Hepatic Encephalopathy, GABA-ergic Neurotransmission and Benzodiazepine Receptor Ligands

  • E. Anthony Jones
  • Anthony S. Basile
  • Phil Skolnick
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 272)


Evidence compatible with increased GABAergic tone contributing to the manifestations of hepatic encephalopathy (HE) in animal models of fulminant hepatic failure (FHF) includes: (i) increased resistance to drugs which induce seizures by reducing GABAergic tone;(ii) abnormalities of visual evoked responses (VERs) which resemble those induced by drugs which augment GABAergic tone; (iii) increased sensitivity of CNS neurons to a GABA agonist; and (iv) ameliorations of the encephalopathy induced by a GABA receptor antagonist.

Evidence compatible with a benzodiazepine (BZ) receptor ligand with agonist properties contributing to increased GABA-ergic tone in animal models of FHF includes: (i) abnormalities of VERs which resemble those in BZ agonist-induced coma; (ii) increased sensitivity of CNS neurons to a BZ receptor agonist; (iii) excitation of CNS neurons induced by BZ receptor antagonists; (iv) reversal of the increased sensitivity of CNS neurons to a GABA agonist by a BZ receptor antagonist; (v) presence of a ligand(s) in brain which displaces a radiolabeled ligand from BZ receptors; and (vi) increased affinity of this ligand(s) for BZ receptors in the presence of GABA (“positive GABA shift”).


Hepatic Encephalopathy Rabbit Model Chloride Channel Fulminant Hepatic Failure Hepatic Coma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Schafer DF, Fowler JM, Brody LE, Jones EA. Hepatic coma and inhibitory neurotransmission: The enteric bacterial flora as a source of γ-aminobutyric acid. Gastroenterology 1980; 79: 1052.Google Scholar
  2. 2.
    Schafer DF, Jones EA. Hepatic encephalopathy and the γ-aminobutyric acid neurotransmitter system. Lancet 1982; i: 18–20.CrossRefGoogle Scholar
  3. 3.
    Schafer DF, Pappas SC, Brody LE, “et al”. Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas. Gastroenterology 1984; 86: 540–545.PubMedGoogle Scholar
  4. 4.
    Schafer DF, Brody LE, Jones EA. Visual evoked potentials: An objective measurement of hepatic encephalopathy in the rabbit. Gastroenterology 1979; 77: A38 (abstr).Google Scholar
  5. 5.
    Bassett ML, Mullen KD, Skolnick P, Jones EA. Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA/benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 1987; 93: 1069–1077.PubMedGoogle Scholar
  6. 6.
    Chiappa KH, Ropper AH. Evoked potentials in clinical medicine. N. Engl. J. Med 1982; 306: 1140–1147.PubMedCrossRefGoogle Scholar
  7. 7.
    Zemon V, Kaplan E, Katloff F. Bicuculline enhances a negative component and diminishes a positive component of the visual evoked cortical potential in the cat. Proc. Natl. Acad. Sci. USA 1980; 77: 7476–7478.PubMedCrossRefGoogle Scholar
  8. 8.
    Nakayama K. The relationship of visual evoked potentials to cortical physiology. Ann. NY Acad. Sci. 1982; 388: 21–36.PubMedCrossRefGoogle Scholar
  9. 9.
    Dyer RS, Jensen KF, Boyer WK. Focal lesion of visual cortex: effects on visual evoked potentials in rats. Exp. Neurol. 1987; 95: 100–115.PubMedCrossRefGoogle Scholar
  10. 10.
    Blitzer BL, Waggoner JG, Jones EA, “et al”. A model of fulminant hepatic failure in the rabbit. Gastroenterology 1978; 74: 664–671.PubMedGoogle Scholar
  11. 11.
    Study RE, Barker JL. Diazepam and (−)-pentobarbital : Fluctuation analysis reveals different mechanisms for potentiation of γ-aminobutyric acid responses in cultured neurons. Proc. Natl. Acad. Sci. USA 1981; 78: 7180–7184.PubMedCrossRefGoogle Scholar
  12. 12.
