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Benzodiazepines in perspective (II): The GABAA-Benzodiazepine Receptor Ligands

Published online by Cambridge University Press:  18 September 2015

P.J.L. Vermeulen  and
F.G. Zitman
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Summary

A huge number of natural and synthetic compounds modulate the function of the γ-aminobutyric acid type A receptor (GABAA-R) by interacting with several allosteric binding sites which may differ in the various GABAA-R subtypes. The benzodiazepine receptor (BDZ-R) is the most intensively studied allosteric site. It is the first allosteric modulatory site on a neurotransmitter receptor that has been found to mediate two opposite functions: facilitation and depression of GABAA-R function. The effects of BDZ-R ligands on behavior range from agonistic (anxiolytic, anticonvulsant, myore-laxant/ataxic and hypno-sedative effects) to inverse-agonistic (anxiety and panic, hypervigilance and convulsions). Of particular interest for the future are BDZ-R partial agonists, as they lack several of the undesired properties of classic full agonists. Furthermore the GABAA-R system shows a high plasticity. This polymorphism raises the possibility that ligands selective for distinct subtypes of BDZ-R may emerge as useful drugs. In both cases the possibility exists of achieving very subtle manipulations of GABAA-R function by using allosteric modulators.

Keywords

GABAA receptorsbenzodiazepine receptorsallosteric modulationligandsagonistinverse-agonistcentral nervous system
Type
Articles
Information
Acta Neuropsychiatrica , Volume 12 , Issue 1 , March 2000 , pp. 9 - 18
Copyright
Copyright © Scandinavian College of Neuropsychopharmacology 2000

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References

Literatuur

1.Vermeulen, PJL, Zitman, FG. Benzodiazepinen in perspectief (I): De GABA.-benzodiazepine-receptor. Acta Neuropsychiatrica 1996;3:48–5CrossRefGoogle Scholar
2.Burgen, A. Introduction. In: Burgen, A, Barnard, EA, eds. Receptor Subunits and Complexes. Cambridge, Cambridge University Press, 1992, pp 1–7.Google Scholar
3.Taylor, P, Insel, PA. Molecular basis of pharmacologic selectivity. In: Pratt, WB, Taylor, P, eds. Principles of Drug Action. 3rd ed. New York, Churchill Livingstone, 1990, pp 1–102.Google Scholar
4.Barnard, EA. The Molecular Biology of GABAA Receptors and their Structural Determinants. In: Biggio, G, Sanna, E, Serra, M, Costa, E, eds. GABAA Receptors and Anxiety. 48th ed. New York, Raven Press, 1995, pp 1–16.Google Scholar
5.Haefely, WE. Allosteric modulation of the GABAA receptor channel: a mechanism for interaction with a multitude of central nervous system functions. In: Mohler, H, Da Prada, M, eds. The Challenge of Neuropharmacology: A Tribute to the Memory of Willy Haefely. Basel, Roche, 1994, pp 15–39.Google Scholar
6.Stephens, DN. Introduction. In: Stephens, DN, ed. Anxiolytic Beta-Carbolines: From Molecular Biology to the Clinic. Berlin, Springer-Verlag, 1993, pp 1–8.CrossRefGoogle Scholar
7.Costa, E, Puia, G, Giusti, P, et al.Mechanistic and pharmacological implications in the partial allosteric modulation of GABAA receptors by imidazenil. In: Mohler, H, Da Prada, M, eds. The Challenge of Neuropharmacology: A Tribute to the Memory of Willy Haefely. Basel, Roche, 1994, pp 15–39.Google Scholar
8.Macdonald, RL, Rogers, CJ, Twyman, RE. Kinetic properties of the GABAA receptor main conductance state of mouse spinal cord neurones in culture. J Physiol 1989;410:479–499.CrossRefGoogle ScholarPubMed
9.Pribilla, I, Neuhaus, R, Huba, R, et al.Abecarnil is a full agonist at some, and a partial agonist at other recombinant G ABAA receptor subtypes. In: Stephens, DN, ed. Anxiolytic Beta-Carbohnes: From Molecular Biology to the Clinic. Berlin, Springer-Verlag, 1993, pp 50–62.Google Scholar
