Abstract
The behavioral effects of the benzodiazepine (BZP)-receptor partial inverse agonists, beta-CCE and FG 7142, are reviewed and the claim that these compounds possess “anxiogenic” properties is examined. Results obtained from human studies and global observations in animals, as well as those from experiments on aggression in animals or from studies of pentylenetetrazole discrimination cannot be considered conclusive. Contradictory findings have been obtained in studies using animal testing procedures derived from BZP-sensitive models of anxiety and in newer experimental situations and these are discussed from various theoretical perspectives: (1) the ability of the models to measure increased anxiety; (2) the possible ability of the drugs to reveal latent anxiety which generalizes from a punished to an otherwise non-fearful component of a testing procedure (“spreading anxiety”); (3) anxiety produced by a pro- or pre-convulsant state. Finally, several hypotheses are considered to account for the behavioral effects of beta-CCE and FG 7142 without assuming anxiogenic properties. These include the possible existence of different forms of anxiety, rate dependency, and drug-induced motivational changes. It is concluded that available data are insufficient to strongly support the notion that FG7142 and beta-CCE are the anxiogenic drugs “par excellence” they are often claimed to be.
Similar content being viewed by others
References
Aron C, Simon P, Larousse C, Boissier JR (1971) Evaluation of a rapid technique for detecting minor transquilizers. Neuropharmacology 10:459–469
Balfour DJK, Graham CA, Vale AL (1986) Studies on the possible role of brain 5-HT systems and adrenocortical activity in behavioral responses to nicotine and diazepam in an elevated X-maze. Psychopharmacology 90:528–532
Barrett JE, Brady LS, Witkin JM, Cook JM, Larscheid P (1985) Interactions between the benzodiazepine receptor antagonist Ro 15–1788 (flumazepil) and the inverse agonist beta-CCE: behavioral studies with squirrel monkeys. Life Sci 36:1407–1414
Barrett JE, Brady LS, Stanley JA, Mansbach RS, Witkin JM (1986) Behavioral studies with anxiolytic drugs. II. Interactions of zopiclone with ethyl-beta-carboline-3-carboxylate and Ro 15–1788 in squirrel monkeys. J Pharm Exp Ther 236:313–319
Beck CHM, Cooper SJ (1986a) The effect of the B-carboline FG 7142 on the behaviour of male rats in a living cage: an ethological analysis of social and nonsocial behaviour. Psychopharmacology 89:203–207
Beck CHM, Cooper SJ (1986b) Beta-carboline FG 7142-reduced aggression in male rats: reversed by the benzodiazepine receptor antagonist, Ro 15–1788. Pharmacol Biochem Behav 24:1645–1649
Beck CHM, Cooper SJ (1986c) Effects of the beta-carboline, FG 7142, on social behaviour in male laboratory rats. Neuropharmacology 25:645–647
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, Nielsen M, Honoré T (1983) Benzodiazepine receptor ligands with positive and negative efficacy. In: Mandel P, DeFudis FV (eds) CNS receptors — from molecular pharmacology to behavior. Raven Press, New York, pp 237–245
Brown CL, Johnson AM (1982) Ethyl beta-carbline-3-carboxylate reverses the effect of benzodiazepines in a test for detecting anxiolytic activity. Br J Pharmacol 75:43P
Cepeda C, Tanaka T, Besselièvre R, Potier P, Naquet R, Rossier J (1981) Proconvulsant effects in baboons of beta-carboline, a putative endogenous ligand for benzodiazepine receptors. Neurosci Lett 24:53–57
Cooper SJ (1985a) The anorectic effect of FG 7142, a partial inverse agonist at benzodiazepine recognition sites, is reversed by CGS 8216 and clonazepam but not by food deprivation. Brain Res 346:190–194
