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Neuroleptics and Dopamine Transporters

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Abstract

The effects of neuroleptic treatments on dopamine transporters and on dopamine receptors was investigated in the forebrain of adult rats treated for 21 days with either haloperidol, clozapine or saline. The dopamine D1receptors, labeled with [3H]SCH23390, increased in nucleus accumbens, latero-dorsal rostral neostriatum and substantia nigra, after clozapine but not haloperidol. The dopamine D2receptors, studied with [3H]raclopride, increased in nucleus accumbens and in dorsolateral, ventro-medial and dorso-medial quadrants of the rostral neostriatum after either haloperidol or clozapine treatments, and also in latero-ventral rostral neostriatum but only after haloperidol. Haloperidol also up-regulated D2receptors in rostral and caudal neostriatum, but clozapine produced a more uneven increase, especially in caudal neostriatum. In contrast, the densities of dopamine uptake sites, or transporters, labeled with [I25I]RTI-121, remained unchanged after both neuroleptic treatments. The observation that dopamine transporters are resistant to treatments that modify D1and D2receptors indicates that these uptake sites can probably be ruled out as the target of neuroleptic drugs, and that dopamine receptor up-regulations can indeed occur independently of the densities of nerve endings at the terminal fields of innervation.

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REFERENCES

  1. Van Rossum, J. M. 1966. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch. Int. Pharmacodyn. Ther. 160:492-494.

    Google Scholar 

  2. Seeman, P., Lee, T., Chau-Wong, M., and Wong, K. 1976. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717-721.

    Google Scholar 

  3. Seeman P. 1987. Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133-152.

    Google Scholar 

  4. Meltzer, H. Y., Matsubara, S., and Lee, J.-C. 1989. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2pKi values. J. Pharmacol. Exp. Ther. 251:238-246.

    Google Scholar 

  5. Chouinard, G., Vainer, J. L., Bélanger, M.-C., Turnier, L., Beaudry, P., Roy, J.-Y., and Milner, R. 1994. Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis. Progr. Neuro-Psychopharmacol. & Biol. Psychiat. 18:1129-1141.

    Google Scholar 

  6. Farde, L., Wiesel, F. A., Nordstrom, A. L., and Sedvall, G. 1989. D1-and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99:(Suppl.) 28-31.

    Google Scholar 

  7. Ellenbroek, B. A., Willemen, A. P., and Cools, A. R. 1989. Are antagonist of dopamine D1receptors drugs that attenuate both positive and negative symptoms of schizophrenia? A pilot study in Java monkeys. Neuropsychopharmacology 2:191-199.

    Google Scholar 

  8. Wiesel, F. A., Farde, L., Nordström, A. L., and Sedvall, G. 1990. Central D1-and D2-receptor occupancy during antipsychotic drug treatment. Progr. Neuro-Psychopharmacol. & Biol. Psychiatr. 14:759-767.

    Google Scholar 

  9. Farde, L., and Nordström, A. L. 1992. PET analysis indicates atypical central dopamine receptor occupancy in clozapine-treated patients. Br. J. Psychiatr. 160:(Suppl. 17) 30-33.

    Google Scholar 

  10. O'Dell, S. J., La Hoste, G. J., Winmark, C. B., Shapiro, R. M., Potkin, S. G., and Marshal, J. F. 1990. Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse 6:146-153.

    Google Scholar 

  11. See, R. E., Toga, A. W., and Ellison, G. 1990. Autoradiographic analysis of regional alterations in brain receptors following chronic administration and withdrawal of typical and atypical neuroleptics in rats. J. Neural Transm. 82:93-109.

    Google Scholar 

  12. Snyder, S. H. 1970. Putative neurotransmitter in the brain: selective neuronal uptake, subcellular localization and interactions with centrally acting drugs. Biol. Psychiat. 2:367-389.

    Google Scholar 

  13. Iversen, L. L. 1973. Catecholamine uptake processes. Br. Med. Bull. 29:130-135.

    Google Scholar 

  14. Raiteri, M., Cerrito, F., Cervoni, A. M., del Carmine, R., RIbera, M. T., and Levi, G. 1978. Studies on dopamine uptake and release in synaptosomes. Adv. Biochem. Psychopharmacol. 19:35-36.

    Google Scholar 

  15. Giros, B., Mestikawy, S. E., Godinot, N., Zheng, K., Han, H., Yang-Feng, T., and Caron, M. G. 1992. Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Molec. Pharmacol. 42:383-390.

    Google Scholar 

  16. Giros, B., Wang, Y.-M., Suter, S., McLeskey, S. B., Pifi, C., and Caron, M. G. 1994. Delineation of discrete domains for substrate, cocaine, and tricyclic anti-depressant interactions using chimeric dopamine-norepinephrine transporters. J. Biol. Chem. 269:15985-15988.

    Google Scholar 

  17. Vandenbergh, S. J., Persico, A. M., and Uhl, G. R. 1992. A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic Taq I RFLPS. Molec. Brain Res. 15:161-166.

    Google Scholar 

  18. Pristupa, Z. B., Wilson, J. M., Hoffman, B. J., Kish, S. J., and Niznik, H. B. 1994. Pharmacological heterogeneity of the cloned and native human dopamine transporter: dissociation of [3H]WIN 35,428 and [3H]GBR 12935 binding. Molec. Pharmacol. 45:125-135.

    Google Scholar 

  19. Amara, S. G., and Kuhar, M. J. 1993. Neurotransmitter transporters: Recent progress. Annu. Rev. Neurosci. 16:73-93.

    Google Scholar 

  20. Huang, N., Ase, A. R., Hébert, C., van Gelder, N. M., and Reader, T. A. 1997. Effects of chronic neuroleptic treatments on dopamine D1and D2receptors: homogenate binding and autoradiographic studies. Neurochem. Int. 30:277-290.