10.Gibbs, TT, Mierlak, D, Geyenes, M, Celentano, JJ, Farb, DH. Functional and structural correlates of GABA receptor modulation. In: Biggio, G, Costa, E, eds. Chloride Channels and their Modulation by Neurotransmitters and Drugs. New York, Raven Press, 1988, pp 95–107.Google Scholar
11.Gardner, CR, Tully, WR, Hedgecock, CJR. The rapidly expanding range of neuronal benzodiazepine receptor ligands. Prog Neurobiol 1993;40:1–61.CrossRefGoogle ScholarPubMed
12.Langer, SZ, Arbilla, S, Scatton, B, Niddam, R, Dubois, A. Receptors involved in the mechanism of action of Zolpidem. In: Bartholini, G, Friedmann, JC, Langer, SZ, Morselli, PL, Wich, A, eds. Imidazopyridines in Sleep Disorders: A Novel Experimental and Therapeutic Approach. New York, Raven Press, 1988, pp 55–70.Google Scholar
13.Haefely, W. Benzodiazepine receptor and ligands: Structural and functional differences. In: Hindmarch, I, Beaumont, G, Brandon, S, Leonard, BE, eds. Benzodiazepines: Current Concepts. Biological, Clinical and Social Perspectives. Chichester, John Wiley and Sons, 1990, pp 1–18.Google Scholar
14.Sanger, DJ, Cohen, C. Fear and anxiety induced by benzodiazepine receptor inverse agonists. In: Sarter, M, Nutt, DJ, Lister, RG, eds. Benzodiazepine Inverse Agonists. New York, Wiley-Liss, 1995, pp 185–213.Google Scholar
15.Sarter, M, McGaughy, J, Holley, LA, Dudchenko, P. Behavioral facilitation and cognition enhancement. In: Sarter, M, Nutt, DJ, Lister, RG, eds. Benzodiazepine Inverse Agonists. New York, Wiley-Liss, 1995, pp 213–243.Google Scholar
16.Sarter, M, Nutt, DJ. Inverse agonists as therapeutic drugs. In: Sarter, M, Nutt, DJ, Lister, RG, eds. Benzodiazepine Inverse Agonists. New York, Wiley-Liss, 1995, pp 271–281.Google Scholar
17.Schmiechen, R, Seidelmann, D, Huth, A. beta-Carboline-3-carbolic acid ethyl ester: A lead for new psychotropic draga. In: Stephens, DN, ed. Anxiolytic Beta-CarboUnes: From Molecular Biology to the Clinic. Berlin, Springer-Verlag, 1993, pp 7–16.Google Scholar
18.Miller, JA. Evidence for a modified model of agonist and inverse agonist actions at the GABA .receptor. In: Sarter, M, Nutt, DJ, Lister, RG, eds. Benzodiazepine Inverse Agonists. New York, Wiley-Liss, 1995, pp 25–41.Google Scholar
19.Nutt, DJ. Benzodiazepine dependence: New insights from basic research. In: Hindmarch, I, Beaumont, G, Brandon, S, Leonard, BE, eds. Benzodiazepines: Current Concepts. Biological, Clinical and Social Perspectives. Chichester, John Wiley and Sons, 1990, pp 19–42.Google Scholar
20.Richards, G, Schoch, P, Haefely, W. Benzodiazepine receptors: New vistas. In: Mohler, H, Da Prada, M, eds. The Challenge of Neuropharmacology: A tribute to the Memory of Willy Haefefr. Basel, Roche, 1994, pp 62–75.Google Scholar
21.Mihic, SJ, Sanna, E, Whiting, PJ, Harris, RA. Pharmacology of Recombinant GABAA Receptors. In: Biggio, G, Sanna, E, Serra, M, Costa, E, eds. GABAA Receptors and Anxiety: From Neurcbiology to Treatment. 48th ed. New York, Raven Press, 1995, pp 17–40.Google Scholar
22.Sieghart, W. GABAA receptors: Ligand-gated CI- ion channels modulated by multiple drug-binding sites. Trends Pharmacol Sci 1992;13:446–450.CrossRefGoogle Scholar
23.Bristow, DR, Moratalla, R, Martin, IL. Flunitrazepam increases the affinity of the GABAA receptor in cryostatcut rat brain sections. Eur J Pharmacol 1990;184:339–440.CrossRefGoogle ScholarPubMed
24.McCabe, RF, Wamsley, JK, Yeznita, JP, Olsen, RW. A novel GABAA antagonist [3H]SR 95531: microscopic analysis of binding in the rat brain and allosteric modulation by several benzodiazepine and barbiturate receptor ligands. Synapse 1988;2:163–173.CrossRefGoogle ScholarPubMed
