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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Beer B, Chasin M, Clody D, Vogel JR, Horovitz ZP (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety. Science 176:428–430
Bernard P, Bergen K, Sobiski R, Robson R (1981) An orally effective benzodiazepine antagonist. Pharmacologist 23:150
Bowling AC, DeLorenzo RJ (1982a) Micromolar affinity benzodiazepine receptors: identification and characterisation in central nervous system. Science 216:1247–1249
Bowling AC, DeLorenzo RJ (1982b) Multiple phenytoin binding sites: identification and characterisation in brain membrane. Neurosci Abstracts 8:505
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 29–36
Braestrup C, Nielsen M (1981) GABA reduces binding of [3H]-methyl β-carboline-3-carboxylate to brain benzodiazepine receptors. Nature 294:472–474
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 77:2288–2292
Braestrup C, Schmiechen R, Neef G, Nielsen M, Petersen EN (1982) Interaction of convulsive ligands with benzodiazepine receptors. Science 216:1241–1243
Braestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterised by high-affinity [3H]-diazepam binding. Proc Natl Acad Sci USA 74:3805–3809
Braestrup C, Squires RF (1978) Pharmacological characterisation of benzodiazepine receptors in the brain. Eur J Pharmaco 48:263–270
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 75:43P
Brown CL, Martin IL (1983) Photoaffinity labelling of the benzodiazepine receptor cannot be used to predict ligand efficacy. Neurosci Lett 35:37–40
Burnham WM, Spero L, Okazaki MM, Madras BK (1981) Saturable binding of [3H]-phenytoin to rat brain membrane fractions. Can J Physiol Pharmacol 59:402–407
Chiu TH, Rosenberg HC (1983) Conformational changes in benzodiazepine receptors induced by the antagonist Ro 15-1788. Mol Pharmacol 23:289–294
Cooper SJ (1983) Benzodiazepines, barbiturates and drinking. In: Cooper SJ (ed) Theory in psychopharmacology, vol. 2. Academic Press, New York
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 80:2072–2076
Costa T, Rodbard D, Pert CB (1979) Is the benzodiazepine receptor coupled to a chloride anion channel? Nature 277:315–317
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 30:363–372
Dantzer R, Perio A (1982) Behavioural evidence for partial antagonist properties of Ro 15-1788, a benzodiazepine receptor antagonist. Eur J Pharmacol 81:655–658
Doble A, Iversen LL, Martin IL (1982) The benzodiazepine binding site: one receptor or two? Br J Pharmacol 75:42P
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:98–99
Ehlert FJ, Roeske WR, Gee KW, Yamamura HI (1983) An allosteric model for benzodiazepine receptor function. Biochem Pharmacol 32:2375–2383
Ehlert FJ, Roeske WR, Yamamura HI (1981) Multiple benzodiazepine receptors and their regulation by γ-aminobutyric acid. Life Sci 29:235–248
File SE (1980) The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods 2:219–238
File SE (1983) Proconvulsant action of CGS 8216. Neurosci Lett 35:317–320
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 82:199–202
File SE, Hyde JRG (1978) Can social interaction be used to measure anxiety? Br J Pharmacol 62:19–24
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 11:65–69
File SE, Lister RG (1983a) Quinolines and anxiety: anxiogenic effects of CGS 8216 and partial anxiolytic profile of PK 9084. Pharmacol Biochem Behav 18:185–188
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 39:91–94
File SE, Lister RG (1983c) β-CCE and chlordiazepoxide reduce exploratory head-dipping and rearing: no mutual antagonism. Neuropharmacology 21:1215–1218
File SE, Lister RG (1983d) The anxiogenic action of Ro 5-4864 is reversed by phenytoin. Neurosci Lett 35:93–96
File SE, Lister RG (1984) Do the reductions in social interaction produced by picrotoxin and pentylenetetrazol indicate anxiogenic actions. Neuropharmacology 23:793–796
File SE, Lister RG, Maninov R, Tucker JC (1984a) Intrinsic behavioral actions of n-propyl-β-carboline-3-carboxylate. Neuropharmacology 23:463–466
File SE, Lister RG, Nutt DJ (1982a) The anxiogenic actions of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
File SE, Lister RG, Nutt DJ (1982b) Intrinsic actions of benzodiazepine antagonists. Neurosci Lett 32:165–168
File SE, Mabbutt PS (1983) Behavioural effects of Ro 5-4864, a ligand for the micromolar benzodiazepine receptor. Br J Pharmacol 78:76P
File SE, Pellow S (1983a) Ro 5-4864, a ligand for benzodiazepine micromolar and peripheral binding sites: antagonism and enhancement of behavioural effects. Psychopharmacology 80:166–170
File SE, Pellow S (1983b) Anxiogenic action of a convulsant benzodiazepine: reversal by chlordiazepoxide. Brain Res 278:370–372
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)
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)
