Abstract
A new method involving the blockade of operant behaviour induced by the withdrawal of a conditioned signal for safety without presentation of a punishment signal has been developed for studying drugs with anxiolytic or anxiogenic properties. For this purpose, rats were trained under two alternating components of a multiple schedule of reinforcement FR8 (food)/FR1 (food) + RR 50% (shocks randomly delivered with 50±15% of the presses). The nonpunished and punished periods were signalled by one cue light above the right lever (safety signal) or the left lever (punishment signal), respectively. On the test session (safety signal withdrawal), the safety signal was turned off at the end of the first nonpunished period, but the punishment signal was not presented (every press was food rewarded and no shocks were delivered). During this period (4 min), rats exhibited a strong blockade of responding that lessened over time. This suppression seemed not to be caused by intervening events such as novelty, temporal conditioning, schedule of food delivery or ambiguity of the signal presented. The behavioural blockade induced by withdrawal of the safety signal was reduced by benzodiazepines: diazepam (0.5–4 mg/kg), chlordiazepoxide (4–8 mg/kg), nitrazepam (0.25–2 mg/kg), alprazolam (0.25–1 mg/kg), and partial agonists at benzodiazepine receptors: bretazenil (0.125–8 mg/kg) and ZK 91296 (32–64 mg/kg). Various 5-HT-related drugs also lessened the behavioural blockade: pCPA (3×150 mg/kg) and the 5-HT1A receptor agonists, buspirone (0.25–2 mg/kg), gepirone (0.25–1 mg/kg) but not 8-OH-DPAT. Compounds that may cause anxiety in humans further enhanced the blockade of lever pressing induced by the safety signal withdrawal at doses that did not modify baseline responding:d-amphetamine (0.125–0.5 mg/kg), caffeine (16 mg/kg) and picrotoxin (1 mg/kg). FG 7142 (8 mg/kg) and CGS 8216 (2–8 mg/kg) decreased responding during both components of the session. Therefore, the present paradigm seems sensitive to both “anxiolytic” and “anxiogenic” effects of drugs under identical procedural conditions.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bernard PS, Pastor G, Liebman JM (1986) CGS 8216, a benzodiazepine antagonist, reduces food intake in food-deprived rats. Pharmacol Biochem Behav 24:1703–1706
Chopin P, Briley M (1987) Animal models of anxiety: the effect of compounds that modify 5-HT neurotransmission. TIPS 8:383–388
Dourish CT (1987) Brain 5-HT1A receptors and anxiety. In: Dourish CT, Ahlenius S, Hutson PH (eds) Brain 5-HT1A receptors. Behavioral and neurochemical pharmacology. Ellis Horwood Chichester, England, pp 261–277
Fanselow MS (1980) Signaled shock-free periods and preference for signaled shock. J Exp Psychol [Anim Behav] 6:65–80
File SE, Baldwin HA (1987) Effects of beta-carbolines in animal models of anxiety. Brain Res Bull 19:293–299
File SE, Pellow S (1984) The anxiogenic action of FG 7142 in the social interaction test is reversed by chloridazepoxide and Ro 15-1788 but not by CGS 8216. Arch Int Pharmacodyn 271:198–205
Gardner CR (1988) Potential use of drugs modulating 5HT activity in the treatment of anxiety. Gen Pharmacol 19:347–356
Hamon M, Fattaccini CM, Adrien J, Gallissot MC, Martin P, Gozlan H (1988) Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine 1A agonists with potential anxiolytic properties. J Pharmacol Exp Ther 246:745–752
Hodges H, Green S (1987) Are the effects of benzodiazepines on discrimination and punishment dissociable? Physiol Behav 41:257–264
Howard JL, Pollard GT (1990) Effects of buspirone in the Geller-Seifter conflict test with incremental shock. Drug Dev Res 19:37–49
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
Jensen LH, Petersen EN, Braestrup C, Honore T, Kehr W, Stephens DN, Schneider H, Seidelmann D, Schmiechen R (1984) Evaluation of the beta-carboline ZK 93426 as a benzodiazepine receptor antagonist. Psychopharmacology 83:249–256
Kahn RS, van Praag HM, Wetzler S, Asnis GM, Barr G (1988) Serotonin and anxiety revisited. Biol Psychiatry 23:189–208
Ketelaars CEJ, Bollen EL, Rigter H, Bruinvels J (1988) Gaba-B receptor activation and conflict behaviour. Life Sci 42:933–942
Lader M, Bruce M (1986) States of anxiety and their induction by drugs. Br J Pharmacol 22:251–261
Martin JR, Pieri L, Bonetti EP, Schaffner R, Burkard WP, Cumin R, Haefely WE (1988) Ro 16-6028: a novel anxiolytic acting as a partial agonist at the benzodiazepine receptor. Pharmacopsychiatry 21:360–362
Merlo Pich E, Samanin R (1989) A two-compartment exploratory model to study anxiolytic/anxiogenic effects of drugs in the rat. Pharmacol Res 21:595–602
Mineka S, Hendersen RW (1985) Controllability and predictability in acquired motivation. Annu Rev Psychol 36:495–529
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, 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
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, Jensen LH, Honore T, Braestrup C, Kehr W, Stephens DN, Wachtel H, Seidelman D, Schmiechen R (1984) ZK 91296, a partial agonist at benzodiazepine receptors. Psychopharmacology 83:240–248
Pollard GT, Howard JL (1990) Effects of drugs on punished behavior: pre-clinical test for anxiolytics. Pharmacol Ther 45:403–424
Rickels K, Cohen D, Csanalosi I, Harris H, Koepke H, Werblowsky J (1982) Alprazolam and imipramine in depressed outpatients: a controlled study. Curr Res Ther 32:157–164
Sanger DJ (1987) The benzodiazepine antagonist CGS 8216 decreases both shocked and unshocked drinking in rats. Psychopharmacology 91:485–488
Stavrakaki C, Ellis J (1989) The relationship of anxiety to depression in children and adolescents. Psychiat Clin North Am 12:777–789
Stephens DN, Kehr W (1985) Beta-carbolines can enhance or antagonize the effects of punishment in mice. Psychopharmacology 85:143–147
Stroebel CF (1969) Biologic rhythm correlates of disturbed behavior in the rhesus monkey. Bibl Primatol 9:91–105
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, Jobert A, Soubrié P (1980) Conditioned suppression of behavior: its reversal by intra raphe microinjection of chlordiazepoxide and GABA. Neurosci Lett 16:213–217
Thiébot MH, Childs M, Soubrié P, Simon P (1983) Diazepam-induced release of behavior in an extinction procedure: its reversal by Ro 15-1788. Eur J Pharmacol 88:111–116
Yang XM, Luo ZP, Zhou JH (1989) Behavioral evidence for the role of noradrenaline in the putative anxiogenic actions of the inverse benzodiazepine receptor agonist methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate. J Pharmacol Exp Ther 250:358–363
Yerbury RE, Cooper SJ (1987) The benzodiazepine partial agonists, Ro 16-6028 and Ro 17-1812, increase palatable food consumption in nondeprived rats. Pharmacol Biochem Behav 28:427–431
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
Zitrin CM, Ross DC (1988) Early separation anxiety and adult agoraphobia. J Nerv Ment Dis 176 [10]: 621–625
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thiébot, MH., Dangoumau, L., Richard, G. et al. Safety signal withdrawal: a behavioural paradigm sensitive to both “anxiolytic” and “anxiogenic” drugs under identical experimental conditions. Psychopharmacology 103, 415–424 (1991). https://doi.org/10.1007/BF02244298
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02244298