25.Study, RE, Barker, JL. Diazepam and pentobarbitahfluctuation analysis reveals different mechanisms for potentiation of gamma-ami-nobutyric acid responses in cultured chick neurons. Proc Natl Acad Sci USA 1981;78:7180–7184.CrossRefGoogle Scholar
26.Haefely, W, Pole, P. Physiology of GABA enhancement by benzodiazepines and barbiturates. In: Olsen, RW, Venter, JC, eds. Benzo-diazepine/GABA Receptors and Chloride Channels. New York, Alan R Liss, 1986, pp 195–226.Google Scholar
27.Choi, DW, Farb, DH, Fischbach, GD. Chlordiazepoxide selectively potentiates GABA conductance of spinal cord and sensory neurons in cell culture. J Neurophysiol 1981;45:621–631.CrossRefGoogle ScholarPubMed
28.Puia, G, Vicini, S, Seeburg, PH, Costa, E. Influence of recombinant gamma-aminobutyric acidA-receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated CI- currents. Mol Pharmacol 1991;39:691–696.Google Scholar
29.Petke, JD, Im, HK, Im, WB, et al.Characterization of functional interactions of imidazoquinoxaline derivatives with benzodiazepine-gamma-aminobutyric acidA receptors. Mol Pharmacol 1992;42:294–301.Google ScholarPubMed
30.Pritchett, DB, Luddens, H, Seeburg, PH. Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 1989;245:1389–1392.CrossRefGoogle ScholarPubMed
31.Shivers, BD, Killisch, I, Sprengel, R, et al.Twonovel GABAA. receptor subunits exist in distinct neuronal subpopulations. Neuron 1989;3:327–337.CrossRefGoogle Scholar
32.Pritchett, DB, Sontheimer, H, Shivers, BD, et al.Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 1989;338:582–585.CrossRefGoogle ScholarPubMed
33.Gunther, U, Benson, J, Benke, D, et al.Benzodiazepine-insensitive mice generated by targeted disruption of the gamma(2) subunit gene of gamma- aminobutyric acid type A receptors. Proc Natl Acad Sci USA 1995;92:7749–7753.CrossRefGoogle ScholarPubMed
34.Sigei, E, Baur, R, Trube, G, Mohler, H, Malherbe, P. The effect of sub-unit composition of rat brain GABAA receptors on channel function. Neuron 1990;5:703–711.Google Scholar
35.Nielsen, M, Gredal, O, Braestrup, C. Some properties of 3H-diazepam displacing activity from human urine. Life Sci 1979;25:679–686.CrossRefGoogle ScholarPubMed
36.Braestrup, C, Nielsen, M, Olsen, CE. Urinary and brain beta-carbo-line-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci USA 1980;77:2288–2292.CrossRefGoogle ScholarPubMed
37.Novas, ML, Wolfman, C, Medina, JH, de Robertis, E. Proconvulsant and ‘anxiogenic’ effects of n-butyl beta carboline-3-carboxylate, an endogenous benzodiazepine binding inhibitor from brain. Pharmacol Biochem Behav 1988;30:331–336.CrossRefGoogle ScholarPubMed
38.de Robertis, E, Pena, C, Palandini, AC, Medina, JH. New developments on the search for endogenous ligands of central benzodiazepine receptors. Neurochem Int 1988;13:1–12.CrossRefGoogle Scholar
39.Cowen, PJ, Green, AR, Nutt, DJ. Ethyl beta-carboline carboxylate lowers seizure threshold and antagonizes flurazepam-induced sedation in rats. Nature 1981;290:54–55.CrossRefGoogle ScholarPubMed
40.File, SE, Lister, RG, Nutt, DJ. The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 1982;21:1033–1037.CrossRefGoogle ScholarPubMed
41.Braestrup, C, Schmiechen, R, Neef, G, Nielsen, M, Petersen, EN. Interaction of convulsive ligands with benzodiazepine receptors. Science 1982;216:1241–1243.CrossRefGoogle ScholarPubMed
42.Dorow, R, Horowski, R, Paschelke, G, Amin, M. Severe anxiety induced by FG 7142, a beta-carboline ligand for benzodiazepine receptors. Lancet 1983;2:98–99.CrossRefGoogle ScholarPubMed
43.Dorow, R. FG 7142 and its anxiety-inducing effects in humans. Br J Clin Pharmacol 1987;23:781–782.Google ScholarPubMed
44.Hunkeler, W, Mohler, H, Pieri, L, et al.Selective antagonists of benzodiazepines. Nature 1981;290:514–516.CrossRefGoogle ScholarPubMed