Cooper SJ (1985b) Bidirectional control of palatable food consumption through a common benzodiazepine receptor: theory and evidence. Brain Res Bull 15:397–410
Cooper SJ (1986) Effects of the beta-carboline FG 7142 on saccharin preference and quinine aversion in water-deprived rats. Neuropharmacology 25:213–216
Cooper SJ, Estall LB (1985) Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors. Neurosci Biobehav Rev 3:5–19
Cooper SJ, Barber DJ, Gilbert DB, Moores WR (1985) Benzodiazepine receptor ligands and the consumption of a highly palatable diet in non-deprived male rats. Psychopharmacology 86:348–355
Corda MG, Biggio G (1986) Proconflict effect of GABA receptor complex antagonists. Reversal by diazepam. Neuropharmacology 25:541–544
Corda MG, Blaker WD, Mendelson WB, Guidotti A, Costa E (1983) Beta-carbolines enhance shock-induced suppression of drinking in rats. Proc Natl Acad Sci USA 80:2072–2076
Corda MG, Giorgi O, Gatta F, Biggio G (1985) Long-lasting proconflict effect induced by chronic administration of the betacarboline derivative FG 7142. Neurosci Lett 62:237–240
Crawley JN, Skolnick P, Paul SM (1984) Absence of intrinsic antagonist actions of benzodiazepine antagonists on an exploratory model of anxiety in the mouse. Neuropharmacology 23:531–537
Crawley JN, Ninan PT, Pickar D, Chrousos GP, Linnoila M, Skolnick P, Paul SM (1985) Neuropharmacological antagonism of the beta-carboline-induced “anxiety” response in rhesus monkeys. J Neurosci 5:477–485
Dantzer R (1977) Behavioral effects of benzodiazepines: a review. Biobehav Rev 1:71–86
Davis M (1979) Diazepam and flurazepam: effects on conditioned fear as measured with the potentiated startle paradigm. Psychopharmacology 62:1–7
Dorow R (1987) FG 7142 and its anxiety-inducing effects in humans. Br J Clin Phamacol 23:781–782
Dorow R, Duka T (1986) Anxiety: its generation by drugs and by their withdrawal. In: Biggio G, Costa E (eds) GABAergic transmission and anxiety. Raven Press, New York, pp 211–225
Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C (1983) Severe anxiety induced by FG 7142, a beta-carboline ligand for benzodiazepine receptors. Lancet I (8):98–99
Drugan RC, Maier SF, Skolnick P, Paul SM, Crawley JN (1985) An anxiogenic benzodiazepine receptor ligand induces learned helplessness. Eur J Pharmacol 113:453–457
Duka T, Stephens DN (1986) Potentiation of the propunishment but not the convulsant action of the beta-carboline DMCM by naltrexone. Pharmacol Biochem Behav 25:595–598
Ehlert FJ (1986) “Inverse agonists”, cooperativity and drug action at benzodiazepine receptors. TIPS 7:28–32
Estall LB, Cooper SJ (1987) Differential effects of benzodiazepine receptor ligands on isotonic saline and water consumption in water-deprived rats. Pharmacol Biochem Behav 26:247–252
File SE (1985) Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour. Neuropsychobiology 13:55–62
File SE, Lister RG (1982) Beta-CCE and chlordiazepoxide reduce exploratory head-dipping and rearing: no mutual antagonism. Neuropharmacology 21:1215–1218
File SE, Pellow S (1984) 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 271:198–205
File SE, Pellow S (1985a) The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard. Br J Pharmacol 86:729–735
File SE, Pellow S (1985b) Triazolobenzodiazepines antagonize the effects of anxiogenic drugs mediated at three different central nervous system sites. Neurosci Lett 61:115–119
File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
File SE, Pellow S, Braestrup C (1985) Effects of the beta-carboline, FG 7142, in the social interaction test of anxiety and the holeboard: correlations between behaviour and plasma concentrations. Pharmacol Biochem Behav 22:941–944
Gardner CR (1985) Distress vocalisation in rat pups: a simple screening method for anxiolytic drugs. J Pharmacol Methods 14:181–185