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)
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)
File SE, Vellucci SV (1978) Studies on the role of ACTH and 5HT in anxiety using an animal model. J Pharma Pharmacol 30:105–110
File SE, Wardill AG (1975) Validity of head-dipping as a measure of exploration in a modified holeboard. Psychopharmacologia 44:53–59
Geller I, Seifter J (1960) The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally-induced conflict in the rat. Psychopharmacologia 1:482–492
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 31:2955–2960
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 32:2579–2584
Harrison NL, Simmonds MA (1983) The picrotoxin-like action of a convulsant benzodiazepine, Ro 5-3663. Eur J Pharmacol 87:155–158
Hoffman DK, Britton DR (1983) Anxiogenic-like properties of benzodiazepine antagonists. Neurosci Abstr 9:129
Holmberg G, Gershon S (1961) Autonomic and psychic effects of yohimbine hydrochloride. Psychopharmacologia 2:93–106
Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516
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 33:393–399
Jones BJ, Oakley NR (1981) The convulsant properties of methyl β-carboline-3-carboxylate in the mouse. Br J Pharmacol 74:223–224
Kehr W, Stephens DN (1984) Further evidence that central benzodiazepine receptor ligands may exhibit anxiogenic properties. Br J Pharmacol 81:42P
King GL, Knox JJ, Dingledine R (1983) Effects of benzodiazepines and Ro 15-1788 on inhibition in the hippocampus. Neurosci Abstr 9:412
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 8:571
Lal H, Bennett D, Shearman G, Harvat A (1983) Yohimbine: behavioural and neurochemical properties in common with anxiogenic β-carbolines. Neurosci Abstr 9:437
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 1:127–134
Leeb-Lundberg F, Napias C, Olsen RW (1981) Dihydropicrotoxinin binding sites in mammalian brain: interaction with convulsant and depressant benzodiazepines. Brain Res 216:399–408
Leeb-Lundberg F, Snowman A, Olsen RW (1980) Barbiturate receptors are coupled to benzodiazepine receptors. Proc Natl Acad Sci USA 77:7468–7472
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 32:1839–1847
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 32:1849–1856
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 33:449–457
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 9:412
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 22:26–32
Margules DL, Stein L (1968) Increase of antianxiety activity and tolerance of behavioural depression during chronic administration of oxazepam. Psychopharmacologia 13:74–80
Martin IL, Brown CL, Doble A (1983) Multiple benzodiazepine receptors: structures in the brain or structures in the mind? A critical review. Life Sci 32:1925–1933
Martin IL, Doble A (1983) The benzodiazepine receptor in rat brain and its interaction with ethyl β-carboline-3-carboxylate. J Neurochem 40:1613–1619
Mendelson WB, Davis T, Paul SM, Skolnick P (1983) Do benzodiazepine receptors mediate the anticonflict mechanism of pentobarbital? Life Sci 32:2241–2246
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 77:1666–1670
Möhler H (1982) Benzodiazepine receptors: differential interaction of benzodiazepine agonists and antagonists after photoaffinity labelling with flunitrazepam. Eur J Pharmacol 80:435–436
Möhler H, Okada T (1977) Benzodiazepine receptors: demonstration in the CNS. Science 198:849–851
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 31:77–81
Nielsen M, Braestrup C (1980) Ethyl β-carboline-3-carboxylate shows differential benzodiazepine receptor interaction. Nature 286:606–607
Ninan PT, Insel TM, Cohen RM, Cook JM, Skolnick P, Paul SM (1983) Benzodiazepine receptor-mediated anxiety in primates. Science 218:1332–1334
Nutt DJ, Cohen PJ, Little HJ (1982) Unusual interactions of benzodiazepine receptor antagonists. Nature 295:436–438
Oakley NR, Jones BJ (1980) The proconvulsant and diazepamreversing effects of ethyl β-carboline-3-carboxylate. Eur J Pharmacol 68:381–382
Okazaki MM, Madras BK, Livingston KE, Spero L, Burnham WM (1983) Enhancement of [3H]-phenytoin binding by diazepam and bicuculline. Life Sci 33:409–414
Olsen RW (1982) Drug interactions at the GABA receptor-ionophore complex. Ann Rev Pharmacol Toxicol 22:245–277
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 93–102
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 95:125–129
Pellow S, File SE (1984) Behavioural effects of Ro 5-4864, a ligand for peripheral-type benzodiazepine binding sites. Life Sci 35:229–240
Pellow S, File SE, Herberg LJ (1984a) Intracranial self-stimulation distinguishes between two benzodiazepine antagonists. Neurosci Lett 47:173–177
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, Florence
