Abstract
Ethopharmacological studies on the behavior of socially housed rats and squirrel monkeys were conducted to explore the role of the benzodiazepine GABAA-coupled ionophore receptor complex in aggressive and social interactions. Benzodiazepine receptor (BZR) antagonists, ZK 93426 (1–10 mg/kg) and flumazenil (3–10 mg/kg), the partial agonist, ZK 91296 (1–10 mg/kg) and the partial inverse agonists RO 15-4513 (0.3–10 mg/kg), were administered to (1) squirrel monkeys prior to 1 h focal observations within established social groups or to (2) resident male rats before confrontations with a naive male intruder in their home cage for 5 min. Aggression was modified in a similar manner in both species, although squirrel monkeys were more sensitive to BZR challenges. Specifically, resident male rats showed dose dependent reductions in attack bites directed at intruder males that were significant at the highest dose of ZK 93426 (10 mg/kg). In squirrel monkeys, ZK 93426 (3 and 10 mg/kg) reduced aggressive grasps, threats and displays, as well as reducing the duration of being the target of aggression from untreated group members (1–10 mg/kg). The BZR partial agonist, ZK 91296 and the antagonist, flumazenil produced few effects on social behavior, low and high intensity aggression and motor activity in both species. Flumazenil (10–30 mg/kg) and ZK 91296 (10 mg/kg), but not ZK 93426, produced significant increases in foraging and feeding behaviors in squirrel monkeys. The hyperphagic effects of ZK 91296 and flumazenil, that are typical of BZR agonists compounds, were not observed in rats. Similarly, the inverse agonist-like reductions in social interactions produced by ZK 93426 (3–10 mg/kg) were observed only in squirrel monkeys. The partial inverse agonist Ro 15-4513 reduced aggression in rats, but low doses (1 mg/kg) produced tremors or seizures in 80% of the monkeys tested. Decreases in aggressive and social behaviors are often interpreted to reflect “anxiogenic” drug properties, whereas increased feeding has been associated with “anxiolytic” actions. The concurrent emergence of these apparent opposites suggests independent actions on social and alimentary functions.
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References
Altmann J (1974) Observational study of behavior: sampling methods. Behaviour 49:227–267
Bauen A, Possanza GJ (1970) The mink as a psychopharmacological model. Arch Int Pharmacodyn Ther 186:133–136
Bonetti EP, Pieri L, Cumin R, Schaffner R, Pieri M, Gamzu ER, Muller RKM, Haefely W (1982) Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects. Psychopharmacology 78:8–18
Britton KT, Ehlers CL, Koob GF (1988) Is ethanol antagonist Ro 15-4513 selective for ethanol? Science 239:648–649
Burt DR, Kamatchi GL (1991) GABAA receptor subtypes from pharmacology to molecular biology. FASEB J 5:2916–2923
Christmas AJ, Maxwell DR (1970) A comparison of the effects of some benzodiazepines and other drugs on aggressive and exploratory behaviour in mice and rats. Neuropharmacology 9:17–29
Cole HG, Wolf HH (1966) The effects of some psychotropic drugs on conditioned avoidance and aggressive behaviors. Psychopharmacologia 8:389–396
Cooper SJ (1987a) Bidirectional changes in the consumption of food produced by beta-carbolines. Brain Res Bull 19:347–358
Cooper SJ (1987b) Novel benzodiazepine receptor ligands stimulate intake of hypertonic NaCl solution in rehydrating rats. Pharmacol Biochem Behav 27:425–430
Cooper SJ (1991) Benzodiazepines, appetite and stress. Animal Models of Psychiatric Disorders 3:24–44
Cooper SJ, Moores WR (1985) Chlordiazepoxide-induced hyperphagia in non-food-deprived rats: effects of RO15-1788, CGS 8216 and ZK 93426. Eur J Pharmacol 112:39–45
Cooper SJ, Yerbury RE, Neill JC, Desa A (1987) Partial agonists acting at benzodiazepine receptors can be differentiated in tests of ingestional behaviour. Physiol Behav 41:247–255
De Vry J, Slangen JL (1985) The Ro15-1788 cue: Evidence for benzodiazepine agonists and inverse agonist properties. Eur J Pharmacol 119:193–197
DiMascio A (1973) The effects of benzodiazepines on aggression: reduced or increased? Psychopharmacologia 30:95–102
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, Pellow S (1985) The anxiogenic action of RO 5-4864 in the social interaction test: effect of chlordiazepoxide, RO 15-1788 and CGS 8216. Naunyn-Schmiedeberg's Arch Pharmacol 328:225–228
File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 88:1–11
File SE, Lister RG, Nutt DJ (1982a) The anxiogenic action 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, Pellow S, Jensen LH (1986) Actions of the beta-carboline ZK 93426 in an animal test of anxiety and the holeboard Interactions with Ro 15-1788. J Neural Transm 65:103–114
