Abstract
Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu]), (N-methyl-d-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in forebrain tissue of wild-type controls. Labeling of D1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA1 (21%) and CA3 (25%) regions of D4 knockouts vs wild-type controls. No changes in D2, AMPA or KA receptors were found. The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.
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Ariano M. A., Wang J., Noblett K. L., Larson E. R., and Sibley D. R. (1997) Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera. Brain Res. 752, 26–34.
Baldessarini R. J. and Tarazi F. I. (1996) Brain dopamine receptors: A primer on their current status, basic and clinical. Harvard Rev. Psychiatry 3, 301–325.
Benjamin J., Li L., Patterson C., Greenberg B. D., Murphy D. L., and Hamer D. H. (1996) Population and familial association between D4 dopamine receptor gene and measures of novelty-seeking. Nat. Genet. 12, 81–84.
Bucan M. and Abel T. (2002) The mouse: genetics meets behavior. Nat. Rev. Genet. 3, 114–123.
Carlsson M. and Carlsson A. (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson’s disease. Trends Neurosci. 13, 272–276.
Carlsson A., Waters N., Holm-Waters S., Tedroff J., Nilsson M., and Carlsson M. L. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Ann. Rev. Pharmacol. Toxicol. 41, 237–260.
Damsma G., Robertson G. S., Tham C. S., and Fibiger H. C. (1991) Dopaminergic regulation of striatal acetylcholine release: importance of D1 and N-methyl-D-aspartate receptors. J. Pharmacol. Exp. Ther. 259, 1064–1072.
Defagot M. C., Falzone T. L., Low M. J., Grandy D. K., Rubinstein M., and Antonelli M. C. (2000) Quantitative analysis of the dopamine D4 receptor in the mouse brain. J. Neurosci. Res. 59, 202–208.
Defagot M. C., Malchiodi E. L., Villar M. J., and Antonelli M. C. (1997) Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. Mol. Brain Res. 45, 1–12.
Dulawa S. C., Grady D. K., Low M. J., Paulus M. P., and Geyer M. A. (1999) Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J. Neurosci. 19, 9550–9556.
Ebstein R. P., Novik O., Umansky R., Priel B., Osher Y., Blaine D., et al. (1996) Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nat. Genet. 12, 78–80.
Falzone T. L., Gelman D. M., Young J. I., Grandy D. K., Low M. J., and Rubinstein M. (2002) Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur. J. Neurosci. 15, 158–164.
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. J. Neurophysiol. 88, 3010–3020.
Florijn W. J., Tarazi F.I., and Creese I. (1997) Dopamine receptor subtypes: differential regulation following 8 months treatment with antipsychotic drugs. J. Pharmacol. Exp. Ther. 280, 561–569.
Halpain S., Girault J. A., and Greengard P. (1990) Activation of NMDA receptors induce dephosphorylation of DARPP-32 in rat striatal slices. Nature 343, 369–372.
Hu X. T. and White F. J. (1994) Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: electrophysiological and behavioral studies. Synapse 17, 43–61.
Kebabian J. W., Tarazi F. I., Kula N. S., and Baldessarini R. J. (1997) Compounds selective for dopamine receptor subtypes. Drug Discovery Today 2, 333–340.
Keefe K. A. and Gerfen C. R. (1995) D1-D2 dopamine receptor synergy in striatum: effects of intrastriatal infusions of dopamine agonists and antagonists on immediate early gene expression. Neuroscience 66, 903–113.
Kotecha S. A., Oak J. N., Jackson M. F., Perez Y., Orser B. A., Van Tol H. H. M., and MacDonald J. F. (2002) A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 35, 1111–1122.
Kula N. S., Tarazi F. I., Baldessarini R. J., Xu L., Bakthavachalam V., Pounds S., and True C. D. (1999) Neuropharmacological assessment of potential dopamine D4-selective radioligands. Eur. J. Pharmacol. 367, 139–142.
La Hoste G. J., Swanson J. M., Wigal S. B., Glabe C., Wigal T., King N., and Kennedy J. L. (1996) Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol. Psychiatry 1, 128–131.
Lichter J. B., Barr C. L., Kennedy J. L., Van Tol H. H. M., Kidd K. K., and Livak K. J. (1993) A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum. Mol. Genet. 6, 767–773.