    Skolnick P, Moncada V, Barker JL, “et al”. Pentobarbital: Dual actions to increase brain benzodiazepine receptor affinity. Science 1981; 211: 1448–1450.PubMedCrossRefGoogle Scholar
  13. 13.
    Olsen RW. Drug interactions at the GABA receptor-ionophore complex. Ann Rev. Pharmacol. Toxicol. 1982; 22:245– 277.CrossRefGoogle Scholar
  14. 14.
    McGeer PL, Eccles JC, McGeer EG. Molecular Neurobiology of Mammalian Brain. Plenum Press, New York, 1979, 225.Google Scholar
  15. 15.
    Jung MJ, Lippert B, Metcalf BW. Gamma-vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem. 1977; 29: 797–802.PubMedCrossRefGoogle Scholar
  16. 16.
    Hammond EJ, Wilder BJ. Gamma-vinyl GABA: a new antiepileptic drug. Clin Neuropharmacol 1985; 8: 1–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Jones DB, Mullen KD, Roessle M, “et al”. Hepatic encephalopathy: Application of visual evoked responses to test hypotheses of its pathogenesis in rats. J. Hepatol. 1987; 4: 118–126.PubMedCrossRefGoogle Scholar
  18. 18.
    Zeneroli ML, Penne A, Parrinello G, “et al”. Comparative evaluation of visual evoked potentials in experimental hepatic encephalopathy and in pharmacologically induced coma-like states in rat. Life Sci. 1981; 28: 1507–1515.PubMedCrossRefGoogle Scholar
  19. 19.
    Zeneroli ML, Ventura E, Baraldi M, “et al”. Visual evoked potentials in encephalopathy induced by galactosamine, ammonia, dimethyldisulphide and octanoic acid. Hepatology 1982; 2: 532–538.PubMedCrossRefGoogle Scholar
  20. 20.
    Pappas SC, Ferenci P, Schafer DF, “et al”. Visual evoked potentials in a rabbit model of hepatic encephalopathy. II. Comparison of hyperammonemic encephalopathy, postictal coma and coma induced by synergistic neurotoxins. Gastroenterology 1984; 86: 546–551.PubMedGoogle Scholar
  21. 21.
    Skolnick P, Paul SM. The benzodiazepine/GABA receptor chloride channel complex. ISI Atlas of Science: Pharmacology 1988; 2: 19–22.Google Scholar
  22. 22.
    Roberts E: The establishment of GABA as a neurotransmitter. In: GABA and Benzodiazepine Receptors. Volume 1. Squires R. (ed). CRC Press, Boca Raton, FL, 1988, 1–22.Google Scholar
  23. 23.
    Hamill OP, Bormann J, Sakmann B. Activation of multiple-conductance state chloride channels in spinal neurones by glycine and GABA. Nature 1983; 305: 805–808.PubMedCrossRefGoogle Scholar
  24. 24.
    Bormann J, Hamill OP, Sakmann B. Mechanism of anion permeation through channels gated by glycine and γ -aminobutyric acid in mouse cultured spinal neurones. J. Physiol. 1987; 385: 243–286.PubMedGoogle Scholar
  25. 25.
    Braestrup C, Nielsen M. Benzodiazepine receptors. In: Handbook of Psychopharmacology. Volume 17. Iversen LL, Iversen SD, Snyder SH, (Eds) Plenum Press, New York: 1983, 285–384.Google Scholar
  26. 26.
    Haefely W, Polc P. Physiology of GABA enhancement by benzodiazepines and barbiturates. In: Benzodiazepine-GABA Receptors and Chloride Channels: Structure and Functional Properties. Olsen RW, Venter JC, (Eds) Alan R. Liss, New York, 1986, 97–133.Google Scholar
  27. 27.
    Mohler H, Richards JG. The benzodiazepine receptor: a pharmacologic control element of brain function. Eur. J. Anaesthesiol. Suppl. 1988; 2: 15–24.Google Scholar
  28. 28.
    Ferreira MR, Gammal SH, Jones EA. Hepatic encephalopathy (HE): Evidence of increased GABA-mediated neurotransmission in a rat model of fulminant hepatic failure (FHF). Gastroenterology 1988; 94: A516.Google Scholar
  29. 29.
