Share This Article:

Dopamine receptor D3R and D4R mRNA levels in peripheral lymphocytes in patients with schizophrenia correlate with severity of illness

Abstract Full-Text HTML Download Download as PDF (Size:161KB) PP. 33-39
DOI: 10.4236/ojpsych.2011.12006    4,123 Downloads   8,249 Views   Citations


Schizophrenia is a disease that affects many areas of the brain. The dopamine hypothesis is one of the most widely-accepted ideas in the pathophysiology of schizophrenia. Besides alterations in the dopaminergic system in the central nervous system, there have been several reports of changes in dopaminergic systems in the peripheral blood of schizophrenic patients. Several reports have shown that dopamine receptor expression by lymphocytes is altered in patients with schizophrenia, but the results have been conflicting. We therefore re-assessed D3R and D4R mRNA levels in 11 patients with schizophrenia and 12 healthy subjects and correlated levels with severity of symptoms. D3R and D4R expression in lymphocytes and granulocytes was measured by quantitative RT-PCR and the severity of symptoms and cognitive impairment were assessed using the PANSS and BACS-J. There were no significant differences in mean D3R or D4R mRNA levels in lymphocytes from schizophrenic patients and controls and no significant difference in mean D4R mRNA levels in granulocytes (D3R mRNA undetectable). In patients with schizophrenia, D3R expression was inversely correlated with the total PANSS score (r = 0.768, p = 0.009), while D4R expression was positively correlated with working memory scales (r = 0.895, p = 0.001). In conclusion, these results imply that lymphocyte D3R and D4R are involved in the mechanisms of the disorder and could be used as target markers in the treatment of schizophrenia.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Kawano, M. , Sawada, K. , Tsuru, E. , Nishihara, M. , Kato, K. , Honer, W. and Shimodera, S. (2011) Dopamine receptor D3R and D4R mRNA levels in peripheral lymphocytes in patients with schizophrenia correlate with severity of illness. Open Journal of Psychiatry, 1, 33-39. doi: 10.4236/ojpsych.2011.12006.


