Psychopharmacology

, Volume 83, Issue 4, pp 304–315 | Cite as

Multiple sites of action for anxiogenic drugs: Behavioural, electrophysiological and biochemical correlations

  • Sharon Pellow
  • Sandra E. File
Review

Abstract

This review describes animal models of anxiety that are able to identify an anxiogenic drug effect. Evidence is reviewed for the anxiogenic action of several drugs that act at the GABA-benzodiazepine-chloride ionophore complex in the brain. The effects of their combinations with various other drugs thought to act at the same sites are discussed. The classification of these drugs on the basis of their behavioural profiles is compared with their classification based on biochemical and electrophysiological studies.

Key words

Anxiety Social interaction Conflict Drug discrimination Ro 15-1788 CGS 8216 β-carbolines Ro 5-4864 Ro 5-3663 Picrotoxin Pentylenetetrazol Benzodiazepine receptors Picrotoxinin site 

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References

  1. Beer B, Chasin M, Clody D, Vogel JR, Horovitz ZP (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety. Science 176:428–430Google Scholar
  2. Bernard P, Bergen K, Sobiski R, Robson R (1981) An orally effective benzodiazepine antagonist. Pharmacologist 23:150Google Scholar
  3. Bowling AC, DeLorenzo RJ (1982a) Micromolar affinity benzodiazepine receptors: identification and characterisation in central nervous system. Science 216:1247–1249Google Scholar
  4. Bowling AC, DeLorenzo RJ (1982b) Multiple phenytoin binding sites: identification and characterisation in brain membrane. Neurosci Abstracts 8:505Google Scholar
  5. Braestrup C, Honoré T, Nielsen M, Petersen EN, Jensen LH (1983) Benzodiazepine receptor ligands with negative efficacy: chloride channel coupling. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven Press, New York, pp 29–36Google Scholar
  6. Braestrup C, Nielsen M (1981) GABA reduces binding of [3H]-methyl β-carboline-3-carboxylate to brain benzodiazepine receptors. Nature 294:472–474Google Scholar
  7. Braestrup C, Nielsen M, Olsen CE (1980) Urinary and brain β-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci USA 77:2288–2292Google Scholar
  8. Braestrup C, Schmiechen R, Neef G, Nielsen M, Petersen EN (1982) Interaction of convulsive ligands with benzodiazepine receptors. Science 216:1241–1243Google Scholar
  9. Braestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterised by high-affinity [3H]-diazepam binding. Proc Natl Acad Sci USA 74:3805–3809Google Scholar
  10. Braestrup C, Squires RF (1978) Pharmacological characterisation of benzodiazepine receptors in the brain. Eur J Pharmaco 48:263–270Google Scholar
  11. Brown CL, Johnson AM (1982) Ethyl β-carboline-3-carboxylate reverses the effects of benzodiazepines in a test for detecting anxiolytic activity. Br J Pharmacol 75:43PGoogle Scholar
  12. Brown CL, Martin IL (1983) Photoaffinity labelling of the benzodiazepine receptor cannot be used to predict ligand efficacy. Neurosci Lett 35:37–40Google Scholar
  13. Burnham WM, Spero L, Okazaki MM, Madras BK (1981) Saturable binding of [3H]-phenytoin to rat brain membrane fractions. Can J Physiol Pharmacol 59:402–407Google Scholar
  14. Chiu TH, Rosenberg HC (1983) Conformational changes in benzodiazepine receptors induced by the antagonist Ro 15-1788. Mol Pharmacol 23:289–294Google Scholar
  15. Cooper SJ (1983) Benzodiazepines, barbiturates and drinking. In: Cooper SJ (ed) Theory in psychopharmacology, vol. 2. Academic Press, New YorkGoogle Scholar
  16. Corda MG, Blaker WD, Mendelson WB, Guidotti A, Costa E (1983) β-carbolines enhance shock-induced suppression of drinking in rats. Proc Natl Acad Sci USA 80:2072–2076Google Scholar
  17. Costa T, Rodbard D, Pert CB (1979) Is the benzodiazepine receptor coupled to a chloride anion channel? Nature 277:315–317Google Scholar
