Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra

Abstract

Antischizophrenic drugs exert their primary effects through blockade of dopamine (DA) receptors in the central nervous system (CNS)1–3. However, because of intricate interconnections between neural pathways, alteration of DA function in the CNS can lead to changes in the function of other neurotrans-mitters. In the basal ganglia, the turnover and utilisation of several neurotransmitters, including γ-aminobutyric acid (GABA)4–6, are indirectly influenced by nigrostriatal DA activity7–10. However, although attention has been focused on changes in DA receptors11,12, relatively little is known about changes in receptors for other transmitters after chronic anti-schizophrenic drug treatment. It is likely that changes occurring one or more synapses removed from the drugs' primary site of action may account for some of the time-dependent changes in the therapeutic and adverse clinical effects of antischizophrenic drugs13,14. In the substantia nigra (SN), a reduction in GABAergic inhibitory tone and a possible increase in the release of excitatory transmitter such as substance P are effects which seem to accompany the acute blockade of striatal DA receptors15. Recent studies have shown that a chronic decrease in GABA function in the SN, through the destruction of stria-tonigral pathways16,17, produces an increase in the number of GABA binding sites in the SN14,45. Therefore, if a relative deficit of GABA transmission in the SN were to be maintained by chronic antischizophrenic drug treatment, an increase in nigral GABA binding might occur. To investigate this possibility, two classical prototype antischizophrenic drugs (chlorpromazine and haloperidol) were examined for their effects on specific GABA binding in the SN and striatum of rats. These effects were compared with those of clozapine, an antischizophrenic drug with an atypical biochemical and clinical profile4,18–23. The data obtained, and reported here, support the hypothesis that chronic blockade of dopamine receptors by classical anti-schizophrenic drugs enhances GABA binding in the SN. This effect may be related to the extrapyramidal side effects associated with classical antischizophrenic drug treatment13.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Anden, N. E., Butcher, S. G., Corrodi, H., Fuxe, K. & Ungerstedt, U. Eur. J. Pharmac. 11, 303–314 (1970).

    Article  CAS  Google Scholar 

  2. Creese, I. & Snyder, S. H. in Psychopharmacology: A Generation of Progress (eds Lipton, M. A., DiMascio, A. & Killam, K. F.) 377–388 (Raven, New York, 1978).

    Google Scholar 

  3. Kebabian, J. W., Petzold, G. L. & Greengard, P. Proc. natn. Acad. Sci. U.S.A. 69, 2145–2149 (1972).

    Article  ADS  CAS  Google Scholar 

  4. Mao, C. C., Cheney, D., Marco, E., Revuelta, A. & Costa, E. Brain Res. 132, 375–379 (1977).

    Article  CAS  Google Scholar 

  5. Mao, C. C., Revuelta, A., Marco, E. & Costa, E. in Neuropsychopharmacology (eds Deniker, P., Radouco-Thomas, C. & Villeneuve, A.) 447–452 (Pergamon, Oxford, 1978).

    Google Scholar 

  6. Marco, E., Mao, C. C., Cheney, D. L., Revuelta, A. & Costa, E. Nature 264, 363–365 (1976).

    Article  ADS  CAS  Google Scholar 

  7. Racagni, G., Cheney, D. L., Trabucchi, M. & Costa, E. J. Pharmac. exp. Ther. 196, 323–332 (1976).

    CAS  Google Scholar 

  8. Sethy, D. H. J. Neurochem. 27, 325–326 (1976).

    Article  CAS  Google Scholar 

  9. Hong, J. S. et al. Brain Res. 160, 192–195 (1979).

    Article  CAS  Google Scholar 

  10. Hong, J. S., Yang, H. Y. T. & Costa, E. Neuropharmacology 17, 83–85 (1978).

    Article  CAS  Google Scholar 

  11. Burt, D. R., Creese, I. & Snyder, S. H. Science 196, 326–328 (1977).

    Article  ADS  CAS  Google Scholar 

  12. List, S. J. & Seeman, P. Life Sci. 24, 1447–1452 (1979).

    Article  CAS  Google Scholar 

  13. Baldessarini, R. J. & Tarsy, D. in Psychopharmacology: A Generation of Progress (eds Lipton, M. A., DiMascio, A. & Killam, K. F.) 993–104 (Raven, New York, 1978).