Gardner CR, Budhram P (1987) Effects of agents which interact with central benzodiazepine binding sites on stress-induced ultrasounds in rat pups. Eur J Pharmacol 134:275–283
Geller I, Kulak JT, Seifter J (1962) The effects of chlordiazepoxide and chlorpromazine on a punishment discrimination. Psychopharmacologia 3:374–385
Glowa JR, Skolnick P, Paul SM (1986) Effects of beta-carboline-3-carboxylic acid ethyl ester on suppressed and non-suppressed responding in the rhesus monkey. Eur J Pharmacol 129:39–47
Gray JA (1982) Précis of the neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system. Behav Brain Sci 5:469–534
Guaitani A, Marcucci R, Garattini S (1971) Increased aggression and toxicity in grouped male mice treated with tranquilizing benzodiazepines. Psychopharmacologia 19:241–245
Guy AP, Gardner CR (1985) Pharmacological characterisation of a modified social interaction model of anxiety in the rat. Neuropsychobiology 13:194–200
Handley SL, Mithani S (1984) Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of “fear”-motivated behaviour. Naunyn-Schmiedeberg's Arch Pharmacol 327:1–5
Hansen S, Ferreira A, Selart ME (1985) Behavioural similarities between mother rats and benzodiazepine-treated non-maternal animals. Psychopharmacology 86:344–347
Hodges H, Green S, Glenn B (1987) Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination. Psychopharmacology 92:491–504
Insel TR, Ninan PT, Aloi J, Jimerson DC, Skolnick P, Paul SM (1984) A benzodiazepine receptor-mediated model of anxiety. Arch Gen Psychiatry 41:741–749
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
Karobath M, Supavilai P, Borea PA (1983) Distinction of benzodiazepine receptor agonists and inverse agonists by binding studies in vitro. In: Biggio G, Costa E (eds), Benzodiazepine recognition site ligands: Biochemistry and Pharmacology, Raven Press, New York, pp 37–45
Klein DF (1981) Anxiety reconceptualized. In: Klein DF, Rabkin J (eds) Anxiety: New research and changing concepts. Raven Press, New York
Koob GF, Braestrup C, Thatcher Britton K (1986) The effects of FG 7142 and Ro 15–1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat. Psychopharmacology 90:173–178
Kršiak M (1979) Effects of drugs on behaviour of aggressive mice. Br J Pharmacol 65:525–533
Lader M, Bruce M (1986) States of anxiety and their induction by drugs. Br J Clin Pharmacol 22:251–261
Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185
Little HJ, Nutt DJ, Taylor SC (1984) Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling. Br J Pharmacol 83:951–958
Little HJ, Nutt DJ, Taylor SC (1987) Selective changes in the in vivo effects of benzodiazepine receptor ligands after chemical kindling with FG 7142. Neuropharmacology 26:25–31
Marlatt GA, Rohsenow DJ (1980) Cognitive processes in alcohol use: Expectancy and balanced placebo design. In: Mello NK (ed) Advances in substance abuse: behavioral and biological research, Vol. 1. JAI Press, Greenwich, pp 159–199
Miczek KA (1974) Intraspecies attack and defense in rats: Effects of amphetamine, chlordiazepoxide and alcohol. Fed Proc 33:465
Mizoule J, Gauthier A, Uzan A, Renault C, Dubroeucq MC, Guerémy C, Le Fur G (1985) Opposite effects of two ligands for peripheral type benzodiazepine binding sites, PK 11195 and Ro 5–4864, in a conflict situation in the rat. Life Sci 36:1059–1068
Möhler H, Okada T (1977) Benzodiazepine receptors: demonstration in the CNS. Science 198:849–851
Möhler H, Okada T (1978) Benzodiazepine receptors in normal and pathological human brain. Br J Psychiatry 133:261–268
Nielsen M, Braestrup C (1980) Ethyl B-carboline-3-carboxylate shows differential benzodiazepine receptor interaction. Nature 286:606–607
Nielsen EB, Valentine JD, Holohean AM, Appel JB (1983) Benzodiazepine receptor mediated discriminative cues: effects of GABAergic drugs and inverse agonists. Life Sci 33:2213–2220
Nielsen EB, Jepsen SAa, Nielsen M, Braestrup C (1985) Discriminative stimulus properties of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse agonist at benzodiazepine receptors. Life Sci 36:15–23
Ninan PT, Insel TM, Cohen RM, Cook JM, Skolnick P, Paul SM (1982) Benzodiazepine receptor-mediated experimental “anxiety” in primates. Science 218:1332–1334
Nutt DJ (1983) Pharmacological and behavioural studies of benzodiazepine antagonists and contragonists. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven Press, New York, pp 153–173
Nutt DJ, Cowen 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-beta-carboline-3-carboxylate. Eur J Pharmacol 68:381–382
Ongini E, Barzaghi C, Marzanatti M (1983) Intrinsic and antagonistic effects of beta-carboline FG 7142 on behavioral and EEG actions of benzodiazepines and pentobarbital in cats. Eur J Pharmacol 95:125–129
Pellow S, File SE (1984) Multiple sites of action for anxiogenic drugs: behavioural, electrophysiological and biochemical correlations. Psychopharmacology 83:304–315
Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24:525–529
Pellow S, File SE (1987) Can anti-panic drugs antagonise the anxiety produced in the rat by drugs acting at the GABA-benzodiazepine receptor complex? Neuropsychobiology 17:60–65
Pellow S, Herberg LJ, File SE (1984) The effects of the β-carboline FG 7142, on intracranial self-stimulation in the rat. Pharmacol Biochem Behav 21:667–669
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Peña C, Medina JH, Novas ML, Paladini AC, de Robertis E (1986) Isolation and identification in bovine cerebral cortex of n-butyl β-carboline-3-carboxylate, a potent benzodiazepine binding inhibitor. Proc Natl Acad Sci USA 83:4952–4956
Petersen EN, Jensen LH (1984) Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function. Eur J Pharmacol 103:91–97
Petersen EN, Paschelke G, Kehr W, Nielsen M, Braestrup C (1982) Does the reversal of the anticonflict effect of phenobarbital by beta-CCE and FG 7142 indicate benzodiazepine receptormediated anxiogenic properties? Eur J Pharmacol 82:217–221
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
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 tranquilizers, beta-carbolines, and phenobarbitone. Naunyn-Schmiedeberg's Arch Pharmacol 321:260–264
Pollard GT, Howard JL (1986) The staircase test: some evidence of nonspecificity for anxiolytics. Psychopharmacology 89:14–19
Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: A new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391
Prado de Carvalho L, Grecksch G, Chapouthier G, Rossier J (1983) Anxiogenic and non-anxiogenic benzodiazepine antagonists. Nature 301:64–66
Quintero S, Henney S, Lawson P, Mellanby J, Gray JA (1985) The effects of compounds related to γ-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: punished barpressing. Psychopharmacology 85:244–251
Rodgers RJ, Waters AJ (1985) Benzodiazepines and their antagonists: a pharmacoethological analysis with particular reference to effects on “aggression”. Neurosci Biobehav Rev 9:21–35
Sanger DJ (1987) The benzodiazepine antagonist CGS 8216 decreases both shocked and unshocked drinking in rats. Psychopharmacology 91:485–488
Sanger DJ, Blackman DE (1975) The effects of tranquilizing drugs on timing behaviour in rats. Psychopharmacology 44:153–156
Sanger DJ, Blackman DE (1976) Rate-dependent effects of drugs: a review of the literature. Pharmacol Biochem Behav 4:73–83
Schachter S, Singer JE (1962) Cognitive, social and physiological determinants of emotional state. Psychol Rev 69:379–399