  18. Czernik AJ, Petrack B, Kalinsky HJ, Psychoyos S, Cash WD, Tsai C, Rinehart RK, Granat FR, Lovell RA, Brundish DE, Wade R (1982) CGS 8216: receptor binding characteristics of a potent benzodiazepine antagonist. Life Sci 30:363–372Google Scholar
  19. Dantzer R, Perio A (1982) Behavioural evidence for partial antagonist properties of Ro 15-1788, a benzodiazepine receptor antagonist. Eur J Pharmacol 81:655–658Google Scholar
  20. Doble A, Iversen LL, Martin IL (1982) The benzodiazepine binding site: one receptor or two? Br J Pharmacol 75:42PGoogle Scholar
  21. Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C (1983) Severe anxiety induced by FG 7142, a β-carboline ligand for benzodiazepine receptors. Lancet II:98–99Google Scholar
  22. Ehlert FJ, Roeske WR, Gee KW, Yamamura HI (1983) An allosteric model for benzodiazepine receptor function. Biochem Pharmacol 32:2375–2383Google Scholar
  23. Ehlert FJ, Roeske WR, Yamamura HI (1981) Multiple benzodiazepine receptors and their regulation by γ-aminobutyric acid. Life Sci 29:235–248Google Scholar
  24. File SE (1980) The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods 2:219–238Google Scholar
  25. File SE (1983) Proconvulsant action of CGS 8216. Neurosci Lett 35:317–320Google Scholar
  26. File SE, Green AR, Nutt DJ, Vincent ND (1984b) On the convulsant action of Ro 5-4864 and the existence of a micromolar benzodiazepine binding site in rat brain. Psychopharmacology 82:199–202Google Scholar
  27. File SE, Hyde JRG (1978) Can social interaction be used to measure anxiety? Br J Pharmacol 62:19–24Google Scholar
  28. File SE, Hyde JRG (1979) A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor tranquilisers and of stimulants. Pharmacol Biochem Behav 11:65–69Google Scholar
  29. File SE, Lister RG (1983a) Quinolines and anxiety: anxiogenic effects of CGS 8216 and partial anxiolytic profile of PK 9084. Pharmacol Biochem Behav 18:185–188Google Scholar
  30. File SE, Lister RG (1983b) Interactions of ethyl-β-carboline-3-carboxylate and Ro 15-1788 with CGS 8216 in an animal model of anxiety. Neurosci Lett 39:91–94Google Scholar
  31. File SE, Lister RG (1983c) β-CCE and chlordiazepoxide reduce exploratory head-dipping and rearing: no mutual antagonism. Neuropharmacology 21:1215–1218Google Scholar
  32. File SE, Lister RG (1983d) The anxiogenic action of Ro 5-4864 is reversed by phenytoin. Neurosci Lett 35:93–96Google Scholar
  33. File SE, Lister RG (1984) Do the reductions in social interaction produced by picrotoxin and pentylenetetrazol indicate anxiogenic actions. Neuropharmacology 23:793–796Google Scholar
  34. File SE, Lister RG, Maninov R, Tucker JC (1984a) Intrinsic behavioral actions of n-propyl-β-carboline-3-carboxylate. Neuropharmacology 23:463–466Google Scholar
  35. File SE, Lister RG, Nutt DJ (1982a) The anxiogenic actions of benzodiazepine antagonists. Neuropharmacology 21:1033–1037Google Scholar
  36. File SE, Lister RG, Nutt DJ (1982b) Intrinsic actions of benzodiazepine antagonists. Neurosci Lett 32:165–168Google Scholar
  37. File SE, Mabbutt PS (1983) Behavioural effects of Ro 5-4864, a ligand for the micromolar benzodiazepine receptor. Br J Pharmacol 78:76PGoogle Scholar
  38. File SE, Pellow S (1983a) Ro 5-4864, a ligand for benzodiazepine micromolar and peripheral binding sites: antagonism and enhancement of behavioural effects. Psychopharmacology 80:166–170Google Scholar
  39. File SE, Pellow S (1983b) Anxiogenic action of a convulsant benzodiazepine: reversal by chlordiazepoxide. Brain Res 278:370–372Google Scholar
  40. File SE, Pellow S (1984a) The anxiogenic action of Ro 15-1788 is reversed by chronic, but not by acute, treatment with chlordiazepoxide. Brain (in press)Google Scholar
  41. File SE, Pellow S (1984b) The anxiogenic action of Ro 5-4864: effect of chlordiazepoxide, Ro 15-1788 and CGS 8216. Naunyn-Schmiedeberg's Arch Pharmacol (in press)Google Scholar
