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Anesth Prog. 1986 Sep-Oct; 33(5): 213–219.
PMCID: PMC2177483

The Benzodiazepine Receptor

Abstract

The benzodiazepines are among the most widely used drugs in the world. When first introduced, little was known about their mechanism of action. However, in the last 20 years, our understanding of the chemistry and function of the central nervous system (CNS) has increased substantially. This knowledge has shed some light on the mechanism of action of the benzodiazepines and other centrally acting drugs. It is well established that the benzodiazepines act by combining with specific receptors in the central nervous system. These receptors are anatomically in close association with gamma amino butyric acid (GABA) receptors and appear to reside on the neuronal membrane in the same supramolecular protein complex. GABA is the major inhibitory neurotransmitter of the CNS. The benzodiazepines act by increasing the affinity of the GABA receptor for its ligand, thereby augmenting the inhibitory effect of a given concentration of GABA. Two hypotheses of benzodiazepine ligand-receptor interactions in this supramolecular protein complex have been proposed: (1) multiple receptor subtypes analogous to the opioid receptors; (2) single receptor with multiple conformations. The multiple receptor hypothesis suggests that each pharmacologic effect of the benzodiazepines (i.e., anxiolysis) is mediated by interaction with a specific receptor subtype. On the other hand, the alternative hypothesis suggests that only one receptor exists which has a dynamic conformation. Experimental evidence in support of each hypothesis is presented and critically evaluated.