    Google Scholar 

  14. Davis, J. M. Am. J. Psychiat. 132, 1237–1245 (1975).

    Article  CAS  Google Scholar 

  15. Gale, K., Costa, E., Toffano, G., Hong, J. S. & Guidotti, A. J. Pharmac. exp. Ther. 206, 29–37 (1978).

    CAS  Google Scholar 

  16. Waddington, J. L. & Cross, A. J. Nature 276, 618–620 (1978).

    Article  ADS  CAS  Google Scholar 

  17. Guidotti, A., Gale, K., Suria, A. & Toffano, G. Brain Res. 172, 566–571 (1979).

    Article  CAS  Google Scholar 

  18. Costall, B. & Naylor, R. J. Psychopharmacology 43, 69–74 (1975).

    Article  CAS  Google Scholar 

  19. Gerlach, J., Koppelhus, P., Helweg, E. & Monrad, A. Acta psychiat. scand. 50, 410–424 (1974).

    Article  CAS  Google Scholar 

  20. Hauser, D. & Closse, A. Life Sci. 23, 557–562 (1978).

    Article  CAS  Google Scholar 

  21. Sayers, A. C., Burki, H. R., Ruch, W. & Asper, H. Psychopharmacology 41, 97–104 (1975).

    Article  CAS  Google Scholar 

  22. Gale, K. in Long-Term Effects of Neuroleptics, Pharmacological Basis and Clinical Implications (eds Catabeni, F., Racagni, G., Spano, P. F. & Costa, E.) (Raven, New York, in the press).

  23. Miller, R. J. & Hiley, C. R. Nature 248, 596–597 (1974).

    Article  ADS  CAS  Google Scholar 

  24. Enna, S. J. & Snyder, S. H. Molec. Pharmac. 13, 442–453 (1977).

    CAS  Google Scholar 

  25. Toffano, G., Guidotti, A. & Costa, E. Proc. natn. Acad. Sci. U.S.A. 75, 4024–4028 (1978).

    Article  ADS  CAS  Google Scholar 

  26. Gale, K. & Guidotti, A. Nature 263, 691–693 (1976).

    Article  ADS  CAS  Google Scholar 

  27. Asper, H. et al. Eur. J. Pharmac. 22, 287–294 (1973).

    Article  CAS  Google Scholar 

  28. Bowers, M. B. & Rozitis, A. J. Pharm. Pharmac. 26, 743–745 (1974).

    Article  CAS  Google Scholar 

  29. Scatton, B. Eur. J. Pharmac. 46, 363–369 (1977).

    Article  CAS  Google Scholar 

  30. Waldmeir, P. C. & Maitre, L. Eur. J. Pharmac. 38, 197–204 (1976).

    Article  Google Scholar 

  31. Ribak, C. E., Vaughn, V. E., Saito, K., Barber, R. & Roberts, E. Brain Res. 116, 287–298 (1976).

    Article  CAS  Google Scholar 

  32. Walters, J. & Lakoski, J. L. Eur. J. Pharmac. 47, 469–471 (1978).

    Article  CAS  Google Scholar 

  33. Gale, K. Soc. Neurosci. Abstr. no. 231 (1979).

  34. Oberlander, C., Dumont, C. & Boissier, J. R. Eur. J. Pharmac. 43, 389–390 (1976).

    Article  Google Scholar 

  35. Koob, G. F., Del Fiacco, M. & Iversen, S. D. Adv. biochem. Psychopharmac. 16, 589–595 (1977).

    CAS  Google Scholar 

  36. Scheel-Kruger, J., Arnt, J. & Magelund, G. Neurosci. Lett. 4, 351–356 (1977).

    Article  CAS  Google Scholar 

  37. Palfreyman, M. G., Huot, S., Lippert, B. & Schecter, P. J. Eur. J. Pharmac. 50, 325–336 (1978).

    Article  CAS  Google Scholar 

  38. Matsui, Y. & Kamioka, T. Eur. J. Pharmac. 50, 243–251 (1978).

    Article  CAS  Google Scholar 

  39. Klawans, H. L. & Rubovits, R. J. neural Transmission 33, 235–246 (1972).

    Article  Google Scholar 

  40. Tarsy, D. & Baldessarini, R. J. Neuropharmacology 13, 927–940 (1974).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gale, K. Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra. Nature 283, 569–570 (1980). https://doi.org/10.1038/283569a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/283569a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing