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. 1994 Jan;19(1):24–29.

Pharmacology of benzodiazepine receptors: an update.

W Sieghart 1
PMCID: PMC1188559  PMID: 8148363

Abstract

Benzodiazepine receptors are allosteric modulatory sites on GABAA receptors. GABAA receptors are probably composed of five protein subunits, at least some of which belong to different subunit classes. So far six alpha-, four beta-, three gamma-, and delta- and two rho = p subunits of GABAA receptors have been identified. A large number of different subunit combinations, each of which will result in a GABAA receptor with distinct electrophysiological and pharmacological properties, are therefore possible. Many compounds from different chemical classes which are able to bind to benzodiazepine receptors have been identified. Depending on their individual efficacy, binding of these compounds either enhances, reduces or does not influence GABAergic transmission. However, the individual efficacy of the benzodiazepine receptor ligands changes with the subunit composition of the GABAA receptor. The investigation of the regional distribution, subunit composition and pharmacology of GABAA receptors will result in the development of new and more selective compounds for psychiatry.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benke D., Mertens S., Trzeciak A., Gillessen D., Mohler H. GABAA receptors display association of gamma 2-subunit with alpha 1- and beta 2/3-subunits. J Biol Chem. 1991 Mar 5;266(7):4478–4483. [PubMed] [Google Scholar]
  2. Benke D., Mertens S., Trzeciak A., Gillessen D., Mohler H. Identification and immunohistochemical mapping of GABAA receptor subtypes containing the delta-subunit in rat brain. FEBS Lett. 1991 May 20;283(1):145–149. doi: 10.1016/0014-5793(91)80573-l. [DOI] [PubMed] [Google Scholar]
  3. Bowling A. C., DeLorenzo R. J. Micromolar affinity benzodiazepine receptors: identification and characterization in central nervous system. Science. 1982 Jun 11;216(4551):1247–1250. doi: 10.1126/science.6281893. [DOI] [PubMed] [Google Scholar]
  4. Bristow D. R., Moratalla R., Martin I. L. Flunitrazepam increases the affinity of the GABAA receptor in cryostat-cut rat brain sections. Eur J Pharmacol. 1990 Aug 10;184(2-3):339–340. doi: 10.1016/0014-2999(90)90629-k. [DOI] [PubMed] [Google Scholar]
  5. Burt D. R., Kamatchi G. L. GABAA receptor subtypes: from pharmacology to molecular biology. FASEB J. 1991 Nov;5(14):2916–2923. doi: 10.1096/fasebj.5.14.1661244. [DOI] [PubMed] [Google Scholar]
  6. Doble A., Martin I. L. Multiple benzodiazepine receptors: no reason for anxiety. Trends Pharmacol Sci. 1992 Feb;13(2):76–81. doi: 10.1016/0165-6147(92)90027-4. [DOI] [PubMed] [Google Scholar]
  7. Duka T., Höllt V., Herz A. In vivo receptor occupation by benzodiazepines and correlation with the pharmacological effect. Brain Res. 1979 Dec 21;179(1):147–156. doi: 10.1016/0006-8993(79)90498-0. [DOI] [PubMed] [Google Scholar]
  8. Fritschy J. M., Benke D., Mertens S., Oertel W. H., Bachi T., Möhler H. Five subtypes of type A gamma-aminobutyric acid receptors identified in neurons by double and triple immunofluorescence staining with subunit-specific antibodies. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6726–6730. doi: 10.1073/pnas.89.15.6726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Glencorse Thora A., Bateson Alan N., Darlison Mark G. Differential Localization of Two Alternatively Spliced GABAA Receptor gamma2-Subunit mRNAs in the Chick Brain. Eur J Neurosci. 1992;4(3):271–277. doi: 10.1111/j.1460-9568.1992.tb00874.x. [DOI] [PubMed] [Google Scholar]