[1] Schultz, S.K. and Andreasen, N.C. (1999) Schizophrenia. Lancet, 353, 1425-1430. doi:10.1016/S0140-6736(98)07549-7
[2] Seeman, P. (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse, 1, 133-52. doi:10.1002/syn.890010203
[3] Howes, O.D. and Kapur, S. (2009) The dopamine hypothesis of schizophrenia: Version III-the final common pathway. Schizophr Bull, 35, 549-562. doi:10.1093/schbul/sbp006
[4] Kerwin, R. (2000) From pharmacological profiles to clinical outcomes. International Clinical Psychopharmacology, 15, S1-S4.
[5] Missale, C., Nash, S.R., Robinson, S.W., et al. (1998) Dopamine receptors: From structure to function. Physiological Review, 78, 189-225.
[6] Sibley, D.R., Monsma, F.J.Jr. and Shen, Y. (1993) Molecular neurobiology of dopaminergic receptors. International Review of Neurobiology, 35, 391-415. doi:10.1016/S0074-7742(08)60573-5
[7] Landwehrmeyer, B., Mengod, G. and Palacios, J.M. (1993) Dopamine D3 receptor mRNA and binding sites in human brain. Molecular Brain Research, 18, 187-92. doi:10.1016/0169-328X(93)90188-U
[8] Meador-Woodruff, J.H., Damask, S.P., Wang, J., et al. (1996) Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology, 15, 17-29. doi:10.1016/0893-133X(95)00150-C
[9] Suzuki, M., Hurd, Y.L., Sokoloff, P., et al. (1998) D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Research, 779, 58-74. doi:10.1016/S0006-8993(97)01078-0
[10] Meador-Woodruff, J.H., Grandy, D.K., Van Tol, H.H., et al. (1994) Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology, 10, 239-248.
[11] Meador-Woodruff, J.H., Haroutunian, V., Powchik, P., et al. (1997) Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia. Archives of General Psychiatry, 54, 1089-1095.
[12] Matsumoto, M., Hidaka, K., Tada, S., et al. (1996) Low levels of mRNA for dopamine D4 receptor in human cerebral cortex and striatum. Journal of Neurochemistry, 66, 915-919. doi:10.1046/j.1471-4159.1996.66030915.x
[13] Mulcrone, J. and Kerwin, R.W. (1996) No difference in the expression of the D4 gene in post-mortem frontal cortex from controls and schizophrenics. Neuroscience Letters, 219, 163-166. doi:10.1016/S0304-3940(96)13191-8
[14] Schmauss, C., Haroutunian, V., Davis, K.L., et al. (1993) Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. Proceeding of National Academy Science of United States of America, 90, 8942-8946. doi:10.1073/pnas.90.19.8942
[15] Reynolds, G.P., Yao, Z., Zhang, X., et al. (2005) Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. European Neuropsychopharmacology, 15, 143-151. doi:10.1016/j.euroneuro.2004.07.001
[16] Herrmann, M.J., Walter, A., Schreppel, T., et al. (2007) D4 receptor gene variation modulates activation of prefrontal cortex during working memory. Neuroscience, 26, 2713-2718. doi:10.1111/j.1460-9568.2007.05921.x
[17] Zhang, K., Grady, C.J., Tsapakis, E.M., et al. (2004) Regulation of working memory by dopamine D4 receptor in rats. Neuropsychopharmacology, 29, 1648-1655. doi:10.1038/sj.npp.1300491
[18] Qiu, Y., Peng, Y. and Wang, J. (1996) Immunoregulatory role of neurotransmitters. Advance in Neuroimmunology, 6, 223-231. doi:10.1016/S0960-5428(96)00018-6
[19] Josefsson, E., Bergquist, J., Ekman, R., et al. (1996) Catecholamines are synthesized by mouse lymphocytes and regulate function of these cells by induction of apoptosis. Immunology, 88, 140-146. doi:10.1046/j.1365-2567.1996.d01-653.x
[20] Kirillova, G.P., Hrutkay, R.J., Shurin, M.R., et al. (2008) Dopamine receptors in human lymphocytes: Radioligand binding and quantitative RT-PCR assays. Journal of Neuroscience Methods, 174, 272-280. doi:10.1016/j.jneumeth.2008.07.018
[21] Sarkar, C., Das, S., Chakroborty, D., et al. (2006) Cutting Edge: Stimulation of dopamine D4 receptors induce T cell quiescence by up-regulating Kruppel-like factor-2 expression through inhibition of ERK1/ERK2 phosphorylation. Journal of Immunology, 177, 7525-7529.
[22] Vile, J.M. and Strange, P.G. (1996) D2-like dopamine receptors are not detectable on human peripheral blood lymphocytes. Official Journal of the Society of Biological Psychiatry, 40, 881-885. doi:10.1016/0006-3223(95)00498-X
[23] Amenta, F., Bronzetti, E., Felici, L., et al. (1999) Dopamine D2-like receptors on human peripheral blood lymphocytes: A radioligand binding assay and immunocytochemical study. Autonomic and Autacoid Pharmacology, 19, 151-159. doi:10.1046/j.1365-2680.1999.00135.x
[24] Ricci, A., Bronzetti, E., Felici, L., et al. (1998) Labeling of dopamine D3 and D4 receptor subtypes in human peripheral blood lymphocytes with [3H]7-OH-DPAT: A combined radioligand binding assay and immunochemical study. Journal of Neuroimmunology, 92, 191-195. doi:10.1016/S0165-5728(98)00207-0
[25] Ilani, T., Ben-Shachar, D., Strous, R.D., et al. (2001) A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proceeding of National Academy Science of the United States of America, 98, 625-628. doi:10.1073/pnas.021535398
[26] Kwak, Y.T., Koo, M.S., Choi, C.H., et al. (2001) Change of dopamine receptor mRNA expression in lymphocyte of schizophrenic patients. BMC Medical Genetics, 2, 3. doi:10.1186/1471-2350-2-3
[27] Boneberg, E.M., von Seydlitz, E., Propster, K., et al. (2006) D3 dopamine receptor mRNA is elevated in T cells of schizophrenic patients whereas D4 dopamine receptor mRNA is reduced in CD4+ -T cells. Journal of Neuroimmunology, 173, 180-187. doi:10.1016/j.jneuroim.2005.11.018
[28] Czermak, C., Lehofer, M., Renger, H., et al. (2004) Dopamine receptor D3 mRNA expression in human lymphocytes is negatively correlated with the personality trait of persistence. Journal of Neuroimmunology, 150, 145-149. doi:10.1016/j.jneuroim.2004.01.009
[29] Rodrigues, K.P., Souza, P.A., Lima, P.M., et al. (2005) Expression of D3 and D4 dopamine receptors in leukocytes is related to schizophrenic symptoms. Schizophrenia Research, 80, 363-365. doi:10.1016/j.schres.2005.06.010
[30] Constantinidis, C., Williams, G.V. and Goldman-Rakic, P.S. (2002) A role for inhibition in shaping the temporal flow of information in prefrontal cortex. Nature Neuroscience, 5, 175-180. doi:10.1038/nn799
[31] Lewis, D.A., Hashimoto, T. and Volk, D.W. (2005) Cortical inhibitory neurons and schizophrenia. Nature Review Neuroscience, 6, 312-324. doi:10.1038/nrn1648
[32] Yuen, E.Y. and Yan, Z. (2009) Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex. Journal of Neuroscience, 29, 550-562. doi:10.1523/JNEUROSCI.5050-08.2009
[33] Graziane, N.M., Yuen, E.Y. and Yan, Z. (2009) Dopamine D4 receptors regulate GABAA receptor trafficking via an actin/cofilin/myosin-dependent mechanism. Journal of Biological Chemistry, 284, 8329-8336. doi:10.1074/jbc.M807387200
[34] Engelhardt, B. (2008) Immune cell entry into the central nervous system: Involvement of adhesion molecules and chemokines. Journal of Neurological Science, 274, 23-26. doi:10.1016/j.jns.2008.05.019
[35] Brochard, V., Combadiere, B., Prigent, A., et al. (2009) Infiltration of CD4 + lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. Journal of Clinical Investigation, 119, 182-192. doi:10.1172/JCI36470
[36] Sullivan, P.F., Fan, C. and Perou, C.M. (2006) Evaluating the comparability of gene expression in blood and brain. American Journal of Medical Genetics, 141B, 261-268. doi:10.1002/ajmg.b.30272
[37] Padin, J.F., Rodriguez, M.A., Dominguez, E., et al. (2006) Parallel regulation by olanzapine of the patterns of expression of 5-HT2A and D3 receptors in rat central nervous system and blood cells. Neuropharmacology, 51, 923-932. doi:10.1016/j.neuropharm.2006.06.005

comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.