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Benzodiazepines specifically modulate GABA-mediated postsynaptic inhibition in cultured mammalian neurones

Abstract

BENZODIAZEPINES (BDZ) such as diazepam (DZ) and chlordiazepoxide (CDZ) are commonly used anticonvulsants, muscle relaxants, antianxiety agents and hypnotics. The cellular mechanisms underlying these clinically important effects have not been established, but attention has been focused on the effect of BDZ on pre- and postsynaptic responses to the putative neurotransmitter amino acids, specifically glycine (Gly)1,2 and γ-aminobutyric acid (GABA)3–7. An effect of BDZ on postsynaptic Gly receptors was suggested by the finding that BDZ reduce strychnine binding to central nervous system (CNS) synaptic membrane fractions in vitro2, but physiological studies, in vivo, have provided little support for such an interaction with Gly3. BDZ have been reported (1) to facilitate presynaptic inhibition in the spinal cord4,5, at least partially GABA-mediated8–10; (2) to facilitate GABA-mediated pre- and postsynaptic inhibition in the cuneate nucleus6; (3) to mimic the presynaptic action of GABA on preganglionic nerve terminals12, and (4) to antagonise13,14 and to enhance15,16 the postsynaptic action of GABA on CNS neurones. It has also been suggested that BDZ alter GABA metabolism4,5 or mobilise GABA from neuronal storage sites17, and BDZ have been demonstrated to bind specific receptors on synaptosomal membrane preparations derived from rat brain18, an effect which is independent of amino acid receptors. Thus, it is uncertain whether BDZ action is GABA or Gly receptor-mediated, due to an alteration of GABA metabolism, or due to direct binding to a specific receptor which binds BDZ. We have studied the effect of DZ and CDZ on amino acid-mediated postsynaptic responses in cultured mammalian spinal cord neurones and report that the BDZ selectively modify GABA-mediated postsynaptic inhibition in a dose-dependent fashion, augmenting the response at low doses and antagonising the response at higher doses.

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References

  1. Snyder, S. H. Br. J. Pharmac. 53, 473–484 (1975).

    Article  CAS  Google Scholar 

  2. Young, A. B., Zukin, S. R. & Snyder, S. H. Proc. natn. Acad. Sci. U.S.A. 71, 2246–2250 (1974).

    Article  ADS  CAS  Google Scholar 

  3. Dray, A. & Straughan, D. W. J. Pharm. Pharmac. 28, 314–315 (1976).

    Article  CAS  Google Scholar 

  4. Polc, P., Mohler, H. & Haefely, W. Archs Pharmac. 284, 319–337 (1974).

    Article  CAS  Google Scholar 

  5. Haefely, W. et al. Adv. Biochem. Psychophamacol. 10, 131–153 (1975).

    Google Scholar 

  6. Polc, P. & Haefely, W. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak. 294, 121–131, (1976).

    Article  CAS  Google Scholar 

  7. Costa, E., Guidotti, A. & Mao, C. C. in Advances in Biochemical Pharmacology (eds Costa, E. & Greengard, P.) (Raven, New York, 1900).

    Google Scholar 

  8. Davidoff, R. Science 175, 331–333 (1972).

    Article  ADS  CAS  Google Scholar 

  9. Barker, J. L., Nicoll, R. A. & Padjen, A. J. Physiol., Lond. 245, 521–536 (1975).

    Article  CAS  Google Scholar 

  10. Barker, J. L., Nicoll, R. A. & Padjen, A. J. Physiol., Lond. 245, 537–548 (1975).

    Article  CAS  Google Scholar 

  11. Suria, A. & Costa, E. Brain Res. 87, 102–106 (1975).

    Article  CAS  Google Scholar 

  12. Suria, A. & Costa, E. in Mechanism of Action of Benzodiazepines (eds Costa, E. & Greengard P.) 103–112 (Raven, New York, 1975).

    Google Scholar 

  13. Steiner, F. A. & Felix, D. Nature 260, 346–347 (1976).

    Article  ADS  CAS  Google Scholar 

  14. Gahwiler, B. H. Brain Res. 107, 176–179 (1976).

    Article  CAS  Google Scholar 

  15. Curtis, D. R., Lodge, D., Johnston, G. A. R. & Brand, S. S. Brain Res. 118, 344–347 (1976).

    Article  CAS  Google Scholar 

  16. Raabe, W. & Gumnit, R. J. Epilepsia 18, 117–120 (1977).

    Article  CAS  Google Scholar 

  17. Costa, E., Guidotti, A., Mao, C. C. & Suria, A. Life Sci. 17, 167–186 (1976).

    Article  Google Scholar 

  18. Squires, R. F. & Braestrup, C. Nature 266, 732–734 (1977).

    Article  ADS  CAS  Google Scholar 

  19. Ransom, B. R., Neale, E., Henkart, M., Bullock, P. N. & Nelson, P. G. J. Neurophysiol. 40, 1132–1150 (1977).

    Article  CAS  Google Scholar 

  20. Barker, J. L., Macdonald, R. L. & Ransom, B. R. in Iontophoresis and Transmitter Mechanism in the Mammalian Central Nervous Systems (eds Kelly, J. S. & Ryall, R. W.) (in the press).

  21. Macdonald, R. L. & Barker, J. L. Ann. Neurol. 1, 507 (1977).

    Google Scholar 

  22. Macdonald, R. L. & Barker, J. L. Transactions of the American Neurological Association 1977 (in the press).

  23. Ayala, G. F., Johnston, D., Lin, S. & Dichter, H. N. Brain Res. 121, 259–270 (1977).

    Article  CAS  Google Scholar 

  24. Choi, D. W., Farb, D. H. & Fischbach, G. D. Nature 269, 342 (1977).

    Article  ADS  CAS  Google Scholar 

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MACDONALD, R., BARKER, J. Benzodiazepines specifically modulate GABA-mediated postsynaptic inhibition in cultured mammalian neurones. Nature 271, 563–564 (1978). https://doi.org/10.1038/271563a0

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