  42. File SE, Pellow S (1984c) The anxiogenic action of FG 7142 in the social interaction test is reversed by chlordiazepoxide and Ro 15-1788 but not by CGS 8216. Arch Int Pharmacodyn Ther (in press)Google Scholar
  43. File SE, Pellow S, Braestrup C (1984c) Effects of the β-carboline FG 7142 in the social interaction test of anxiety and the holeboard: correlations between brain and plasma concentrations. Brain (in press)Google Scholar
  44. File SE, Vellucci SV (1978) Studies on the role of ACTH and 5HT in anxiety using an animal model. J Pharma Pharmacol 30:105–110Google Scholar
  45. File SE, Wardill AG (1975) Validity of head-dipping as a measure of exploration in a modified holeboard. Psychopharmacologia 44:53–59Google Scholar
  46. Geller I, Seifter J (1960) The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally-induced conflict in the rat. Psychopharmacologia 1:482–492Google Scholar
  47. Gherezghiher T, Lal H (1982) Ro 15-1788 selectively reverses the antagonism of the pentylenetetrazol-induced discriminative stimulus by benzodiazepines but not by barbiturates. Life Sci 31:2955–2960Google Scholar
  48. Greksch G, Prado de Carvalho L, Venault P, Chapouthier G, Rossier J (1983) Convulsions induced by an submaximal dose of pentylenetetrazol in mice are antagonised by the benzodiazepine antagonist, Ro 15-1788. Life Sci 32:2579–2584Google Scholar
  49. Harrison NL, Simmonds MA (1983) The picrotoxin-like action of a convulsant benzodiazepine, Ro 5-3663. Eur J Pharmacol 87:155–158Google Scholar
  50. Hoffman DK, Britton DR (1983) Anxiogenic-like properties of benzodiazepine antagonists. Neurosci Abstr 9:129Google Scholar
  51. Holmberg G, Gershon S (1961) Autonomic and psychic effects of yohimbine hydrochloride. Psychopharmacologia 2:93–106Google Scholar
  52. Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516Google Scholar
  53. Jensen LH, Petersen EN, Braestrup C (1983) Audiogenic seizures in DBA/2 mice discriminate sensitively between low efficacy benzodiazepine receptor agonists and inverse agonists. Life Sci 33:393–399Google Scholar
  54. Jones BJ, Oakley NR (1981) The convulsant properties of methyl β-carboline-3-carboxylate in the mouse. Br J Pharmacol 74:223–224Google Scholar
  55. Kehr W, Stephens DN (1984) Further evidence that central benzodiazepine receptor ligands may exhibit anxiogenic properties. Br J Pharmacol 81:42PGoogle Scholar
  56. King GL, Knox JJ, Dingledine R (1983) Effects of benzodiazepines and Ro 15-1788 on inhibition in the hippocampus. Neurosci Abstr 9:412Google Scholar
  57. Lal H, Bennett D, Ellmesallamy F (1982) Anxiogenic potential of β-carboline compounds as bioassayed by generalisation to interoceptive stimuli produced by pentylenetetrazol. Neurosci Abstr 8:571Google Scholar
  58. Lal H, Bennett D, Shearman G, Harvat A (1983) Yohimbine: behavioural and neurochemical properties in common with anxiogenic β-carbolines. Neurosci Abstr 9:437Google Scholar
  59. Lal H, Shearman GT (1982) Attenuation of chemically-induced anxiogenic stimuli as a novel method for evaluating anxiolytic drugs: a comparison of clobazam with other benzodiazepines. Drug Dev Res Suppl 1:127–134Google Scholar
  60. Leeb-Lundberg F, Napias C, Olsen RW (1981) Dihydropicrotoxinin binding sites in mammalian brain: interaction with convulsant and depressant benzodiazepines. Brain Res 216:399–408Google Scholar
  61. Leeb-Lundberg F, Snowman A, Olsen RW (1980) Barbiturate receptors are coupled to benzodiazepine receptors. Proc Natl Acad Sci USA 77:7468–7472Google Scholar
  62. LeFur G, Perrier ML, Vaucher N, Imbault F, Flamier A, Benavides J, Uzan A, Renault C, Dubroeucq MC, Guérémy C (1983a) Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide. I. In vitro studies. Life Sci 32:1839–1847Google Scholar
