognitive functions in rats. Subchronic PCP treatment did not alter levels of D2, D4, and 5HT2A receptors in all brain regions examined, which suggests a minimal role for these receptors in mediating subchronic actions of PCP in adult rats.

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References

  • Abdul-Monim, Z., Reynolds, G. P., & Neill, J. C. (2006). The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm. Behavioural Brain Research, 169, 263–273.

    Article  PubMed  CAS  Google Scholar 

  • Abdul-Monim, Z., Neill, J. C., & Reynolds, G. P. (2007). Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. Journal of Psychopharmacology (Oxford, England), 21, 198–205.

    Article  CAS  Google Scholar 

  • Adams, B. W., & Moghaddam, B. (2001). Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biological Psychiatry, 50, 750–757.

    Article  PubMed  CAS  Google Scholar 

  • Aghajanian, G. K., & Marek, G. J. (2000). Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Research Reviews, 31, 302–312.

    Article  PubMed  CAS  Google Scholar 

  • Amargós-Bosch, M., López-Gil, X., Artigas, F., & Adell, A. (2006). Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine. The International Journal of Neuropsychopharmacology, 9, 565–573.

    Article  PubMed  CAS  Google Scholar 

  • Arborelius, L., Chergui, K., Murase, S., Nomikos, G. G., Höök, B. B., Chouvet, G., et al. (1993). The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons. Naunyn-Schmiedeberg's Archives of Pharmacology, 347, 353–362.

    Article  PubMed  CAS  Google Scholar 

  • Baldessarini, R. J., & Tarazi, F. I. (2005). Pharmacotherapy of psychosis and mania. In L. L. Brunton, J. S. Lazo & K. L. Parker (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics (pp. 461–500). New York: McGraw-Hill.

    Google Scholar 

  • Barros, D. M., Mello e Souza, T., De David, T., Choi, H., Aguzzoli, A., Madche, C., et al. (2001). Simultaneous modulation of retrieval by dopaminergic D1, beta-noradrenergic, serotonergic-1A and cholinergic muscarinic receptors in cortical structures of the rat. Behavioural Brain Research, 124, 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Carlsson, M., & Carlsson, A. (1990). Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson's disease. Trends in Neurosciences, 13, 272–276.

    Article  PubMed  CAS  Google Scholar 

  • Carlsson, A., Waters, N., Holm-Waters, S., Tedroff, J., Nilsson, M., & Carlsson, M. L. (2001). Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annual Review of Pharmacology and Toxicology, 41, 237–260.

    Article  PubMed  CAS  Google Scholar 

  • Damsma, G., Robertson, G. S., Tham, C. S., & Fibiger, H. C. (1991). Dopaminergic regulation of striatal acetylcholine release: importance of D1 and N-methyl-D-aspartate receptors. The Journal of Pharmacology and Experimental Therapeutics, 259, 1064–1072.

    PubMed  CAS  Google Scholar 

  • Ellenbroek, B. A., Budde, S., & Cools, A. R. (1996). Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex. Neuroscience, 75, 535–542.

    Article  PubMed  CAS  Google Scholar 

  • Flores-Hernandez, J., Cepeda, C., Hernandez-Echeagaray, E., Calvert, C. R., Jokel, E. S., Fienberg, A. A., et al. (2002). Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32. Journal of Neurophysiology, 88, 3010–3020.

    Article  PubMed  CAS  Google Scholar 

  • Francis, P. T., Pangalos, M. N., Pearson, R. C., Middlemiss, D. N., Stratmann, G. C., & Bowen, D. M. (1992). 5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin. The Journal of Pharmacology and Experimental Therapeutics, 261, 1273–1281.

    PubMed  CAS  Google Scholar 

  • Goff, D. C., & Coyle, J. T. (2001). The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. The American Journal of Psychiatry, 158, 1367–1377.

    Article  PubMed  CAS  Google Scholar 

  • Gray, J. A., & Roth, B. L. (2007). Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophrenia Bulletin, 33, 1100–1119.

    Article  PubMed  Google Scholar 

  • Grayson, B., Idris, N. F., & Neill, J. C. (2007). Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behavioural Brain Research, 184, 31–38.

    Article  PubMed  CAS  Google Scholar 

  • Hagan, J. J., & Jones, D. N. C. (2005). Predicting efficacy for cognitive deficits in schizophrenia. Schizophrenia Bulletin, 31, 830–853.

    Article  PubMed  Google Scholar 

  • Hagiwara, H., Fujita, Y., Ishima, T., Kunitachi, S., Shirayama, Y., Iyo, M., et al. (2008). Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptors. European Neuropsychopharmacology, 18, 448–454.

    Article  PubMed  CAS  Google Scholar 

  • Halpain, S., Girault, J. A., & Greengard, P. (1990). Activation of NMDA receptors induce deophosphorylaton of DARPP-32 in rat striatal slices. Nature, 343, 369–372.

