Hostname: page-component-7dd5485656-6kn8j Total loading time: 0 Render date: 2025-10-28T08:37:27.616Z Has data issue: false hasContentIssue false
  • English
  • Français

Molecular Mechanisms Mediating the Action of Diazepam on GABA Receptors

Published online by Cambridge University Press:  29 January 2018

E. Costa ,
A. Guidotti  and
G. Toffano
E. Costa
Affiliation:
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032
A. Guidotti
Affiliation:
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032
G. Toffano
Affiliation:
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032
Get access Rights & Permissions [Opens in a new window]

Summary

Two types of crude synaptic membranes have been prepared which differ in their kinetic properties to bind 3H-GABA in a Na+-free medium. One type (B) has one type of receptor (affinity or KD about 0.2 μM), the other type (A) has two populations of receptors which have a high (0.16 μM) and a low (.02 μM) KD for GABA binding. This difference is due to the presence of a selective endogenous inhibitor of the high affinity receptor for GABA, a thermostable protein of about 15,000 molecular weight. Inhibitor action is counteracted by diazepam (7 x 10-7M), competitively. Clonazepam is more active but chlordiazepoxide is less active than diazepam. Two enantiomers of a benzodiazepine were studied. One of them is endowed with anxiolytic activity and nullifies the action of the endogenous inhibitor on high affinity GABA binding, the other is devoid of anxiolytic activity and is inactive against the inhibitor. The endogenous protein inhibitor also competitively blocks the high affinity binding of 3H-diazepam to Type A membranes. It is concluded that the endogenous inhibitor and diazepam act on the same receptor; and suggested that the endogenous inhibitor may be the natural ligand for the brain receptors that bind benzodiazepines with high affinity.