45.Noderer, J, Duka, T, Dorow, R. [Benzodiazepine antagonism by Ro 15-1788: psychometric, hormonal and biophysical parameters] Ben-zodiazepin-Antagonisierung mit RO 15-1788: psychometrische, hormonelle und biophysikalische Parameter. Anaesthesist 1988;37:535–542.Google Scholar
46.Lavie, P, Peled, R, Wollman, M, Zomer, J, Tzischinsky, O. Agonist-like effects of the benzodiazepine receptor antagonist Ro 15-1788. Neuropsychobiology 1987;17:72–76.CrossRefGoogle ScholarPubMed
47.Scollo Lavizzari, G. The clinical anti-convulsant effects of flumazenil, a benzodiazepine antagonist. Eur J Anaesthesiol Suppl 1988;2:129–138.Google ScholarPubMed
48.Sharief, MK, Sander, JWAS, Shorvon, SD. The effect of oral fluma-zenil on interictal epileptic activity - results of a double-blind, placebo-controlled study. Epilepsy Res 1993;15:53–60.CrossRefGoogle ScholarPubMed
49.Buldakova, S, Weiss, M. Electrophysiological evidence for agonist properties of flumazenil, a benzodiazepine receptor antagonist, in rat hippocampus slices. J Neurol Sci 1997;149:121–126.CrossRefGoogle ScholarPubMed
50.Rodgers, RJ, Waters, AJ, Rosenfield, S. Evidence for intrinsic behavioural activity of the benzodiazepine antagonist, R015-1788, in male mice. Pharmacol Biochem Behav 1983;19:895–898.CrossRefGoogle Scholar
51.Higgitt, A, Lader, M, Fonagy, P. The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 1986;89:395–403.CrossRefGoogle ScholarPubMed
52.Woods, SW, Charney, DS, Silver, JM, Krystal, JH, Heninger, GR. Behavioral, biochemical, and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder. Psychiatry Res 1991;36:115–127.CrossRefGoogle Scholar
53.Schopf, J, Laurian, S, Le, PK, Gaillard, JM. Intrinsic activity of the benzodiazepine antagonist Ro 15-1788 in man: An electrophysiological investigation. Pharmacopsychiatry 1984;17:79–83.CrossRefGoogle Scholar
54.Forster, A, Crettenand, G, Klopfenstein, CE, Morel, DR. Absence of agonist effects of high-dose flumazenil on ventilation and psychometric performance in human volunteers. Anesth Analg 1993;77:980–994.CrossRefGoogle ScholarPubMed
55.Darragh, A, Lambe, R, O'Boyle, C, Kenny, M, Brick, I. Absence of central effects in man of the benzodiazepine antagonist RO 15-1788. Psychopharmacology 1983;80:192–195.CrossRefGoogle ScholarPubMed
56.Lupolover, Y, Safran, AB, Desangles, D, et al.Evaluation of visual function in healthy subjects after administration of RO 15-1788. J Clin Pharmacol 1984;27:505–507.Google ScholarPubMed
57.Darragh, A, Lambe, R, Kenny, M, Brick, I. Tolerance of healthy volunteers to intravenous administration of the benzodiazepine antagonist Ro 15-1788. J Clin Pharmacol 1983;24:569–570.Google ScholarPubMed
58.File, SE, Hitchcott, PK. A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena. Psychopharmacology 1990;101:525–532.CrossRefGoogle ScholarPubMed
59.File, SE, Pellow, S. Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 1986;88:1–11.CrossRefGoogle ScholarPubMed
60.Kapczinski, F, Curran, HV, Gray, J, Lader, M. Flumazenil has an anxiolytic effect in simulated stress [published erratum appears in Psychopharmacology (Beri) 1995 Sep;121(2):284]. Psychopharmacology 1994;114:187–189.CrossRefGoogle Scholar
61.Stephens, DN, Turski, L, Jones, GH, Steppuhn, KG, Schneider, HH. Abecarnil: A novel anxiolytic with mixed full agonist/partial agonist properties in animal models of anxiety and sedation. In: Stephens, DN, ed. Anxiolytic Beta-Carbolines: From Molecular Biology to the Clinic. Berlin, Springer-Verlag, 1993, pp 79–96.CrossRefGoogle Scholar
62.Zorumski, CF, Iseberg, KE. Insights into the structure and function of GABA-benzodiazepine receptors: ion channels and psychiatry. Am J Psychiatry 1991;148:162–173.Google ScholarPubMed
63.Petersen, EN, Jensen, LH, Orejer, LH, Honore, J. New perspectives in benzodiazepine receptor pharmacology. Pharmacopsychiatry 1986;19:4–6.CrossRefGoogle Scholar