  10. Haefely W., Facklam M., Schoch P., Martin J. R., Bonetti E. P., Moreau J. L., Jenck F., Richards J. G. Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders. Adv Biochem Psychopharmacol. 1992;47:379–394. [PubMed] [Google Scholar]
  11. Izquierdo I., Medina J. H. GABAA receptor modulation of memory: the role of endogenous benzodiazepines. Trends Pharmacol Sci. 1991 Jul;12(7):260–265. doi: 10.1016/0165-6147(91)90567-c. [DOI] [PubMed] [Google Scholar]
  12. Killisch I., Dotti C. G., Laurie D. J., Lüddens H., Seeburg P. H. Expression patterns of GABAA receptor subtypes in developing hippocampal neurons. Neuron. 1991 Dec;7(6):927–936. doi: 10.1016/0896-6273(91)90338-z. [DOI] [PubMed] [Google Scholar]
  13. Laurie D. J., Seeburg P. H., Wisden W. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J Neurosci. 1992 Mar;12(3):1063–1076. doi: 10.1523/JNEUROSCI.12-03-01063.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McKernan R. M., Quirk K., Prince R., Cox P. A., Gillard N. P., Ragan C. I., Whiting P. GABAA receptor subtypes immunopurified from rat brain with alpha subunit-specific antibodies have unique pharmacological properties. Neuron. 1991 Oct;7(4):667–676. doi: 10.1016/0896-6273(91)90379-e. [DOI] [PubMed] [Google Scholar]
  15. Petersen E. N., Lassen J. B. A water lick conflict paradigm using drug experienced rats. Psychopharmacology (Berl) 1981;75(3):236–239. doi: 10.1007/BF00432430. [DOI] [PubMed] [Google Scholar]
  16. Polc P., Bonetti E. P., Schaffner R., Haefely W. A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, beta-carbolines, and phenobarbitone. Naunyn Schmiedebergs Arch Pharmacol. 1982 Dec;321(4):260–264. doi: 10.1007/BF00498510. [DOI] [PubMed] [Google Scholar]
  17. Polc P. Electrophysiology of benzodiazepine receptor ligands: multiple mechanisms and sites of action. Prog Neurobiol. 1988;31(5):349–423. doi: 10.1016/0301-0082(88)90014-7. [DOI] [PubMed] [Google Scholar]
  18. Puia G., Ducic I., Vicini S., Costa E. Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at gamma-aminobutyric acid type A receptor. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3620–3624. doi: 10.1073/pnas.89.8.3620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Puia G., Vicini S., Seeburg P. H., Costa E. Influence of recombinant gamma-aminobutyric acid-A receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated Cl- currents. Mol Pharmacol. 1991 Jun;39(6):691–696. [PubMed] [Google Scholar]
  20. Sarter M., Schneider H. H., Stephens D. N. Treatment strategies for senile dementia: antagonist beta-carbolines. Trends Neurosci. 1988 Jan;11(1):13–17. doi: 10.1016/0166-2236(88)90042-2. [DOI] [PubMed] [Google Scholar]
  21. Schofield P. R. The GABAA receptor: molecular biology reveals a complex picture. Trends Pharmacol Sci. 1989 Dec;10(12):476–478. doi: 10.1016/0165-6147(89)90041-2. [DOI] [PubMed] [Google Scholar]
  22. Sieghart W. GABAA receptors: ligand-gated Cl- ion channels modulated by multiple drug-binding sites. Trends Pharmacol Sci. 1992 Dec;13(12):446–450. doi: 10.1016/0165-6147(92)90142-s. [DOI] [PubMed] [Google Scholar]