Shearman GT, Lal H (1980) Generalization and antagonism studies with convulsant, GABAergic and anticonvulsant drugs in rat trained to discriminate pentylenetetrazol from saline. Neuropharmacology 19:473–479
Sherman AD, Sacquitne JL, Petty F (1982) Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16:449–454
Simiand J, Keane PE, Morre M (1984) The staircase test in mice: a simple and efficient procedure for primary screening of anxiolytic agents. Psychopharmacology 84:48–53
Skolnick P, Ninan P, Insel T, Crawley J, Paul S (1984) A novel chemically induced animal model of human anxiety. Psychopathology 17:25–36
Skolnick P, Reed GF, Paul SM (1985) Benzodiazepine-receptor mediated inhibition of isolation-induced aggression in mice. Pharmacol Biochem Behav 23:17–20
Stephens DN, Kehr W (1985) Beta-carbolines can enhance or antagonize the effects of punishment in mice. Psychopharmacology 85:143–147
Stephens DN, Kehr W, Schneider HH, Schmiechen R (1984a) Beta-carbolines with agonistic and inverse agonistic properties at benzodiazepine receptors of the rat. Neurosci Lett 47:333–338
Stephens DN, Shearman GT, Kehr W (1984b) Discriminative stimulus properties of beta-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors. Psychopharmacology 83:233–239
Stephens DN, Kehr W, Duka T (1986a) Anxiolytic and anxiogenic beta-carbolines: Tools for the study of anxiety mechanisms. In: Biggio G, Costa E (eds) GABAergic transmission and anxiety. Raven Press, New York, pp 91–105
Stephens DN, Meldrum BS, Weidmann R, Schneider C, Grützner M (1986b) Does the excitatory amino acid receptor antagonist 2-APH exhibit anxiolytic activity? Psychopharmacology 90:166–169
Stutzmann JM, Böhme GA, Cochon M, Roux M, Blanchard JC (1987) Proconflict and electrocorticographic effects of drugs modulating GABAergic neurotransmission. Psychopharmacology 91:74–79
Sulcová A, Kršiak M (1985) Effects of ethyl beta-carboline-3-carboxylate and diazepam on aggressive and timid behaviour in mice. Act Nerv Super (Praha) 27:308–310
Sulcová A, Kršiak M (1986) Beta-carbolines (beta-CCE, FG 7142) and diazepam: synergistic effects on aggression and antagonistic effects on timidity in mice. Act Nerv Super (Praha) 28:312–314
Takada K, Winger G, Cook J, Larscheid P, Woods JH (1986) Discriminative and aversive properties of beta-carboline-3-carboxylic acid ethyl ester, a benzodiazepine receptor inverse agonist, in rhesus monkeys. Life Sci 38:1049–1056
Thiébot MH, Soubrié P (1983) Behavioral pharmacology of the benzodiazepines. In: Costa E (ed) The benzodiazepines: from molecular biology to clinical practice. Raven Press, New York, pp 67–92
Thiébot MH, Soubrié P, Simon P, Boissier JR (1976) Spécificité d'action des tranquillisants mineurs dans le test de l'escalier. Relation entre ces effets et leurs propriétés anxiolytiques. J Pharmacol 7:87–102
Thiébot MH, Le Bihan C, Soubrié P, Simon P (1985) Benzodiazepines reduce the tolerance to reward delay in rats. Psychopharmacology 86:147–152
Treit D (1985) The inhibitory effect of diazepam on defensive burying: anxiolytic vs. analgesic effect. Pharmacol Biochem Behav 22:47–52
Vellucci SV, Webster RA (1982) Antagonism of the anticonflict effects of chlordiazepoxide by beta-carboline carboxylic acid ethyl ester, Ro 15–1788 and ACTH(4–10). Psychopharmacology 78:256–260
Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing antianxiety agents. Psychopharmacologia 21:1–7
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thiébot, MH., Soubrié, P. & Sanger, D. Anxiogenic properties of beta-CCE and FG 7142: a review of promises and pitfalls. Psychopharmacology 94, 452–463 (1988). https://doi.org/10.1007/BF00212837
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00212837