64.Stephens, DN, Turski, L, Hillman, M, Turner, JD, Schneider, HH, Yamaguchi, M. What are the differences between Abecarnil and conventional benzodiazepine anxiolytics? In: Biggio, G, Concas, A, Costa, E, eds. GABAergic Synaptic Transmission: Molecular, Pharmacological, and Clinical Aspects. 47th ed. New York, Raven Press, 1992, pp 395–407.Google Scholar
65.Martin, JR, Pieri, L, Bonetti, EP, et al.Ro 16-6028: a novel anxiolytic acting as a partial agonist at the benzodiazepine receptor. Pharmacopsychiatry 1988;21:360–402.CrossRefGoogle ScholarPubMed
66.Haefely, W, Facklam, M, Schoch, P, et al.Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders. GABAergic Synaptic Transmission 47 1992;1:1–394.Google Scholar
67.Duka, T, Schutt, B, Krause, W, Dorow, R, McDonald, S, Fichte, K. Human Studies on abecarnil a new beta-carboline anxiolytic - safety, tolerability and preliminary pharmacological profile. Br J Clin Pharmacol 1993;35:386–394.CrossRefGoogle ScholarPubMed
68.Delini-Stula, A. Bretazenil: Clinical experience. Neuroscience Facts 1992;3:72–3.Google Scholar
69.Natolino, F, Zanotti, A, Contarino, A, Lipartiti, M, Giusti, P. Abecarnil, a beta-carboline derivative, does not exhibit anticonvulsant tolerance or withdrawal effects in mice. Naunyn Schmiedebergs Arch Pharmacol 1996;354:612–617.CrossRefGoogle ScholarPubMed
70.Miller, LG, Galpern, WR, Greenblatt, DJ, Lumbin, M, Shader, RI. Chronic benzodiazepine administration. VI. A partial agonist produces behavioral effects without tolerance or receptor alterations. J Pharmacol Exp Ther 1990;254:33–38.Google ScholarPubMed
71.Haigh, JRM, Feely, M. Ro 16-6028, a benzodiazepine receptor partial agonist does not exhibit anticonvulsant tolerance in mice. Eur J Pharmacol 1988 147:283–285.CrossRefGoogle Scholar
72.Moreau, JL, Jenck, F, Pieri, L, Schoch, P, Martin, JR, Haefely, WE. Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028. Eur J Pharmacol 1990;190:69–73.CrossRefGoogle Scholar
73.Sannerud, CA, Ator, NA, Griffiths, RR. Behavioral Pharmacology of Abecarnil in Baboons - Self- Injection, Drug Discrimination and Physical Dependence. Behav Pharmacol 1992;3:507–516.CrossRefGoogle ScholarPubMed
74.Haefely, W. Partial agonists of the benzodiazepine receptor: from animal data to results in patients. Adv Biochem Psychopharmacol 1988;45:275–292.Google ScholarPubMed
75.Sarter, M, Stephens, DN. Disinhibitory properties of beta-carboline antagonists of benzodiazepine receptors: a possible therapeutic approach for senile dementia? Biochem Soc Trans 1989;17:81–83.CrossRefGoogle ScholarPubMed
76.Yasui, M, Kawasaki, K, Matsushita, A, Satoh, M. Benzodiazepine Inverse Agonists Augment Long-Term Potentiation in CA1 and CA3 of Guinea Pig Hippocampal Slices. Neuropharmacology 1993;32:127–131.CrossRefGoogle ScholarPubMed
77.Seabrook, GR, Easter, A, Dawson, GR, Bowery, BJ. Modulation of long-term potentiation in CA1 region of mouse hippocampal brain slices by GABAA receptor benzodiazepine site ligands. Neuropharmacology 1997;36:823–830.CrossRefGoogle ScholarPubMed
78.Deacon, RMJ, Budhram, P, Dowson, D, Galliani, G, Guy, AP, Gardner, CR. Investigation of potential cognition enhancing proprties of RU 33965, a benzodiazepine receptor partial inverse agonist. Psychopharmacology 1990;101:45–46.Google Scholar
79.Venault, P, Chapouthier, G, Simiand, J, Dodd, RH, Rossier, J. Enhancement of performance by methyl beta-carboline-3-carboxylate in learning and memory tasks. Brain Res Bull 1987;19:365–370.CrossRefGoogle ScholarPubMed
80.Martin, JR, Schoch, P, Jenck, F, Moreau, JL, Haefely, WE. Pharmacological Characterization of Benzodiazepine Receptor Ligands with Intrinsic Efficacies Ranging from High to Zero. Psychopharmacology 1993;111:415–422.CrossRefGoogle ScholarPubMed