    Google Scholar 

  21. Paxinos, G., and Watson, C. 1982. The Rat Brain in Stereotaxic Coordinates, Academic Press, Sydney.

    Google Scholar 

  22. Boja, J. W., Cadet, J. L., Kopajtic, T. A., Lever, J., Seltzman, H. H., Wyric, C. D., Lewin, A. H., Abraham, P., and Carrol, F. I. 1995. Selective labeling of the dopamine transporter by the high affinity ligand 3 β-(4-[125I]iodophenyl)tropane-2β-carboxylic acid isopropyl ester. Molec. Pharmacol. 47:779-786.

    Google Scholar 

  23. Staley, J. K., Boja, J., Carroll F. I., Seltzman, H. H., Wyrick, C. D., Lewin, A. H., Abraham, P., and Mash, D. C. 1995. Mapping dopamine transporters in the human brain with novel selective cocaine analog [125I]RTI-121. Synapse 21:364-372.

    Google Scholar 

  24. Carli, M., Morissette, M., Hébert, C., Di Paolo, T., and Reader, T. A. 1997. Effects of a chronic lithium treatment on central dopamine transporters. Biochem. Pharmacol. (in press).

  25. Dawson, T. M., Gehlert, D. R., Yamamura, H. I., Barnett, A., and Wamsley, J. K. 1985. D1 dopamine receptors in the rat brain: autoradiographic localization using [3H]SCH23390. Eur. J. Pharmacol. 108:323-325.

    Google Scholar 

  26. Radja, F., El Mansari, M., Soghomonian, J.-J., Dewar, K. M., Ferron, A., Reader, T. A., and Descarries, L. 1993. Changes of D1and D2receptors in adult rat neostriatum after neonatal dopamine denervation. Correlation of quantitative data from ligand binding autoradiography, in situ hybridization and iontophoresis. Neuroscience 57:635-648.

    Google Scholar 

  27. Reader, T. A., Radja, F., Dewar, K. M., and Descarries, L. 1995. Denervation, hyperinnervation and interactive regulation of dopamine and serotonin receptors. Ann. N. Y. Acad. Sci. 757:293-310.

    Google Scholar 

  28. Köhler, C., and Radestäter, A. C. 1986. Autoradiographic localization of D2receptors in monkey brain using the selective benzamide drug [3H]raclopride. Neurosci. Lett. 66:85-90.

    Google Scholar 

  29. Barlow, R. B. 1983. Biodata Handling with Microcomputers. Elsevier Science Publishers, Amsterdam.

    Google Scholar 

  30. Frank, H., and Althoen, S. C. 1994. Statistics: Concepts and Applications. Cambridge University Press, New York.

    Google Scholar 

  31. Boyson, S. J., McGonigle, P., and Molinoff, P. B. 1986. Quantitative autoradiographic localization of the D1and D2subtypes of dopamine receptors in rat brain. J. Neurosci. 6:3177-3188.

    Google Scholar 

  32. Criswell, H., Mueller, R. A., and Breese, G. R. 1989. Priming of D1-dopamine receptor responses: long-lasting behavioral supersensitivity to a D1-dopamine agonist following repeated administration to neonatal 6-OHDA-lesioned rats. J. Neurosci. 9:125-133.

    Google Scholar 

  33. Reader, T. A., Brière, R., Gottberg, E., Diop, L., and Grondin, L. 1988. Specific [3H]SCH23390 binding to dopamine D1receptors in cerebral cortex and neostriatum: Evidence for heterogeneity in affinity states and cortical distribution. J. Neurochem. 50:451-463.

    Google Scholar 

  34. Gerlach, J., and Hansen, L. 1992. Clozapine and D1/D2antagonism in extrapyramidal functions. Br. J. Psychiatr. 160:(Suppl 17) 34-37.

    Google Scholar 

  35. Martres, M. P., Sokoloff, P., Giros, B., and Schwartz, J.-C. 1992. Effects of dopaminergic transmission interruption on the D2receptor isoforms in various cerebral tissues. J. Neurochem. 58:673-679.

    Google Scholar 

  36. Allikmets, L. H., Žarkovsky, A. M., and Nurk, A. M. 1981. Changes in catalepsy and receptor sensitivity following chronic neuroleptic treatment. Eur. J. Pharmacol. 75:145-147.

    Google Scholar 

  37. Janowsky, A., Neve, K. A., Kinzie, J. M., Taylor, B., de Paulis, T., and Belknap, J. K. 1992. Extrastriatal dopamine D2receptors: distribution, pharmacological characterization and region-specific regulation by clozapine. J. Pharmacol. Exp. Ther. 261:1282-1290.

    Google Scholar 

  38. Kuhar, M. J., Sanchez-Roa, P. M., Wong, D. F., Dannals, R. F., Grigoriadis, D. E., Lew, R., and Milberger, M. 1990. Dopamine transporter: biochemistry, pharmacology and imaging. Eur. Neurol. 30(Suppl):15-20.

    Google Scholar 

  39. Kennedy, L. T., and Hanbauer, I. 1983. Sodium-sensitive cocaine binding to rat striatal membrane: possible relationship to dopamine uptake sites. J. Neurochem. 42:172-178.

    Google Scholar 

  40. Reith, M. E. A., Meisler, B. E., Sershen, H., and Lajtha, A. 1986. Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior. Biochem. Pharmacol. 35:1123-1129.

    Google Scholar 

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Reader, T.A., Ase, A.R., Huang, N. et al. Neuroleptics and Dopamine Transporters. Neurochem Res 23, 73–80 (1998). https://doi.org/10.1023/A:1022405621365

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