    Carlsson A. Fonnum F, Malthe-Sorrenson D. “et al”, Effect of the convulsive agent 3, mercaptopropionic acid on the levels of GABA, other amino acids and glutamate decarboxylase in different regions of the rat brain. Biochem. Pharmacol. 1974; 23: 352–361.Google Scholar
  30. 30.
    Basile AS, Gammal SH, Mullen KD, “et al”. Differential responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine receptor ligands in an animal model of hepatic encephalopathy. J. Neurosci. 1988; 8: 2414–2421.PubMedGoogle Scholar
  31. 31.
    Baraldi M, Zeneroli ML. Experimental hepatic encephalopathy: changes in the binding of γ-aminobutyric acid. Science 1982; 216: 427–429.PubMedCrossRefGoogle Scholar
  32. 32.
    Schafer DF, Fowler JM, Munson PJ, “et al”. Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. J. Lab. Clin. Med. 1983; 102; 870–880.PubMedGoogle Scholar
  33. 33.
    Maddison JE, Dodd PR, Morrison M, “et al”. Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy. Hepatology 1987; 7: 621–628.PubMedCrossRefGoogle Scholar
  34. 34.
    Roy S, Pomier-Layrargues G, Butterworth RF, “et al”. Hepatic encephalopathy in cirrhotic and portacaval shunt ed dogs: lack of changes in brain GABA uptake, brain GABA levels, brain glutamic acid decarboxylase activity and brain postsynaptic GABA receptors. Hepatology 1988; 8: 845–849PubMedCrossRefGoogle Scholar
  35. 35.
    Rossle M, Deckert J, Jones EA. Autoradiographic analysis of GABA-benzodiazepine receptors in an animal model of acute hepatic encephalopathy. Hepatology 1989; 10: 143–147.PubMedCrossRefGoogle Scholar
  36. 36.
    Zimmerman C, Ferenci P, Pifl C, “et al”. Hepatic encephalopathy in thioacetamide-induced acute liver failure in rats. Characterization of an improved model and study of amino acid-ergic neurotransmission. Hepatology 1989; 9: 594–601.CrossRefGoogle Scholar
  37. 37.
    Butterworth RF, Lavoie J, Giguere JF, Pomier-Layrargues G. Affinities and densities of high affinity 3H-muscimol (GABAA) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 1988; 8: 1084–1088.PubMedCrossRefGoogle Scholar
  38. 38.
    Rossle M, Mullen KD, Jones EA. Cortical benzodiazepine receptor binding in a rabbit model of hepatic encephalopathy: The effect of Triton X-100 on receptor solubilization. Metabolic Brain Disease 1989; 4: 203–212.PubMedCrossRefGoogle Scholar
  39. 39.
    Jones EA, Skolnick P. Benzodiazepine receptor ligands and the syndrome of hepatic encephalopathy. In: Progress in Liver Diseases, volume IX. Popper H, Schaffner F (Eds.) W.B. Saunders, Philadelphia 1990; 345–370.Google Scholar
  40. 40.
    Bassett ML, Mullen KD, Scholz B, “et al”: Increased brain uptake of GABA in a rabbit model of hepatic encephalopathy. Gastroenterology 1990; 98: 747-757.PubMedGoogle Scholar
  41. 41.
    Paul SM, Marangos PJ, Skolnick P. The benzodiazepine-GABA-chloride ionophore receptor complex. Common site of minor tranquillizer action. Biol. Psych. 1981; 16: 213–229.Google Scholar
  42. 42.
    Squires RF. Benzodiazepine receptors, In: Handbook of Neurochemistry, 2nd ed. Volume 6. Lajtha A. (Ed.) Plenum, New York 1984; 261–306.Google Scholar
  43. 43.
    Mullen KD, Martin JV, Mendelson WB, “et al”. Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? Lancet 1988; i: 457–459.CrossRefGoogle Scholar
  44. 44.
    Hunkeler W, Mohler H, Pieri L, “et al”. Selective antagonists of benzodiazepines. Nature 1981; 290: 514–516.PubMedCrossRefGoogle Scholar
  45. 45.