  63. LeFur G, Guilloux F, Rufat P, Benavides J, Uzan A, Renault C, Dubroeucq MC, Guérémy C (1983b) Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide. II. In vivo studies. Life Sci 32:1849–1856Google Scholar
  64. LeFur G, Vaucher N, Perrier ML, Flamier A, Benavides J, Renault C, Dubroeucq MC, Guérémy C, Uzan A (1983c) Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]-Ro 5-4864 and [3H]-PK 11195, by thermodynamic studies. Life Sci 33:449–457Google Scholar
  65. MacNeil DA, D'Amico JA, Horst WD, O'Brien RA, Spirt N (1983) Influences of two atypical benzodiazepines, Ro 5-3663 and Ro 5-4864, on GABAergic mechanisms. Neurosci Abstr 9:412Google Scholar
  66. Marangos PJ, Patel J, Boulenger J-P, Clark-Rosenberg R (1982) Characterisation of peripheral-type benzodiazepine binding sites in brain using [3H]-Ro 5-4864. Mol Pharmacol 22:26–32Google Scholar
  67. Margules DL, Stein L (1968) Increase of antianxiety activity and tolerance of behavioural depression during chronic administration of oxazepam. Psychopharmacologia 13:74–80Google Scholar
  68. Martin IL, Brown CL, Doble A (1983) Multiple benzodiazepine receptors: structures in the brain or structures in the mind? A critical review. Life Sci 32:1925–1933Google Scholar
  69. Martin IL, Doble A (1983) The benzodiazepine receptor in rat brain and its interaction with ethyl β-carboline-3-carboxylate. J Neurochem 40:1613–1619Google Scholar
  70. Mendelson WB, Davis T, Paul SM, Skolnick P (1983) Do benzodiazepine receptors mediate the anticonflict mechanism of pentobarbital? Life Sci 32:2241–2246Google Scholar
  71. Möhler H, Battersby MK, Richards JG (1980) Benzodiazepine receptor protein identified and visualised in brain tissue by a photoaffinity label. Proc Natl Acad Sci USA 77:1666–1670Google Scholar
  72. Möhler H (1982) Benzodiazepine receptors: differential interaction of benzodiazepine agonists and antagonists after photoaffinity labelling with flunitrazepam. Eur J Pharmacol 80:435–436Google Scholar
  73. Möhler H, Okada T (1977) Benzodiazepine receptors: demonstration in the CNS. Science 198:849–851Google Scholar
  74. Morelli M, Gee KW, Yamamura HI (1982) The effect of GABA on in vitro binding of two novel non-benzodiazepines, PK 8165 and CGS 8216, to benzodiazepine receptors in rat brain. Life Sci 31:77–81Google Scholar
  75. Nielsen M, Braestrup C (1980) Ethyl β-carboline-3-carboxylate shows differential benzodiazepine receptor interaction. Nature 286:606–607Google Scholar
  76. Ninan PT, Insel TM, Cohen RM, Cook JM, Skolnick P, Paul SM (1983) Benzodiazepine receptor-mediated anxiety in primates. Science 218:1332–1334Google Scholar
  77. Nutt DJ, Cohen PJ, Little HJ (1982) Unusual interactions of benzodiazepine receptor antagonists. Nature 295:436–438Google Scholar
  78. Oakley NR, Jones BJ (1980) The proconvulsant and diazepamreversing effects of ethyl β-carboline-3-carboxylate. Eur J Pharmacol 68:381–382Google Scholar
  79. Okazaki MM, Madras BK, Livingston KE, Spero L, Burnham WM (1983) Enhancement of [3H]-phenytoin binding by diazepam and bicuculline. Life Sci 33:409–414Google Scholar
  80. Olsen RW (1982) Drug interactions at the GABA receptor-ionophore complex. Ann Rev Pharmacol Toxicol 22:245–277Google Scholar
  81. Olsen RW, Leeb-Lundberg F (1981) Convulsant and anticonvulsant drug binding site related to the GABA receptor-ionophore system. In: Morselli PL, Lloyd KG, Löscher W, Meldrum BS, Reynolds EH (eds) Neurotransmitters, seizures and epilepsy. Raven Press, New York, pp 93–102Google Scholar
  82. Ongini E, Barzaghi C, Marzanatti M (1983) Intrinsic and antagonistic effects of β-carboline FG 7142 in behavioural actions of benzodiazepines and pentobarbital in cats. Eur J Pharmacol 95:125–129Google Scholar
  83. Pellow S, File SE (1984) Behavioural effects of Ro 5-4864, a ligand for peripheral-type benzodiazepine binding sites. Life Sci 35:229–240Google Scholar