81.Ducic, I, Puia, G, Vicini, S, Costa, E. Triazolam Is More Efficacious Than Diazepam in a Broad Spectrum of Recombinant GABAA Receptors. Eur J Pharmacol Mol Pharmacol 1993;244:29–35.CrossRefGoogle Scholar
82.Wafford, KA, Whiting, PJ, Kemp, JA. Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant gamma-aminobutyric acid-A receptor subtypes. Mol Pharmacol 1993;43:240–244.Google Scholar
83.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 USA 1992,89:3620–3624.CrossRefGoogle ScholarPubMed
84.Stephens, DN, Schneider, HH, Kehr, W, et al.Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors. J Pharmacol Exp Ther 1990;253:334–343.Google ScholarPubMed
85.Loscher, W, Honack, D, Scherkl, R, Hashem, A, Frey, HH. Pharmacokinetics, anticonvulsant efficacy and adverse effects of the beta-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs. J Pharmacol Exp Ther 1990;255:541–548.Google ScholarPubMed
86.Ozawa, M, Nakada, Y, Sugimachi, K, et al.Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates. Jpn J Pharmacol 1994;64:179–187.CrossRefGoogle ScholarPubMed
87.Pole, P, Bonetti, EP, Pieri, L, et al.Caffeine antagonizes several central effects of diazepam. Life Sci 1981;29:2265–2275.Google Scholar
88.Skolnick, P, Paul, SM. Benzodiazepine receptors in the central nervous system. Int Rev Neurobiol 1982;23:103–140.CrossRefGoogle ScholarPubMed
89.Braestrup, C, Nielsen, M. Discovery of beta-carboline ligands for benzodiazepine receptors. In: Stephens, DN, ed. Anxiolytic Beta-Carbolines: From Molecular Biology to the Clinic. Berlin, Springer-Verlag, 1993, pp 1–6.Google Scholar
90.Marangos, P, Paul, SM, Parma, A, Goodwin, F, Syapin, P, Skolnick, P. Purinergic inhibition of diazepam binding to rat brain. Life Sci 1979;24:851–858.CrossRefGoogle ScholarPubMed
91.Marangos, P, Patel, J, Hirata, F, et al.Inhibition of diazepam binding by tryptophan derivatives including melatonin and its brain metabolite N-acetyl-5-methoxykyurenamine. Life Sci 1981;29:259–267.CrossRefGoogle Scholar
92.Skolnick, P, Marangos, PJ, Paul, SM. Endogenous ligands of the benzodiazepine receptor. In: Malick, JB, Enna, JJ, Yamamura, HI, eds. Anxiolytics: Neurochemical, Behavioral and Clinical Perspectives. New York, Raven Press, 1983.Google Scholar
93.Guidotti, A, Toffano, G, Costa, E. An endogenous protein modulates the affinity of GABA and benzodiazepine receptors in rat brain. Nature 1987;275:553–555.CrossRefGoogle Scholar
94.Massotti, M, Guidotti, A, Costa, E. Characterisation of benzodiaze pine and GABA recognition sites and their endogenous modulators. J Neurosci 1981;1:409–418.CrossRefGoogle Scholar
95.Olsen, RW. GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 1981;37:1–13.CrossRefGoogle ScholarPubMed
96.Sandler, R. The emergence of tribulin. Trends Pharmacol Sci 1982;3:471–472.CrossRefGoogle Scholar
97.Clow, A, Glover, V, Armando, I, Sandler, M. New endogenous benzodiazepine receptor ligand in human urine: identity with endogenous monoamine oxidase inhibitor? Life Sci 1983;33:735–741.CrossRefGoogle ScholarPubMed
98.Bhattacharya, SK, Glover, V, Sandler, M, et al.Raised endogenous monoamine oxidase inhibitor output in post withdrawal alcoholics: effects of 1-dopa and ethanol. Biol Psychiatry 1982;17:687–694.Google Scholar
99.Petursson, H, Bhattacharya, SK, Glover, V, Sandler, M, Lader, MH. Urinary monoamine oxidase inhibitor and benzodiazepine withdrawal. Br J Psychiatry 1982;140:7–10.CrossRefGoogle ScholarPubMed
100.Clow, A, Glover, V, Weg, MW, et al.Urinary catecholamine metabolite and tribulin output during lactate infusion. Br J Psychiatry 1988;152:122–126.CrossRefGoogle ScholarPubMed
101.Davidson, J, Glover, V, Clow, A, Kundler, H, Meador, K, Sandler, M. Tribulin in post-traumatic stress disorder. Psychol Med 1988;4:833–836.CrossRefGoogle Scholar
102.Clow, A, Glover, V, Sandler, M, Tiller, J. Increased urinary tribulin output in generalized anxiety disorder. Psychopharmacology 1988;95:378–380.CrossRefGoogle Scholar