  23. Sieghart W. Molecular basis of pharmacological heterogeneity of GABAA receptors. Cell Signal. 1992 May;4(3):231–237. doi: 10.1016/0898-6568(92)90062-d. [DOI] [PubMed] [Google Scholar]
  24. Sieghart W. Multiplicity of GABAA--benzodiazepine receptors. Trends Pharmacol Sci. 1989 Oct;10(10):407–411. doi: 10.1016/0165-6147(89)90189-2. [DOI] [PubMed] [Google Scholar]
  25. Sieghart W., Schlerka W. Potency of several type I-benzodiazepine receptor ligands for inhibition of [3H]flunitrazepam binding in different rat brain tissues. Eur J Pharmacol. 1991 May 2;197(1):103–107. doi: 10.1016/0014-2999(91)90371-v. [DOI] [PubMed] [Google Scholar]
  26. Sigel E., Barnard E. A. A gamma-aminobutyric acid/benzodiazepine receptor complex from bovine cerebral cortex. Improved purification with preservation of regulatory sites and their interactions. J Biol Chem. 1984 Jun 10;259(11):7219–7223. [PubMed] [Google Scholar]
  27. Skerritt J. H., Willow M., Johnston G. A. Diazepam enhancement of low affinity GABA binding to rat brain membranes. Neurosci Lett. 1982 Mar 17;29(1):63–66. doi: 10.1016/0304-3940(82)90365-2. [DOI] [PubMed] [Google Scholar]
  28. Thompson C. L., Bodewitz G., Stephenson F. A., Turner J. D. Mapping of GABAA receptor alpha 5 and alpha 6 subunit-like immunoreactivity in rat brain. Neurosci Lett. 1992 Sep 14;144(1-2):53–56. doi: 10.1016/0304-3940(92)90714-i. [DOI] [PubMed] [Google Scholar]
  29. Ticku M. K. Alcohol and GABA-benzodiazepine receptor function. Ann Med. 1990;22(4):241–246. doi: 10.3109/07853899009148934. [DOI] [PubMed] [Google Scholar]
  30. Venault P., Chapouthier G., de Carvalho L. P., Simiand J., Morre M., Dodd R. H., Rossier J. Benzodiazepine impairs and beta-carboline enhances performance in learning and memory tasks. 1986 Jun 26-Jul 2Nature. 321(6073):864–866. doi: 10.1038/321864a0. [DOI] [PubMed] [Google Scholar]
  31. Verma A., Snyder S. H. Peripheral type benzodiazepine receptors. Annu Rev Pharmacol Toxicol. 1989;29:307–322. doi: 10.1146/annurev.pa.29.040189.001515. [DOI] [PubMed] [Google Scholar]
  32. Vicini S. Pharmacologic significance of the structural heterogeneity of the GABAA receptor-chloride ion channel complex. Neuropsychopharmacology. 1991 Jan;4(1):9–15. [PubMed] [Google Scholar]
  33. Wafford K. A., Burnett D. M., Leidenheimer N. J., Burt D. R., Wang J. B., Kofuji P., Dunwiddie T. V., Harris R. A., Sikela J. M. Ethanol sensitivity of the GABAA receptor expressed in Xenopus oocytes requires 8 amino acids contained in the gamma 2L subunit. Neuron. 1991 Jul;7(1):27–33. doi: 10.1016/0896-6273(91)90071-7. [DOI] [PubMed] [Google Scholar]
  34. Wisden W., Laurie D. J., Monyer H., Seeburg P. H. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci. 1992 Mar;12(3):1040–1062. doi: 10.1523/JNEUROSCI.12-03-01040.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zezula J., Sieghart W. Isolation of type I and type II GABAA-benzodiazepine receptors by immunoaffinity chromatography. FEBS Lett. 1991 Jun 17;284(1):15–18. doi: 10.1016/0014-5793(91)80750-w. [DOI] [PubMed] [Google Scholar]
  36. Zimprich F., Zezula J., Sieghart W., Lassmann H. Immunohistochemical localization of the alpha 1, alpha 2 and alpha 3 subunit of the GABAA receptor in the rat brain. Neurosci Lett. 1991 Jun 10;127(1):125–128. doi: 10.1016/0304-3940(91)90910-l. [DOI] [PubMed] [Google Scholar]

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