  84. Pellow S, File SE, Herberg LJ (1984a) Intracranial self-stimulation distinguishes between two benzodiazepine antagonists. Neurosci Lett 47:173–177Google Scholar
  85. Pellow S, File SE, Simmonds MA (1984b) The benzodiazepine Ro 5-4864 antagonises the electrophysiological effects of flurazepam and has convulsant and anxiogenic properties. Poster presented to 14th CINP Congress, FlorenceGoogle Scholar
  86. Petersen EN, Jensen LH, Honoré T, Braestrup C (1983) Differential pharmacological effects of benzodiazepine receptor inverse agonists. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven Press, New York, pp 57–64Google Scholar
  87. Petersen EN, Paschelke G, Kehr W, Nielsen M, Braestrup C (1982) Does the reversal of the anticonflict effect of phenobarbital by β-CCE and FG 7142 indicate benzodiazepine receptor-mediated anxiogenic properties? Eur J Pharmacol 82:217–221Google Scholar
  88. Pieri L, Pole P, Bonetti W, Burkard W, Cumin R, Scherschlicht R, Haefely W (1984) Some pharmacological effects of Ro 5-4864, a specific ligand for the peripheral type of benzodiazepine binding sites. Naunyn-Schmiedeberg's Arch Pharmacol, in pressGoogle Scholar
  89. Polc P, Bonetti EP, Schaffner R, Haefely W (1982) A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilisers, β-carbolines and phenobarbital. Naunyn-Schmiedeberg's Arch Pharmacol 321:260–264Google Scholar
  90. Polc P, Laurent J-P, Scherschlicht R, Haefely W (1981) Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn-Schmiedeberg's Arch Pharmacol 316:317–325Google Scholar
  91. Polc P, Schaffner R (1984) Electrophysiological effects of the peripheral-type benzodiazepine receptor ligand Ro 5-4864 in cat spinal cord and rat hippocampus. Naunyn-Schmiedeberg's Arch Pharmacol, in pressGoogle Scholar
  92. Prado de Carvalho L, Greksch G, Chapouthier G, Rossier J (1983a) Anxiogenic and non-anxiogenic benzodiazepine antagonists. Nature 301:64–66Google Scholar
  93. Prado de Carvalho L, Venault P, Rossier J, Chapouthier G (1983b) Anxiogenic properties of convulsive agents. Neurosci Abstr 9:128Google Scholar
  94. Ramanjaneyulu R, Ticku MK (1983) Differential interactions of depressant and convulsant drugs with the components of the benzodiazepine-GABA receptor-ionophore complex. Neurosci Abstr 9:403Google Scholar
  95. Richards JG, Möhler H, Haefely W (1982) Benzodiazepine binding sites: receptors or acceptors? TIPS 3:233–235Google Scholar
  96. Rickels K, Sablosky L, Silverman H, Case WG, Rial W, Mirman M, Gottlieb S (1977) Prazepam in anxiety. Comp Psychiatry 3:239–249Google Scholar
  97. Rodin E (1958) Metrazol tolerance in a “normal” and volunteer population. EEG Clin Neurophysiol 10:433–446Google Scholar
  98. Rodin EA, Calhoun HD (1970) Metrazol tolerance in a “normal” volunteer population. J Nerv Ment Dis 150:438–450Google Scholar
  99. Rossier J, Dodd RH, Feldblum S, Valin A, Prado de Carvalho L, Potier P, Naquet R (1983) Methylamide β-carboline (FG 7142), an anxiogenic benzodiazepine antagonist, is also a proconvulsant. Lancet I:77–78Google Scholar
  100. Schlosser W, Franco S (1979) Reduction of GABA-mediated transmission by a convulsant benzodiazepine. J Pharmacol Exp Ther 211:290–295Google Scholar
  101. Schoemaker H, Bliss M, Yamamura HI (1981) Specific high affinity saturable binding of [3H]-Ro 5-4864 to benzodiazepine binding sites in rat cerebral cortex. Eur J Pharmacol 71:173–175Google Scholar
  102. Schoemaker H, Boles RG, Horst WD, Yamamura HI (1983) Specific high affinity binding sites for [3H]-Ro 5-4864 in rat brain and kidney. J Pharmacol Exp Ther 225:61–69Google Scholar
  103. Shah DS, Chambon P, Guidotti A (1981) Binding of [3H]-5,5 diphenylhydantoin to rat brain membranes. Neuropharmacology 20:1115–1119Google Scholar