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 57–64
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 82:217–221
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 press
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 321:260–264
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 316:317–325
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 press
Prado de Carvalho L, Greksch G, Chapouthier G, Rossier J (1983a) Anxiogenic and non-anxiogenic benzodiazepine antagonists. Nature 301:64–66
Prado de Carvalho L, Venault P, Rossier J, Chapouthier G (1983b) Anxiogenic properties of convulsive agents. Neurosci Abstr 9:128
Ramanjaneyulu R, Ticku MK (1983) Differential interactions of depressant and convulsant drugs with the components of the benzodiazepine-GABA receptor-ionophore complex. Neurosci Abstr 9:403
Richards JG, Möhler H, Haefely W (1982) Benzodiazepine binding sites: receptors or acceptors? TIPS 3:233–235
Rickels K, Sablosky L, Silverman H, Case WG, Rial W, Mirman M, Gottlieb S (1977) Prazepam in anxiety. Comp Psychiatry 3:239–249
Rodin E (1958) Metrazol tolerance in a “normal” and volunteer population. EEG Clin Neurophysiol 10:433–446
Rodin EA, Calhoun HD (1970) Metrazol tolerance in a “normal” volunteer population. J Nerv Ment Dis 150:438–450
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:77–78
Schlosser W, Franco S (1979) Reduction of GABA-mediated transmission by a convulsant benzodiazepine. J Pharmacol Exp Ther 211:290–295
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 71:173–175
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 225:61–69
Shah DS, Chambon P, Guidotti A (1981) Binding of [3H]-5,5 diphenylhydantoin to rat brain membranes. Neuropharmacology 20:1115–1119
Sherman GT, Miksic S, Lal H (1979) Lack of tolerance development to benzodiazepines in antagonising the pentylenetetrazol discriminative stimulus. Pharmacol Biochem Behav 10:795–797
Shearman GT, Lal H (1980) Generalisation and antagonism studies with convulsant, GABAergic and anticonvulsant drugs in rats trained to discriminate pentylenetetrazol from saline. Neuropharmacology 19:473–479
Simmonds MA (1982) Classification of some GABA antagonists with regard to site of action and potency in slices of cuneate nucleus. Eur J Pharmacol 80:347–358
Soubrié P, Schoonhoed L, Simon P, Boissier JR (1972) Conflict behaviour in a heated floor-maze: effects of oxazepam. Psychopharmacologia 26:317–320
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 10:825–830
Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734
Squires RF, Saederup E (1983) Diverse groups of psychotropic drugs interact with GABA/picrotoxin receptor complexes. Neurosci Abstr 9:1039
Tallman JF, Thomas JW, Gallager DW (1978) GABAergic modulation of benzodiazepine binding site sensitivity. Nature 274: 383–385
Thomas JW, Tallman JF (1981) Characterisation of photoaffinity labelling of benzodiazepine binding sites. J Biol Chem 256:9838–9842
Thomas JW, Tallman JF (1983) Photoaffinity labelling of benzodiazepine receptors causes altered agonist-antagonist interactions. J Neurosci 3:433–440
Ticku MK, Ban M, Olsen RW (1978) Binding of [3H]-α-dihydropicrotoxinin, a GABA synaptic antagonist, to rat brain membranes. Mol Pharmacol 14:391–402
Ticku MK, Maksay G (1983) Convulsant/depressant site of action at the allosteric benzodiazepine-GABA receptor-ionophore complex. Life Sci 33:2363–2375
Ticku MK, Olsen RW (1978) Interaction of barbiturates with dihydropicrotoxinin binding sites related to the GABA receptor-ionophore system. Life Sci 22:1643–1652
Ticku MK, Olsen RW (1979) Cage convulsants inhibit picrotoxinin binding. Neuropharmacology 18:315–318
Ticku MK, Ramanjaneyulu R (1984) Ro 5-4864 inhibits the binding of [35S]t-butylbicyclophosphorothionate to rat brain membranes. Life Sci 34:631–638
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 78:256–260
Velluci SV, Webster RA (1984) Antagonism of caffeine-induced seizures in mice by Ro 15-1788. Eur J Pharmacol 97:289–293
Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing antianxiety agents. Psychopharmacologia 21:1–7
Warner RS (1965) Management of the office patient with anxiety and depression. Psychosomatics 6:347–351
Weissman BA, Cott J, Paul SM, Skolnick P (1983) Ro 5-4864: a potent benzodiazepine convulsant. Eur J Pharmacol 90:149–150
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 25:337–339
Zbinden G, Randall LO (1967) Pharmacology of benzodiazepines: laboratory and clinical correlations. Adv Pharmacol 5:213–291
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pellow, S., File, S.E. Multiple sites of action for anxiogenic drugs: Behavioural, electrophysiological and biochemical correlations. Psychopharmacology 83, 304–315 (1984). https://doi.org/10.1007/BF00428536
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00428536