    Article  PubMed  CAS  Google Scholar 

  • Harder, J. A., & Ridley, R. M. (2000). The 5-HT1A antagonist, WAY 100635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys. Neuropharmacology, 39, 547–552.

    Article  PubMed  CAS  Google Scholar 

  • Hondo, H., Yonezawa, Y., Nakahara, T., Nakamura, K., Hirano, M., Uchimura, H., et al. (1994). Effect of phencyclidine on dopamine release in the rat prefrontal cortex; an in vivo micriodialysis study. Brain Research, 633, 337–342.

    Article  PubMed  CAS  Google Scholar 

  • Javitt, D. C., & Zukin, S. R. (1991). Recent advances in the phencyclidine model of schizophrenia. The American Journal of Psychiatry, 148, 1301–1308.

    PubMed  CAS  Google Scholar 

  • Jentsch, J. D., Taylor, J. R., Redmond, D. E., Jr., Elsworth, J. D., Youngren, K. D., & Roth, R. H. (1999). Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. Psychopharmacology, 142, 78–84.

    Article  PubMed  CAS  Google Scholar 

  • Kapur, S., & Seeman, P. (2002). NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors-implications for models of schizophrenia. Molecular Psychiatry, 7, 837–844.

    Article  PubMed  CAS  Google Scholar 

  • Large, C. H. (2007). Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? Journal of Psychopharmacology (Oxford, England), 21, 283–301.

    Article  CAS  Google Scholar 

  • Martin, P., Carlsson, M. L., & Hjorth, S. (1998). Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats. Neuroreport, 9, 2985–2988.

    Article  PubMed  CAS  Google Scholar 

  • McCoy, L., Cox, C., & Richfield, E. K. (1998). Antipsychotic drug regulation of AMPA receptor affinity states and GluR1, GluR2 splice variant expression. Synapse (New York, N.Y.), 28, 195–207.

    CAS  Google Scholar 

  • McLean, S. L., Beck, J. P., Woolley, M. L., & Neill, J. C. (2008a). A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats. Behavioural Brain Research, 189, 152–158.

    Article  PubMed  CAS  Google Scholar 

  • McLean, S. L., Woolley, M. L., & Neill, J. C. (2008b). Phencyclidine-induced reversal learning deficits in rats; role of 5-HT 2C and 5-HT 1A receptors. Program No. 291.9. Neuroscience Meeting Planner. Washington: Society for Neuroscience. Online.

    Google Scholar 

  • McLean, S.L., Idris, N.F., Woolley, M.L., & Neill, J.C. (2009). D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia. European Neuropsychopharmacology, 19, 440–450.

    Article  PubMed  CAS  Google Scholar 

  • Mohn, A. R., Gainetdinov, R. R., Caron, M. G., & Koller, B. H. (1999). Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell, 98, 427–436.

    Article  PubMed  CAS  Google Scholar 

  • Moller, P., & Husby, R. (2000). The initial prodrome in schizophrenia: searching for naturalistic core dimensions of experience and behavior. Schizophrenia Bulletin, 26, 217–232.

    PubMed  CAS  Google Scholar 

  • Nagi, T., Murai, R., Matsui, K., Kamei, H., Noda, Y., Furukawa, H., & Nabeshima, T. (2009). Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors. Psychopharmacology, 202, 315–328.

    Article  CAS  Google Scholar 

  • Okubo, Y., Suhara, T., Suzuki, K., Kobayashi, K., Inoue, O., Terasaki, O., et al. (1997). Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature, 385, 634–636.

    Article  PubMed  CAS  Google Scholar 

  • Paxinos, F., & Watson, C. (1982). The rat brain in stereotaxic coordinates. New York: Academic.

    Google Scholar 

  • Pazos, A., & Palacios, J. M. (1985). Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Research, 346, 205–230.

    Article  PubMed  CAS  Google Scholar 

  • Pompeiano, M., Palacios, J. M., & Mengod, G. (1992). Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. The Journal of Neuroscience, 12, 440–453.

    PubMed  CAS  Google Scholar 

  • Riva, M. A., Tascedda, F., Lovati, E., & Racagni, G. (1997). Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs. Molecular Brain Research, 50, 136–142.

    Article  PubMed  CAS  Google Scholar 

  • Rollema, H., Lu, Y., Schmidt, A. W., Sprouse, J. S., & Zorn, S. H. (2000). 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biological Psychiatry, 48, 229–337.

    Article  PubMed  CAS  Google Scholar 

  • Rothman, R. B. (1994). PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site. Neurotoxicology and Teratology, 16, 343–353.

    Article  PubMed  CAS  Google Scholar 

  • Silver, H., Feldman, P., Bilker, W., & Gur, R. C. (2003). Working memory deficit as a core neuropsychological dysfunction in schizophrenia. The American Journal of Psychiatry, 160, 1809–1816.