Mrzljak L., Bergson C., Pappy M., Huff R., Levenson R., and Goldman-Rakic P. S. (1996) Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 381, 245–248.
Neve K. A. and Neve R. L. (1997) The Dopamine Receptors, Humana Press, Totowa, NJ.
Rubinstein M., Cepeda C., Hurst R. S., Flores-Hernandez J., Ariano M. A., Falzone T., et al. (2001) Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J. Neurosci. 21, 3756–3763.
Rubinstein M., Phillips T. J., Bunzow J. R., Falzone T. L., Dziewczapolski G., Zhang G., et al. (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90, 991–1001.
Singh N. A., Bush L. G., Gibb J. W., and Hanson G. R. (1990) Dopamine-mediated changes in central nervous system neurotensin systems: a role for NMDA receptors. Eur. J. Pharmacol. 187, 337–344.
Surmeier D. J., Song W. J., and Yan Z. (1996) Coordinated expression of dopamine receptors in neuostriatal medium spiny neurons. J. Neurosci. 16, 6579–6591.
Swanson J. M., Sunahara G. A., Kennedy J. L., Regino R., Fineberg E., Wigal T., et al. (1998) Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD). Mol. Psychiatry 3, 38–41.
Tarazi F. I. and Baldessarini R. J. (1999a) Dopamine D4 receptors: significance for molecular psychiatry at the millennium. Mol. Psychiatry 4, 529–538.
Tarazi F. I. and Baldessarini R. J. (1999b) Regional localization of dopamine and glutamate receptor subtypes in striatolimbic brain regions. J. Neurosci. Res. 55, 401–410.
Tarazi F. I. and Baldessarini R. J. (2000) Comparative postnatal development of dopamine D1, D2 and D4 receptors in rat forebrain. Int. J. Dev. Neurosci. 18, 29–37.
Tarazi F. I., Baldessarini R. J., Kula N. S., and Zhang K. (2003) Long-term effects of olanzapine, risperidone, and quetiapine on ion otropic glutamate receptor types: Implications for antipsychotic drug treatment. J. Pharmacol. Exp. Ther. 306, 1145–1151.
Tarazi F. I., Campbell A., Yeghiayan S. K., and Baldessarini R. J. (1998) Localization of glutamate receptor subtypes in caudate-putamen and nucleus accumbens septi: Comparison of NMDA, AMPA and kainate receptors. Synapse 30, 227–235.
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.
Tarazi F. I., Kula N. S., and Baldessarini R. J. (1997a) Regional distribution of dopamine D4 receptors in rat forebrain. NeuroReport 8, 3423–3426.
Tarazi F. I., Yeghiayan S. K., Baldessarini R. J., Kula N. S., and Neumeyer J. L. (1997b) 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.
Tarazi F. I., Zhang K., and 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. J. Pharmacol. Exp. Ther. 297, 711–717.
Van Tol H. H. M., Bunzow J. R., Guan H.-C., Sunahara R. K., Seeman P., Niznik H. B., and Civelli O. (1991) Cloning of a human dopamine D4 receptor gene with high affinity for the antipsychotic clozapine. Nature 350, 614–619.
Van Tol H. H. M., Wu C. M., Guan H.-C., Ohara K., Bunzow J. R., Civelli O., et al. (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358, 149–152.
Wullner U., Testa C.M., Catania M. V., Young A. B., and Penney J. B. (1994) Glutamate receptors in striatum and substantia nigra: Effects of medial forebrain bundle lesions. Brain Res. 645, 98–102.
Zhang K., Davids E., Tarazi F. I., and Baldessarini R. J. (2002) Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions. Psychopharmacology 161, 100–106.
Zhang K., Tarazi F. I., and Baldessarini R. J. (2001) Role of dopamine D4 receptors in motor hyperactivity induced by neonatal 6-hydroxydopamine lesions in rats. Neuropsychopharmacology 25, 624–632.
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Gan, L., Falzone, T.L., Zhang, K. et al. Enhanced expression of dopamine D1 and glutamate NMDA receptors in dopamine D4 receptor knockout mice. J Mol Neurosci 22, 167–177 (2004). https://doi.org/10.1385/JMN:22:3:167
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DOI: https://doi.org/10.1385/JMN:22:3:167