Abstract
Chronic administration of the neuroleptic drug haloperidol previously has been shown to increase the density of striatal dopamine D2 receptor, which is believed to be the underlying factor in neuroleptic-induced tardive dyskinesia. To search for the mechanism of receptor upregulation, the expression of the isoforms of dopamine D2 receptor mRNA in rat striatum was analyzed by Northern, solution, andin situ hybridizations in haloperidol-treated rats (1–35 days). Northern blot analysis of poly(A)+ RNA hybridized with a probe common for both isoforms as well as an insert-specific probe for the long isoform of the receptor revealed no significant difference in hybridization signal between the control and any of the haloperidol-treated groups of rats. The receptor density, however, was increased by 30–40% in animals receiving haloperidol for 7–35 days. Solution hybridization with an antisense riboprobe specific for a consensus sequence as well asin situ hybridization with a consensus oligonucleotide probe similarly failed to detect any increase in the expression of receptor mRNA following haloperidol treatment. The results suggest that post-transcriptional mechanisms may be responsible for regulating the haloperidol-induced increase in dopamine D2 receptors.
Similar content being viewed by others
References
Autelitano, D.J., Snyder, L., Sealfon, S.C., Roberts, J.L. (1989). Dopamine D2-receptor messenger RNA is differentially regulated by dopaminergic agents in rat anterior and neurointermediate pituitary. Mol. Cell. Endocrinol. 67:101–105
Baldessarini, R.J., Tarsy, D. (1980). Dopamine and the pathophysiology of dyskinesias induced by antipsychotic drugs. Annu. Rev. Neurosci. 3:23–41
Boyson, S.J., McGonigle, P., Luthin, G.R., Wolfe, B.B., Molinoff, P.B. (1988). Effects of chronic administration of neuroleptic and anticholinergic agents on densities of D2 dopamine and muscarinic cholinergic receptors in rat striatum. J. Pharmacol. Exp. Ther. 244:987–993
Bunzow, J.R., van Tol, H.H.M., Grandy, D.K., Albert, P., Salon, J., Christie, M., Machida, C.A., Neve, K.A., Civelli, O. (1988). Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336:783–787
Burt, D.R., Creese, I., Snyder, S.H. (1977). Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain. Science 196:326–328
Chio, C.L., Hess, G.F., Graham, R.S., Huff, R.M. (1990). A second molecular form of D2 dopamine receptor in rat and bovine caudate nucleus. Nature 343:266–269
Chiu, S., Paulose, C.S., Mishra, R.K. (1981). Neuroleptic drug-induced dopamine receptor supersensitivity: Antagonism byl-prolyl-l-leucyl-glycinamide. Science 214:1261–1262
Creese, I., Sibley, D.R. (1981). Receptor adaptations to centrally acting drugs. Annu. Rev. Pharmacol. Toxicol. 21:357–391
Dal Toso, R., Sommer, B., Ewert, M., Herb, A., Pritchett, D.B., Bach, A., Shivers, B.D., Seeburg, P.H. (1989). The dopamine D2 receptor: Two molecular forms generated by alternative splicing. EMBO J. 8:4025–4034
Giros, B., Sokoloff, P., Martres, M.P., Riou, J.F., Emorine, L.J., Schwartz, J.C. (1989). Alternative splicing directs the expression of two D2 dopamine receptor isoforms. Nature 342:923–926
Grandy, D.K., Marchionni, M.A., Makam, H., Stofko, R.E., Alfano, M., Frothingham, L., Fischer, J.B., Burke-Howie, K.J., Bunzow, J.R., Server, A.C., Civelli, O. (1989). Cloning of the cDNA and gene for a human D2 dopamine receptor. Proc. Natl. Acad. Sci. U.S.A. 86:9762–9766
Hess, E.J., Norman, A.B., Creese, I. (1988). Chronic treatment with dopamine receptor antagonists: Behavioral and pharmacologic effects of D1 and D2 dopamine receptors. J. Neurosci. 8:2361–2370
Lee, J.J., Costlow, N.A. (1987). A molecular titration assay to measure transcript prevalence levels. Methods Enzymol. 152:633–648
Le Moine, C., Normand, E., Guitteny, A.F., Fouque, B., Teoule, R., Bloch, B. (1990). Dopamine receptor gene expression by enkephalin neurons in rat forebrain. Proc. Natl. Acad. Sci. U.S.A. 87:230–234
MacDonald, R.J., Swift, G.H., Przybyla, A.E., Chirgwin, J.M. (1987). Isolation of RNA using guanidinium salts. Methods Enzymol. 152:219–227
Mackenzie, R.G., Zigmond, M.J. (1985). Chronic neuroleptic treatment increases D-2 but not D-1 receptors in rat striatum. Eur. J. Pharmacol. 113:159–165
Maniatis, T., Fritsch, E.F., Sambrook, J. (1982). Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 122–123
Meador-Woodruff, J.H., Mansour, A., Bunzow, J.R., van Tol, H.H.M., Watson, S.J., Jr., Civelli, O. (1989). Distribution of D2 receptor mRNA in rat brain. Proc. Natl. Acad. Sci. U.S.A. 86:7625–7628
Meinkoth, J., Wahl, G.M. (1987). Nick translation. Methods Enzymol. 152:91–94
Mengod, G., Martinez-Mir, M.I., Vilaro, M.T., Palacios, J.M. (1989). Localization of the mRNA for the dopamine D2 receptor in the rat brain by in situ hybridization histochemistry. Proc. Natl. Acad. Sci. U.S.A. 86:8560–8564
Miller, J.C. (1990). Induction ofc-fos mRNA expression in rat striatum by neuroleptic drugs. J. Neurochem. 54:1453–1455
Mishra, R.K. (1986). Central nervous system dopamine receptors. Neuromethods, Vol. 4. A. Boulton, G. Baker, P. Hrdina (eds). Humana Press, Clifton, NJ. pp 23–54
Monsma, F.J., Jr., McVittie, L.D., Gerfen, C.R., Mahan, L.C., Sibley, D.R. (1989). Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 342:926–929
Pich, E.M., Benfenati, F., Farabegoli, C., Fuxe, K., Meller, E., Aronsson, M., Goldstein, M., Agnati, L.F. (1987). Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade. Brain Res. 435:147–152
Seeman, P. (1980). Brain dopamine receptors. Pharmacol. Rev. 32:229–313
Seeman, P. (1987). Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152
Selbie, L.A., Hayes, G., Shine, J. (1989). The major dopamine D2 receptor: Molecular analysis of the human D2A subtype. DNA 8:683–689
Srivastava, L.K., Bajwa, S.B., Johnson, R.L., Mishra, R.K. (1988). Interaction ofl-prolyl-l-leucyl-glycinamide (PLG) with dopamine D2 receptor: Evidence for modulation of agonist affinity states in bovine striatal membranes. J. Neurochem. 50:960–968
van Tol, H.H.M., Riva, M., Civelli, O., Creese, I. (1990). Lack of effect of chronic dopamine receptor blockade on D2 dopamine receptor mRNA level. Neurosci. Lett. 111:303–308
Weiner, D.M., Brann, M.R. (1989). The distribution of a dopamine D2 receptor mRNA in rat brain. FEBS Lett. 253:207–213
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Srivastava, L.K., Morency, M.A., Bajwa, S.B. et al. Effect of haloperidol on expression of dopamine D2 receptor mRNAs in rat brain. J Mol Neurosci 2, 155 (1990). https://doi.org/10.1007/BF02896840
DOI: https://doi.org/10.1007/BF02896840