103.Glover, V, Halket, JM, Watkins, PJ, Clow, A, Goodwin, BL, Sandler, M. Isatin: identity with the purified endogenous monoamine oxidase inhibitor tribulin. J Neurochem 1988;51:656–659.CrossRefGoogle ScholarPubMed
104.Glover, V. Trials and tribulations with tribulin. Biog Amine 1993;9:443–451.Google Scholar
105.Bhattacharya, SK, Acharya, SB. Further Investigations on the anxiogenic action of isatin. Biog Amine 1993;9:453–463.Google Scholar
106.Malagon, M, Vaudry, H, Vanstrien, F, Pelletier, G, Gracianavarro, F, Tonon, MC. Ontogeny of diazepam-binding inhibitor-related peptides (endozepines) in the rat brain. Neuroscience ER 1993;57:777–786.Google Scholar
107.Gray, PW, Glaister, D, Seeburg, PH, Guidotti, A, Costa, E. Cloning and expression of cDNA for human diazepam-binding inhibitor, a natural ligand of an allosteric regulatory site of the g-aminobutyric acid type A receptor. Proc Natl Acad Sci USA 1986;83:7547–7551.CrossRefGoogle Scholar
108.Malagon, M, Vallarino, M, Tonon, MC, Vaudry, H. Localization and characterization of diazepam-binding inhibitor (DBI)-like peptides in the brain and pituitary of the trout (Salmo-Gairdneri). Brain Res 1992;576:208–214.CrossRefGoogle ScholarPubMed
109.Ferrero, P, Guidotti, A, Conti-Tronconi, B, Costa, E. A brain octade-caneuropeptide generated by tryptic digestion of BDI (diazepam binding inhibitor) functions as a proconflict ligand of benzodiazepine recognition sites. Neuropharmacology 1984;23:1359–1362.CrossRefGoogle Scholar
110.Ferrero, P, Santi, M, Conti-Tronconi, B, Costa, E, Guidotti, A. Study of an octadecaneuropeptide derived from BDI: biological activity and presence in rat brain. Proc Natl Acad Sci USA 1986;83:827–8231.CrossRefGoogle Scholar
111.Rouetsmih, F, Tonon, MC, Pelletier, G, Vaudry, H. Characterization of Endozepine-Related Peptides in the Central Nervous System and in Peripheral Tissues of the Rat. Peptides 1992;13:1219–1225.CrossRefGoogle ScholarPubMed
112.Knudsen, J, Mandrup, S, Rasmussen, JT, Andreasen, PH, Poulsen, F, Kristiansen, K. The Function of Acyl-CoA-Binding Protein (ACBP)/Diazepam Binding Inhibitor (DBI). Mol Cell Biochem 1993;123:129–138.CrossRefGoogle ScholarPubMed
113.Knudsen, J, Nielsen, M. Diazepam-binding inhibitor: a neuropeptide and/or an acyl-CoA ester binding protein? Biochem J 1990;265:927–929.CrossRefGoogle ScholarPubMed
114.Mukhin, AG, Papadopoulos, V, Costa, E, Krueger, KE. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis. Proc Natl Acad Sci USA 1989;86:9813–9816.CrossRefGoogle ScholarPubMed
115.Chen, Z, Agerberth, B, Geli, K, et al.Isolation and characterization of porcine diazepam binding inhibitor, a polypeptide not only of cerebral occurrence but also common in intestinal tissues and with effects on regulation of insulin release. Eur J Biochem 1988;174:239–245.CrossRefGoogle Scholar
116.Guidotti, A, Forchetti, CM, Corda, MG, Konkel, D, Bennett, CD, Costa, E. Isolation, characterization and purification to homogenie-ty of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci USA 1983;80:3531–3535.CrossRefGoogle ScholarPubMed
117.Guidotti, A, Forchetti, CM, Ebstein, B, Costa, E. Purification and characterization of an endogenous peptide putative effector for the benzodiazepine recognition site. In: Usdin, E, Skolnicck, P, Tallman, D, Greenblatt, D, Paul, SM, eds. Pharmacology of Benzodiazepines. Weinheim, Verlag Chemie, 1983, pp 66–78.Google Scholar
118.Alho, H, Costa, E, Ferrero, P, Fujimoto, M, Cosenza-Murphy, D, Guidotti, A. Diazepam Binding Inhibitor: A neuropeptide located in selected neuronal populations of rat brain. Science 1985;229:179–182.CrossRefGoogle ScholarPubMed