  104. Sherman GT, Miksic S, Lal H (1979) Lack of tolerance development to benzodiazepines in antagonising the pentylenetetrazol discriminative stimulus. Pharmacol Biochem Behav 10:795–797Google Scholar
  105. Shearman GT, Lal H (1980) Generalisation and antagonism studies with convulsant, GABAergic and anticonvulsant drugs in rats trained to discriminate pentylenetetrazol from saline. Neuropharmacology 19:473–479Google Scholar
  106. Simmonds MA (1982) Classification of some GABA antagonists with regard to site of action and potency in slices of cuneate nucleus. Eur J Pharmacol 80:347–358Google Scholar
  107. Soubrié P, Schoonhoed L, Simon P, Boissier JR (1972) Conflict behaviour in a heated floor-maze: effects of oxazepam. Psychopharmacologia 26:317–320Google Scholar
  108. Squires RF, Benson DI, Braestrup C, Coupet J, Klepner CA, Myers V, Beer B (1979) Some properties of the specific benzodiazepine receptor: new evidence for multiple benzodiazepine receptors. Pharmacol Biochem Behav 10:825–830Google Scholar
  109. Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734Google Scholar
  110. Squires RF, Saederup E (1983) Diverse groups of psychotropic drugs interact with GABA/picrotoxin receptor complexes. Neurosci Abstr 9:1039Google Scholar
  111. Tallman JF, Thomas JW, Gallager DW (1978) GABAergic modulation of benzodiazepine binding site sensitivity. Nature 274: 383–385Google Scholar
  112. Thomas JW, Tallman JF (1981) Characterisation of photoaffinity labelling of benzodiazepine binding sites. J Biol Chem 256:9838–9842Google Scholar
  113. Thomas JW, Tallman JF (1983) Photoaffinity labelling of benzodiazepine receptors causes altered agonist-antagonist interactions. J Neurosci 3:433–440Google Scholar
  114. Ticku MK, Ban M, Olsen RW (1978) Binding of [3H]-α-dihydropicrotoxinin, a GABA synaptic antagonist, to rat brain membranes. Mol Pharmacol 14:391–402Google Scholar
  115. Ticku MK, Maksay G (1983) Convulsant/depressant site of action at the allosteric benzodiazepine-GABA receptor-ionophore complex. Life Sci 33:2363–2375Google Scholar
  116. Ticku MK, Olsen RW (1978) Interaction of barbiturates with dihydropicrotoxinin binding sites related to the GABA receptor-ionophore system. Life Sci 22:1643–1652Google Scholar
  117. Ticku MK, Olsen RW (1979) Cage convulsants inhibit picrotoxinin binding. Neuropharmacology 18:315–318Google Scholar
  118. Ticku MK, Ramanjaneyulu R (1984) Ro 5-4864 inhibits the binding of [35S]t-butylbicyclophosphorothionate to rat brain membranes. Life Sci 34:631–638Google Scholar
  119. Velluci S, Webster R (1982) Antagonism of the anticonflict effects of chlordiazepoxide by β-carboline-3-carboxylic acid ethyl ester, Ro 15-1788 and ACTH. Psychopharmacology 78:256–260Google Scholar
  120. Velluci SV, Webster RA (1984) Antagonism of caffeine-induced seizures in mice by Ro 15-1788. Eur J Pharmacol 97:289–293Google Scholar
  121. Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing antianxiety agents. Psychopharmacologia 21:1–7Google Scholar
  122. Warner RS (1965) Management of the office patient with anxiety and depression. Psychosomatics 6:347–351Google Scholar
  123. Weissman BA, Cott J, Paul SM, Skolnick P (1983) Ro 5-4864: a potent benzodiazepine convulsant. Eur J Pharmacol 90:149–150Google Scholar
  124. Yokoyama N, Ritter B, Neubert AD (1982) 2-Arylpyrazolo [4,3-c]quinolin-3-ones: Novel agonist, partial agonist and antagonist of benzodiazepines. J Med Chem 25:337–339Google Scholar
  125. Zbinden G, Randall LO (1967) Pharmacology of benzodiazepines: laboratory and clinical correlations. Adv Pharmacol 5:213–291Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • Sharon Pellow
    • 1
  • Sandra E. File
    • 1
  1. 1.MRC Neuropharmacology Research Group, Department of Pharmacology, The School of PharmacyUniversity of LondonLondonUK

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