Abstract
In a previous study, we showed that the psychoactive drug caffeine alters the expression of the dopamine 2 receptor (D2R) gene in vitro and in vivo. Here, we report that acute administration of antipsychotic and antiparkinsonian drugs also regulate D2R gene expression in PC12 cells and in the mouse striatum. Treatment of PC12 cells with the atypical antipsychotic and specific 5-HT antagonist clozapine (60µM) reduced D2R/luciferase reporter expression by 46% after 24 h. However, male and female mice treated with a clinical dose of clozapine (10 mg/kg) showed no changes in striatal D2R mRNA expression when assayed by quantitative RT-PCR. Treatment of PC12 cells with the specific D2R agonist anti-parkinsonian drug, bromocriptine mesylate (BCM; 5µM) also resulted in decreased D2R/luciferase reporter activity (27%). In contrast to clozapine, a clinical dose of BCM (16 mg/kg) led to a 21% decrease and a 45% increase in striatal D2R mRNA expression in male and female mice, respectively, after 24 h. Coadministration of clozapine and BCM in PC12 cells resulted in a synergistic decrease in D2R/luciferase reporter expression (68%), and coadministration of these drugs in vivo led to decreases in striatal D2R mRNA expression in both male and female mice (45% and 22%, respectively). Collectively, these results indicate that clozapine, BCM, or a combination of these drugs have differential effects on dopamine receptor gene expression and might also affect striatal physiology in a sexually dimorphic manner.
This is a preview of subscription content, log in via an institution to check access.
References
Aizman O., Brismar H., Uhlen P., Zettergren E., Levey A. I., Forssberg H., et al. (2000) Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat. Neurosci. 3, 226–230.
Al-Semaan Y. (1996) Bromocriptine as adjunctive therapy to clozapine in treatment-resistant schizophrenia. Can. J. Psychiatry 41, 484–485.
Al-Semaan Y. M., Clay H. A., and Meltzer H. Y. (1997) Clozapine in treatment of bromocriptine-induced psychosis. J. Clin. Psychopharmacol. 17, 126–128.
Arslan G., Kull B., and Fredholm B. B. (1999) Signaling via A2A adenosine receptor in four PC12 cell clones. Naunyn Schmiedebergs Arch. Pharmacol. 359, 28–32.
Ashby C. R. Jr. and Wang R. Y. (1996) Pharmacological actions of the atypical antipsychotic drug clozapine: a review. Synapse 24, 349–394.
Carlsson A. (1959) The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol. Rev. 11, 490–493.
Copertino D. W., Edelman G. M., and Jones F. S. (1997) Multiple promoter elements differentially regulate the expression of the mouse tenascin gene. Proc. Natl. Acad. Sci. U. S. A. 94, 1846–1851.
Dalla Libera A., Scutari G., Boscolo R., Rigobello M. P., and Bindoli A. (1998) Antioxidant properties of clozapine and related neuroleptics. Free Radic. Res. 29, 151–157.
Damask S. P., Bovenkerk K. A., de la Pena G., Hoversten K. M., Peters D. B., Valentine A. M., and Meador-Woodruff J. H. (1996) Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex. Brain Res. Mol. Brain Res. 41, 241–249.
Diaz-Cabiale Z., Hurd Y., Guidolin D., Finnman U. B., Zoli M., Agnati L. F., et al. (2001) Adenosine A2A agonist CGS21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum. NeuroReport 12, 1831–1834.
D’Souza D. N., Harlan R. E., and Garcia M. M. (1999) Sexual dimorphism in the response to N-methyl-D-aspartate receptor antagonists and morphine on behavior and c-Fos induction in the rat brain. Neuroscience 93, 1539–1547.
D’Souza D. N., Harlan R. E., and Garcia M. M. (2002) Sexually dimorphic effects of morphine and MK-801: sex steroid-dependent and -independent mechanisms. J. Appl. Physiol. 92, 493–503.
Ferre S., von Euler G., Johansson B., Fredholm B. B., and Fuxe K. (1991) Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U. S. A. 88, 7238–7241.
Fredduzzi S., Moratalla R., Monopoli A., Cuellar B., Xu K., Ongini E., et al. (2002) Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors. J. Neurosci. 22, 1054–1062.
Fuxe K. and Ungerstedt U. (1974) Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with DOPA and dopamine receptor agonists. Med. Biol. 52, 48–54.
Gingrich J. A. and Caron M. G. (1993) Recent advances in the molecular biology of dopamine receptors. Annu. Rev. Neurosci. 16, 299–321.
Kartzinel R., Teychenne P., Gillespie M. M., Perlow M., Gielen A. C., Sadowsky D. A., and Calne D. B. (1976) Bromocriptine and levodopa (with or without carbidopa) in parkinsonism. Lancet 2, 272–275.
Kitamura Y., Taniguchi T., Shimohama S., Akaike A., and Nomura Y. (2003) Neuroprotective mechanisms of antiparkinsonian dopamine D2-receptor subfamily agonists. Neurochem. Res. 28, 1035–1040.
Lewis D. A. and Lieberman J. A. (2000) Catching up on schizophrenia: natural history and neurobiology. Neuron 28, 325–334.
McGeer P. L., Itagaki S., Akiyama H., and McGeer E. G. (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann. Neurol. 24, 574–576.
Meltzer H. Y., Kennedy J., Dai J., Parsa M., and Riley D. (1995) Plasma clozapine levels and the treatment of L-DOPA-induced psychosis in Parkinson’s disease. A high potency effect of clozapine. Neuropsychopharmacology 12, 39–45.
Orr G., Munitz H., and Hermesh H. (2001) Low-dose clozapine for the treatment of Parkinson’s disease in a patient with schizophrenia. Clin. Neuropharmacol. 24, 117–119.
Rosenheck R., Cramer J., Xu W., Thomas J., Henderson W., Frisman L., et al. (1997) A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. N. Engl. J. Med. 337, 809–815.
Schiffmann S. N. and Vanderhaeghen J. J. (1993) Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J. Neurosci. 13, 1080–1087.
Silver H. (2003) Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. Int. Clin. Psychopharmacol. 18, 305–313.
Stonehouse A. H., Adachi M., Walcott E. C., and Jones F. S. (2003b) Caffeine regulates neuronal expression of the dopamine 2 receptor gene. Mol. Pharmacol. 64, 1463–1473.
Stoof J. C. and Kebabian J. W. (1984) Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci. 35, 2281–2296.
Svetel M. V., Sternic N. M., Filipovic S. R., Vojvodic N. M., and Kostic V. S. (1997) Clozapine in the treatment of adverse psychiatric manifestations of long-term therapy with levodopa. Srp. Arh. Celok. Lek. 125, 203–206.
Von Voigtlander P. F., Fici G. J., and Althaus J. S. (1998) Pharmacological approaches to counter the toxicity of Dopa. Amino Acids 14, 189–196.
Zhu W. H., Conforti L., and Millhorn D. E. (1997) Expression of dopamine D2 receptor in PC-12 cells and regulation of membrane conductances by dopamine. Am. J. Physiol. 273, C1143–1150.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stonehouse, A.H., Jones, F.S. Bromocriptine and clozapine regulate dopamine 2 receptor gene expression in the mouse striatum. J Mol Neurosci 25, 29–36 (2005). https://doi.org/10.1385/JMN:25:1:029
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:25:1:029