119.Ashmarin, IP, Vakulina, OP, Rozhanets, W, et al.Study of the Seizure Threshold and Increasing Resistance of Rats to Stress After Immunization to Diazepam-Binding Inhibitor Fragment. Bull Exp Biol Med 1992;113:349–352.CrossRefGoogle Scholar
120.Nutt, DJ. The pharmacology of human anxiety. Pharmacol Ther 1990;47:233–266.CrossRefGoogle ScholarPubMed
121.DeRobertis, E, Pena, C, Paladini, AC, et al.New developments in the search for the endogenous ligand(s) of the central benzodiazepine receptors. Neurochem Int 1988;13:1–11.CrossRefGoogle Scholar
122.Ferrarese, C, Appollonio, I, Bianchi, G, et al.Benzodiazepine receptors and diazepam binding inhibitor: a possible link between stress, anxiety and the immune system. Psychoneuroendocrinology 1993;18:3–22.CrossRefGoogle ScholarPubMed
123.Barbaccia, ML, Costa, E, Ferrero, P, et al.Diazepam-binding inhibitor. A brain neuropeptide present in human spinal fluid: studies in depression, schizophrenia, and Alzheimer's disease. Arch Gen Psychiatry 1986;43:1143–1147.CrossRefGoogle ScholarPubMed
124.Payeur, R, Lydiard, RB, Ballenger, JC, Laraia, MT, Fossey, MD, Zealberg, J. CSF diazepam-binding inhibitor concentrations in panic disorder. Biol Psychiatry 1992;32:712–716.CrossRefGoogle ScholarPubMed
125.Kammen, DP van, Guidotti, A, Neylan, T, et al.CSF levels of diazepam-binding inhibitor correlate with REM latency in schizophrenia, a pilot study. Eur Arch Psychiatr Clin Neurosci 1994;244:216–222.CrossRefGoogle ScholarPubMed
126.van Kammen, DP, Guidotti, A, Kelley, ME, et al.CSF diazepam binding inhibitor and schizophrenia: clinical and biochemical relationships. Biol Psychiatry 1993;34:515–522.CrossRefGoogle ScholarPubMed
127.Rothstein, JD, Garland, W, Puia, G, Guidotti, A, Weber, RJ, Costa, E. Purification and characterization of naturally occurring benzodiazepine receptor ligands in rat and human brain. J Neurochem 1992;58:2102–2115.CrossRefGoogle ScholarPubMed
128.Sangameswaran, L, De Blas, AL. Demonstration of benzodiazepine-like molecules in the mammalian brain with a monoclonal antibody to benzodiazepines. Proc Natl Acad Sci USA 1985;82:5560–5564.CrossRefGoogle ScholarPubMed
129.Sangameswaran, L, Fales, HM, Friedrich, P, De Blas, AL. Purification of a benzodiazepine from bovine brain and detection of benzodia-zepine-like immunoreactivity in human brain. Proc Natl Acad Sci USA 1986;83:9236–9240.CrossRefGoogle ScholarPubMed
130.Wildmann, J, Niemann, J, Matthaei, H. Endogenous benzodiazepine receptor agonist in human and mammalian plasma. J Neural Transm 1986;66:151–160.CrossRefGoogle ScholarPubMed
131.De Blas, AL, Sangameswaran, L. Demonstration and purification of an endogenous benzodiazepine from the mammalian brain with monoclonal antibody to benzodiazepines. Life Sci 1986;39:1927–1936.CrossRefGoogle ScholarPubMed
132.Wildmann, J, Mohler, H, Vetter, W, Ranalder, U, Schmidt, K, Maurer, R. Diazepam and N-desmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J Neural Transm 1987;70:383–398.CrossRefGoogle ScholarPubMed
133.Wildmann, J. Increase of natural benzodiazepines in wheat and potato during germination. Biochem Biophys Res Commun 1988;157:1436–1443.CrossRefGoogle ScholarPubMed
134.Wildmann, J, Vetter, W, Ranalder, UB, Schmidt, K, Maurer, R, Mohler, H. Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato. Biochem Pharmacol 1988;37:3549–3559.CrossRefGoogle ScholarPubMed
135.Wildmann, J, Ranalder, U. Presence of lorazepam in the blood plasma of drug free rats. Life Sci 1988;43:1257–1260.CrossRefGoogle Scholar
136.Bruun Meyer, SE. The GABA/benzodiazepine receptor-chloride ionophore complex: nature and modulation. Prog Neuropsycho-pharmacol Biol Psychiatry 1987;11:365–387.CrossRefGoogle ScholarPubMed
137.Andrews, JS. Inverse agonists and schedule-controlled behavior. In: Sarter, M, Nutt, DJ, Lister, RG, eds. Benzodiazepine Inverse Agonists. New York, Wiley-Liss, 1995, pp 139–63.Google Scholar