    Article  PubMed  Google Scholar 

  • Singh, N. A., Bush, L. G., Gibb, J. W., & Hanson, G. R. (1990). Dopamine-mediated changes in central nervous system neurotensin systems: A role for NMDA receptors. European Journal of Pharmacology, 187, 337–344.

    Article  PubMed  CAS  Google Scholar 

  • Snigdha, S., & Neill, J. C. (2008a). Efficacy of antipsychotics to reverse phencyclidine induced social interaction deficits in female rats—A preliminary investigation. Behavioural Brain Research, 187, 489–494.

    Article  PubMed  CAS  Google Scholar 

  • Snigdha, S., & Neill, J. C. (2008b). Improvement of phencyclidine induced social behavior deficits in rats: involvement of 5-HT1A receptors. Behavioural Brain Research, 191, 26–31.

    Article  PubMed  CAS  Google Scholar 

  • Snigdha, S., Li, Z., Dai, J., Shahid, M., Neill, J. C., & Meltzer, H. Y. (2008c). Effect of PCP to attenuate DA efflux in rats performing the object recognition task: An in vivo investigation. Program No 791.14 Neuroscience Meeting Planner. Washington: Society for Neuroscience. Online.

    Google Scholar 

  • Spurney, C. F., Baca, S. M., Murray, A. M., Jaskiw, G. E., Kleinmann, J. E., & Hyde, T. M. (1999). Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats. Synapse (New York, N.Y.), 34, 266–276.

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Tarazi, F. I., Yeghiayan, S. K., Baldessarini, R. J., Kula, N. S., & Neumeyer, J. L. (1997). Long-term effects of S(+) N-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors. Neuropsychopharmacology, 17, 186–196.

    Article  PubMed  CAS  Google Scholar 

  • Tarazi, F. I., Yeghiayan, S. K., Neumeyer, J. L., & Baldessarini, R. J. (1998). Medial prefrontal cortical D2 and striatolimbic D4 dopamine receptors: Common targets for typical and atypical antipsychotic drugs. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 22, 693–707.

    Article  CAS  Google Scholar 

  • Tarazi, F. I., Zhang, K., & Baldessarini, R. J. (2001). Long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment. The Journal of Pharmacology and Experimental Therapeutics, 297, 711–717.

    PubMed  CAS  Google Scholar 

  • Tarazi, F. I., Zhang, K., & Baldessarini, R. J. (2002). Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology, 161, 263–270.

    Article  PubMed  CAS  Google Scholar 

  • Tarazi, F. I., Baldessarini, R. J., Kula, N. S., & Zhang, K. (2003). Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. The Journal of Pharmacology and Experimental Therapeutics, 306, 1145–1151.

    Article  PubMed  CAS  Google Scholar 

  • Tarazi, F.I., Moran-Gates, T., Wong, E.H.F., Henry, B., & Shahid, M. (2009). Asenapine induces differential regional effects on serotonin receptor subtypes. Journal of Psychopharmacology (Oxford, England), in press.

  • Tauscher, J., Kapur, S., Verhoeff, N. P., Hussey, D. F., Daskalakis, Z. J., Tauscher-Wisniewski, S., et al. (2002). Brain serotonin 5-HT1A receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635. Archives of General Psychiatry, 59, 514–520.

    Article  PubMed  CAS  Google Scholar 

  • Tsai, G., & Coyle, J. T. (2002). Glutamatergic mechanisms in schizophrenia. Annual Review of Pharmacology and Toxicology, 42, 165–179.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by US NIH federal grant HD052752 (FIT). We thank Ben Grayson and Nagi Idris for excellent technical assistance.

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Authors and Affiliations

  1. Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA, USA

    Yong Kee Choi & Frank I. Tarazi

  2. Department of Psychiatry and Neuroscience Program, Harvard Medical School, Boston, MA, USA

    Yong Kee Choi & Frank I. Tarazi

  3. The School of Pharmacy, University of Bradford, Bradford, West Yorkshire, BD7 1DP, England, UK

    Shikha Snigdha & Jo C. Neill

  4. Schering-Plough Corporation, Newhouse, Lanarkshire, Scotland, UK

    Mohammed Shahid

  5. Laboratory of Psychiatric Neuroscience, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    Frank I. Tarazi

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  1. Yong Kee Choi
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  2. Shikha Snigdha
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  3. Mohammed Shahid
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Correspondence to Frank I. Tarazi.

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Choi, Y.K., Snigdha, S., Shahid, M. et al. Subchronic Effects of Phencyclidine on Dopamine and Serotonin Receptors: Implications for Schizophrenia. J Mol Neurosci 38, 227–235 (2009). https://doi.org/10.1007/s12031-009-9204-9

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  • DOI: https://doi.org/10.1007/s12031-009-9204-9

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