Information

Type
Research Article
Information
The British Journal of Psychiatry , Volume 133 , Issue 3 , September 1978 , pp. 239 - 248
Copyright
Copyright © Royal College of Psychiatrists, 1978 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Bertilsson, L., Mao, C. C. & Costa, E. (1977) Application of principles of steady state kinetics to the estimation of gamma-aminobutyric acid turnover rate in nuclei of rat brain. Journal of Pharmacology and Experimental Therapeutics, 200, 277–84.Google Scholar
Biggio, G., Brodie, B. B., Costa, E. & Guidotti, A. (1977a) Mechanism by which diazepam muscimol and other drugs change the content of cGMP in cerebellar cortex. Proceedings of the National Academy of Sciences of the United States of America, 74, 3592–6.Google ScholarPubMed
Biggio, G., Costa, E. & Guidotti, A. (1977) Pharmacologically induced changes in the 3′, 5i-cyclic guanosine monophosphate content of rat cerebellar cortex: Differences between apomorphine, haloperidol and harmaline. Journal of Pharmacology, and Experimental Therapeutics, 200, 207–15.Google ScholarPubMed
Choi, D. W., Ferb, O. H. & Fischbach, G. D. (1977) Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature (London), 260, 342–4.Google Scholar
Cook, L. & Sepinwell, J. (1975) Psychopharmacological parameters of emotion. In Emotions—Their Parameters and Measurements. Edited by Levi, L., pp 379–404. New York: Raven Press.Google Scholar
Costa, E., Guidotti, A. & Mao, C. C. (1976) A GABA hypothesis for the action of benzodiazepines. In GABA in Nervous System Function. Edited by Roberts, E., Chase, T. N. and Tower, D. B., pp 413–26. New York: Raven Press.Google Scholar
Costa, E., Guidotti, A. Mao, C. C. & Suria, A. (1975) New concepts on the mechanism of action of benzodiazepines. Life Sciences, 17, 167–86.CrossRefGoogle ScholarPubMed
DeFeudis, F. W. (1977) GABA receptors in the vertebrate nervous system. Progress in Neurobiology, 9, 123–45.CrossRefGoogle ScholarPubMed
Eccles, J. C., Ito, M. & Szentagothoi, J. (1967) The Cerebellum as a Neuronal Machine, Berlin: Springer Verlag.Google Scholar
Edidin, M. (1974) Rotational and translational diffusion in membranes. Annual Review of Biophysics and Bio-engineering, 3, 179–201.CrossRefGoogle ScholarPubMed
Enna, S. J. & Snyder, S. H. (1975) Properties of gamma-aminobutyric acid (GABA) receptor binding in rat brain synaptic membrane fractions. Brain Research, 100, 81–97.CrossRefGoogle ScholarPubMed
Enna, S. J. & Snyder, S. H. (1977) Influence of ions, enzymes and detergents on gamma-aminobutyric acid receptor binding in synaptic membranes of rat brain. Molecular Pharmacology, 13, 442–53.Google ScholarPubMed
Giambalvo, C. T. & Rosenberg, P. (1976) The effects of phospholipases and proteases on the binding of gamma-aminobutyric acid to junctional complexes of rat cerebellum. Biochimica et Biophysica Acta, 436, 741–56.Google Scholar
Guidotti, A. (1978) Synaptic mechanisms in the action of benzodiazepines. In Psychopharmacology: A Generation of Progress. Edited by Lipton, M. A., DiMascio, A. and Killam, K. F., pp 1349–57. New York: Raven Press.Google Scholar
Haefely, W. E. (1978) Behavioural and neuropharmacological aspects of drugs used in anxiety and related states. In Psychopharmacology: A Generation of Progress. Edited by Lipton, M. A., DiMascio, A. and Killam, K. F., pp 1359–74. New York: Raven Press.Google Scholar
Levey, G. S. (1971) Restoration of norepinephrine responsiveness of solubilized myocardial adenylate cyclase by phosphatidylinositol. Journal of Biological Chemistry, 246, 7405–10.CrossRefGoogle ScholarPubMed
MacDonald, R. & Barker, J. L. (1978) Benzodiazepines specifically modulated GABA mediated postsynaptic inhibition in cultured mammalian neurones. Nature (London), 271, 563–4.Google Scholar
Mao, C. C., Marco, E., Revuelta, A., Bertilsson, L. & Costa, E. (1977) The turnover rate of γ-aminobutyric acid in the nuclei of the telencephalon: Implications in the pharmacology of antipsychotics and of a minor tranquillizer. Biological Psychiatry, 12, 359–71.Google Scholar
Okada, Y., Nitsch-Hassler, C., Kim, J. A., Bak, I. J. & Hassler, R. (1971) Role of γ-aminobutyric acid (GABA) in the extrapyramidal motor system. 1. Regional distribution of GABA in rabbit, rat, guinea pig and baboon CNS. Experimental Brain Research, 13, 514–19.CrossRefGoogle Scholar
Olsen, R. W. (1976) Approaches to study GABA receptors. In GABA in Nervous System Function. Edited by Roberts, E., Chase, T. N. and Tower, D. B., pp 287–304. New York: Raven Press.Google Scholar
Pohl, S. L., Krans, H. M. J., Kozyreff, V., Birnbaumer, L. & Rodbell, M. (1971) The glucagon-sensitive adenylate cyclase system in plasma membranes of rat liver. Journal of Biological Chemistry, 246, 4447–54.Google Scholar
Polc, P., Mohler, H. & Haefely, W. (1974) The effect of diazepam on spinal cord activities: Possible sites and mechanism of action. Naunyn-Schmiedeberg's Archives of Pharmacology, 284, 319–37.Google Scholar
Schmidt, R. F., Vogel, M. E. & Zimmermann, M. (1967) Die wirkung von diazepam auf die präsynaptische Hemmung und andere Rückenmarksreflexe. Naunyn-Schmiedeberg's Archives of Pharmacology, 258, 69–82.CrossRefGoogle Scholar
Singer, S. J. & Nicolson, G. L. (1972) The fluid mosiac model of the structure of cell membranes. Science, 175, 720–31.Google Scholar
Suria, A. Costa, E. (1975) Action of diazepam, dibutyryl cGMP and GABA on presynaptic terminals in bullfrog sympathetic ganglia. Brain Research, 87, 102–6.CrossRefGoogle ScholarPubMed
Takeuchi, A. (1976) Studies of inhibitory effects of GABA in invertebrate nervous system. In GABA in Nervous System Function. Edited by Roberts, E., Chase, T. N. and Tower, D. B., pp. 255–67. New York: Raven Press.Google Scholar
Zukin, S. R., Young, A. B. & Snyder, S. H. (1974) Gamma-aminobutyric acid binding to receptor sites in rat central nervous system. Proceedings of the National Academy of Sciences of the United States of America, 71, 4802–7.Google Scholar
Submit a response

eLetters

No eLetters have been published for this article.