    Bonetti E, Pieri L, Cumin R, “et al”. Benzodiazepine antagonist Ro 15–1788: Neurological and behavioral effects. Psychopharmacology 1982; 78: 8–18.PubMedCrossRefGoogle Scholar
  46. 46.
    Haefely W. Antagonists of benzodiazepines: functional aspects. In: Benzodiazepine Recognition Site Ligands: Biochemistry and Pharmacology. Biggio G, Costa E (Eds.). Raven Press, New York, 1983; 73–93.Google Scholar
  47. 47.
    Geller D, Gammal SH, Mullen KD “et al”. An improved rat model of hepatic encephalopathy due to fulminant hepatic failure. The importance of supportive therapy. In: Advances in Ammonia Metabolism and Hepatic Encephalopathy. Soeters PB, Wilson JHP, Meijer AJ, Holm E. (Eds), Excerpta Medica, Amsterdam. 1988; 213–217.Google Scholar
  48. 48.
    Gammal SH, Basile AS, Geller D, Skolnick P, Jones EA. Reversal of the behavioral and electrophysiologic abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands.Hepatology 1990;11:371–378.PubMedCrossRefGoogle Scholar
  49. 49.
    Mullen KD, Martin JV, Mendelson WB, “et al”: Evidence for the presence of a benzodiazepine receptor binding substance in cerebrospinal fluid of a rabbit model of he patic encephalpathy. Metabolic Brain Disease 1989; 4.Google Scholar
  50. 50.
    Basile AS, Ostrowski NL, Gammal SH, “et al”: The GABAA receptor complex in hepatic encephalopathy: Autoradiographic evidence for the presence of elevated levels of a benzodiazepine receptor ligand. Neuropsychopharmacology 1990; 3: 61–67.PubMedGoogle Scholar
  51. 51.
    Basile AS, Gammal SH, Jones EA, Skolnick P. GABAA receptor complex in an experimental model of hepatic encephalopathy: Evidence for elevated levels of an endogenous benzodiazepine receptor ligand. J. Neurochem 1989; 53: 1057–1063.PubMedCrossRefGoogle Scholar
  52. 52.
    Tallman JF. Agonist and antagonist interactions at benzodiazepine receptors. In: Benzodiazepine Recognition Site Ligands. Biochemistry and Pharmacology. Biggio G, Costa E, (Eds). Raven Press, New York, 1983; 21–28.Google Scholar
  53. 53.
    Karobath M, Supavilai P, Borea PA. Distinction of benzodiazepine receptor agonists and inverse agonists by binding studies in vitro. In: Benzodiazepine Recognition Site Ligands: Biochemistry and Pharmacology. Biggio G, Costa E (Eds). Raven Press, New York, 1983, 37–46.Google Scholar
  54. 54.
    Braestrup C, Schmiechen R, Neef G, “et al”: Interaction of convulsive ligands with benzodiazepine receptors. Science, 1982; 216: 1241–1243.PubMedCrossRefGoogle Scholar
  55. 55.
    Wildmann J, Mohler H, Vetter W, “et al”: Diazepam and N-desmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J. Neural Trans., 1987; 70: 383–398.CrossRefGoogle Scholar
  56. 56.
    Wildmann J, Vetter W, Ranalder UB, “et al”: Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato. Biochem. Pharmacol. 1988; 37: 3549–3559.PubMedCrossRefGoogle Scholar
  57. 57.
    Remers W, Malbilia M, Hopfinger A. Conformation of complexes between pyrrolo [1,4] benzodiazepines and DNA sequences. J. Med. Chem. 1986; 29: 2942–2953.Google Scholar
  58. 58.
    Gerlach M, Schwelle N, Lerbs W, Luckner M. Enzymatic synthesis of cyclopeptine intermediates in Penicillium cyclopium. Phytochem 1985; 24: 1935–1939.CrossRefGoogle Scholar
  59. 59.
    Leingruber W, Batcho AD, Schenker F. The structure of anthramycin. J. Am. Chem. Soc. 1965; 87: 5793– 5795.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • E. Anthony Jones
    • 1
  • Anthony S. Basile
    • 1
  • Phil Skolnick
    • 1
  1. 1.Liver Diseases Section Digestive Diseases Branch and Laboratory of Neuroscience National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA

Personalised recommendations