Full text

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Roberts E. Gamma-aminobutyric acid and nervous system function--a perspective. Biochem Pharmacol. 1974 Oct 1;23(19):2637–2649. [PubMed]
  • Curtis DR, Johnston GA. Amino acid transmitters in the mammalian central nervous system. Ergeb Physiol. 1974;69(0):97–188. [PubMed]
  • Iadarola MJ, Gale K. Substantia nigra: site of anticonvulsant activity mediated by gamma-aminobutyric acid. Science. 1982 Dec 17;218(4578):1237–1240. [PubMed]
  • Grant SJ, Huang YH, Redmond DE., Jr Benzodiazepines attenuate single unit activity in the locus coeruleus. Life Sci. 1980 Dec 8;27(23):2231–2236. [PubMed]
  • Study RE, Barker JL. Cellular mechanisms of benzodiazepine action. JAMA. 1982 Apr 16;247(15):2147–2151. [PubMed]
  • Möhler H, Okada T. Properties of 3H-diazepam binding to benzodiazepine receptors in rat cerebral cortex. Life Sci. 1977 Jun 15;20(12):2101–2110. [PubMed]
  • Möhler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science. 1977 Nov 25;198(4319):849–851. [PubMed]
  • Chang RS, Snyder SH. Benzodiazepine receptors: labeling in intact animals with [3H] flunitrazepam. Eur J Pharmacol. 1978 Mar 15;48(2):213–218. [PubMed]
  • Braestrup C, Squires RF. Pharmacological characterization of benzodiazepine receptors in the brain. Eur J Pharmacol. 1978 Apr 1;48(3):263–270. [PubMed]
  • Möhler H, Richards JG, Wu JY. Autoradiographic localization of benzodiazepine receptors in immunocytochemically identified gamma-aminobutyrergic synapses. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1935–1938. [PubMed]
  • Unnerstall JR, Kuhar MJ, Niehoff DL, Palacios JM. Benzodiazepine receptors are coupled to a subpopulation of gamma-aminobutyric acid (GABA) receptors: evidence from a quantitative autoradiographic study. J Pharmacol Exp Ther. 1981 Sep;218(3):797–804. [PubMed]
  • Robertson HA. The benzodiazepine receptor: the pharmacology of emotion. Can J Neurol Sci. 1980 Aug;7(3):243–245. [PubMed]
  • Asano T, Sakakibara J, Ogasawara N. Molecular sizes of photolabeled GABA and benzodiazepine receptor proteins are identical. FEBS Lett. 1983 Jan 24;151(2):277–280. [PubMed]
  • Möhler H, Okada T. Properties of 3H-diazepam binding to benzodiazepine receptors in rat cerebral cortex. Life Sci. 1977 Jun 15;20(12):2101–2110. [PubMed]
  • Braestrup C, Squires RF. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3805–3809. [PubMed]
  • Olsen RW. GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem. 1981 Jul;37(1):1–13. [PubMed]
  • Guidotti A, Toffano G, Costa E. An endogenous protein modulates the affinity of GABA and benzodiazepine receptors in rat brain. Nature. 1978 Oct 12;275(5680):553–555. [PubMed]
  • Marangos PJ, Martino AM. Studies on the relationship of gamma-aminobutyric acid-stimulated diazepam binding and the gamma-aminobutyric acid receptor. Mol Pharmacol. 1981 Jul;20(1):16–21. [PubMed]
  • Tallman JF, Thomas JW, Gallager DW. GABAergic modulation of benzodiazepine binding site sensitivity. Nature. 1978 Jul 27;274(5669):383–385. [PubMed]
  • Olsen RW, Ticku MK, Miller T. Dihydropicrotoxinin binding to crayfish muscle sites possibly related to gamma-aminobutyric acid receptor-ionophores. Mol Pharmacol. 1978 May;14(3):381–390. [PubMed]
  • Olsen RW, Ticku MK, Van Ness PC, Greenlee D. Effects of drugs on gamma-aminobutyric acid receptors, uptake, release and synthesis in vitro. Brain Res. 1978 Jan 13;139(2):277–294. [PubMed]
  • Hunt WA. The effect of ethanol on GABAergic transmission. Neurosci Biobehav Rev. 1983 Spring;7(1):87–95. [PubMed]
  • Möhler H, Richards JG. Agonist and antagonist benzodiazepine receptor interaction in vitro. Nature. 1981 Dec 24;294(5843):763–765. [PubMed]
  • O'Brien RA, Schlosser W, Spirt NM, Franco S, Horst WD, Polc P, Bonetti EP. Antagonism of benzodiazepine receptors by beta carbolines. Life Sci. 1981 Jul 6;29(1):75–82. [PubMed]
  • Czernik AJ, Petrack B, Kalinsky HJ, Psychoyos S, Cash WD, Tsai C, Rinehart RK, Granat FR, Lovell RA, Brundish DE, et al. CGS 8216: receptor binding characteristics of a potent benzodiazepine antagonist. Life Sci. 1982 Jan 25;30(4):363–372. [PubMed]
  • Bonetti EP, Pieri L, Cumin R, Schaffner R, Pieri M, Gamzu ER, Müller RK, Haefely W. Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects. Psychopharmacology (Berl) 1982;78(1):8–18. [PubMed]
  • Darragh A, Lambe R, Scully M, Brick I, O'Boyle C, Downe WW. Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15-1788. Lancet. 1981 Jul 4;2(8236):8–10. [PubMed]
  • Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. [PubMed]
  • Braestrup C, Nielsen M, Olsen CE. Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2288–2292. [PubMed]
  • Braestrup C, Nielsen M. GABA reduces binding of 3H-methyl beta-carboline-3-carboxylate to brain benzodiazepine receptors. Nature. 1981 Dec 3;294(5840):472–474. [PubMed]
  • Braestrup C, Schmiechen R, Neef G, Nielsen M, Petersen EN. Interaction of convulsive ligands with benzodiazepine receptors. Science. 1982 Jun 11;216(4551):1241–1243. [PubMed]
  • Fujimoto M, Kawasaki K, Matsushita A, Okabayashi T. Ethyl beta-carboline-3-carboxylate reverses the diazepam effect on cerebellar cyclic GMP. Eur J Pharmacol. 1982 May 21;80(2-3):259–262. [PubMed]
  • Ninan PT, Insel TM, Cohen RM, Cook JM, Skolnick P, Paul SM. Benzodiazepine receptor-mediated experimental "anxiety" in primates. Science. 1982 Dec 24;218(4579):1332–1334. [PubMed]
  • Bowling AC, DeLorenzo RJ. Micromolar affinity benzodiazepine receptors: identification and characterization in central nervous system. Science. 1982 Jun 11;216(4551):1247–1250. [PubMed]
  • Squires RF, Benson DI, Braestrup C, Coupet J, Klepner CA, Myers V, Beer B. Some properties of brain specific benzodiazepine receptors: new evidence for multiple receptors. Pharmacol Biochem Behav. 1979 May;10(5):825–830. [PubMed]
  • Braestrup C, Nielsen M. [3H]Propyl beta-carboline-3-carboxylate as a selective radioligand for the BZ1 benzodiazepine receptor subclass. J Neurochem. 1981 Aug;37(2):333–341. [PubMed]
  • Braestrup C, Nielsen M, Krogsgaard-Larsen P, Falch E. Two or more conformations of benzodiazepine receptors depending on GABA receptors and other variables. Adv Biochem Psychopharmacol. 1980;21:301–312. [PubMed]
  • Nielsen M, Braestrup C. Ethyl beta-carboline-3-carboxylate shows differential benzodiazepine receptor interaction. Nature. 1980 Aug 7;286(5773):606–607. [PubMed]
  • Sieghart W, Karobath M. Molecular heterogeneity of benzodiazepine receptors. Nature. 1980 Jul 17;286(5770):285–287. [PubMed]
  • Chiu TH, Dryden DM, Rosenberg HC. Kinetics of [3H]flunitrazepam binding to membrane-bound benzodiazepine receptors. Mol Pharmacol. 1982 Jan;21(1):57–65. [PubMed]
  • Gee KW, Yamamura HI. Regional heterogeneity of benzodiazepine receptors at 37 degrees C: an in vitro study in various regions of the rat brain. Life Sci. 1982 Nov 1;31(18):1939–1945. [PubMed]
  • Richards JG, Möhler H. Benzodiazepine receptors. Neuropharmacology. 1984 Feb;23(2B):233–242. [PubMed]

Articles from Anesthesia Progress are provided here courtesy of American Dental Society of Anesthesiology