Foltin RW, Fischman MW, Byrne MF (1989) Food intake in baboons: effects of diazepam. Psychopharmacology 97:443–447
Guidotti A (1978) Synaptic mechanisms in the action of benzodiazepines. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 1349–1357
Gunn J (1979) Drugs in the violence clinic. In: Sandler M (ed) Psychopharmacology of aggression. Raven Press, New York, pp 183–195
Haefely W (1984) Benzodiazepine interactions with GABA receptors. Neurosci Lett 47:201–206
Haefely W (1985) Pharmacology of benzodiazepine antagonists. Pharmacopsychiatry 18:163–166
Haefely W (1990) The GABA-Benzodiazepine Interaction fifteen years later. Neurochemical Research 15(2):169–174
Heise GA, Boff E (1961) Taming action of chlordiazepoxide. Federation Proceedings 20:393
Hopf S, Hartmann-Wiesner E, Kuhlmorgen B, Mayer S (1974) The behavioral repertoire of the squirrel monkey (Saimiri). Folia Primatol 21:225–249
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
Krsiak M (1974) Isolation-induced timidity in mice as a measure of anxiolytic activity of drugs. Activ Nerv Super 16:241–142
Krsiak M (1975) Timid singly-housed mice: their value in prediction of psychtropic activity of drugs. Br J Pharmacol 55:141–150
Krsiak M, Sulcova A (1990) Differential effects of six structurally related benzodiazepines on some ethological measures of timidity, aggression and locomotion in mice. Psychopharmacology 101:396–402
Laurie DS, Seeberg PH, Wisden W (1992). The distribution of B GABAA receptor subunit mRNAs in the rat brain. II. olfactory bulb and cerebellum. Journal of Neuroscience 12(3):1063–1076
Lion JR (1981) Medical treatment of violent individuals. In: Ray Hays J, Roberts TK, Solway KS (eds) Violence and the violent individual. SP Medical and Scientific Books, New York, pp 343–351
Lister RG (1988) Interactions of three benzodiazepine receptor inverse agonists with ethanol in a plus-maze test of anxiety. Pharmacol Biochem Behav 30:1–6
Little HJ, Nutt DJ, Taylor SC (1987) Kindling and withdrawal changes at the benzodiazepine receptor. J Psychopharmacol 1:35–46
Miczek KA (1974) Intraspecies aggression in rats: effects ofd-amphetamine and chlordiazepoxide. Psychopharmacologia 39:275–301
Miczek KA (1979) A new test for aggression in rats without aversive stimulation: differential effects ofd-amphetamine and cocaine. Psychopharmacology 60:253–259
Miczek KA (1982) Ethological analysis of drug action on aggression, defense and defeat. In: Spiegelstein MY, Levy A (eds) Behavioral models and the analysis of drug action. Elsevier, Amsterdam, pp 225–239
Miczek KA (1985) Alcohol and aggressive behavior in rats: interaction with benzodiazepines. Soc Neurosci Abstr 11:1290
Miczek KA, Gold LH (1983)d-Amphetamine in squirrel monkeys of different social status: effects on social and agonistic behavior, locomotion, and stereotypies. Psychopharmacology 81:183–190
Miczek KA, Krsiak M (1979) Drug effects on agonistic behavior. In: Thompson T, Dews PB (eds) Advances in behavioral pharmacology. Academic Press, New York, pp 87–162
Miczek KA, Weerts EM (1987) Seizures in drug-treated animals. Science 235:1127
Miczek KA, Winslow JT, DeBold JF (1984) Heightened aggressive behavior by animals interacting with alcohol-treated conspecifics: studies with mice, rats and squirrel monkeys. Pharmacol Biochem Behav 20:349–353
Miczek KA, Weerts EM, Tornatzky W, DeBold JF, Vatne TM (1992) Alcohol and “bursts” of aggressive behavior: ethological analysis of individual differences in rats. Psychopharmacology 108:196–204
Möhler H, Okada T (1977) Benzodiazepine receptor: demonstration in the central nervous system. Science 198:849–851
Mos J, Olivier B (1986) RO 15-1788 does not influence postpartum aggression in lactating female rats. Psychopharmacology 90:278–280
Mos J, Olivier B (1988) Differential effects of selected psychoactive drugs on dominant and subordinate male rats housed in a colony. Neurosci Res Commun 2:29–36
Mos J, Olivier B, van Oorschot R (1987) Maternal aggression towards different sized male opponents: effect of chlordiazepoxide treatment of the mothers andd-amphetamine treatment of the intruders. Pharmacol Biochem Behav 26:577–584
Nutt DJ, Lister RG (1989) Antagonizing the anticonvulsant effect of ethanol using drugs acting at the benzodiazepine/GABA receptor complex. Pharmacol Biochem Behav 31:751–755
Olivier B, Mos J, Miczek (1991) Ethopharmacological studies of anxiolytics and aggression. Eur Neuropharmacol 1:97–100
Petersen EN, Jensen LH, Honore T, Braestrup C, Kehr W, Stephens DN, Wachtel H, Seidelman D (1984) ZK 91296, a partial agonist at benzodiazepine receptors. Psychopharmacology 83:240–248
Robichaud RC, Gylys JA, Sledge KA, Hillyard IW (1970) The pharmacology of prazepam a new benzodiazepine derivative. Arch Int Pharmacodyn Ther 185:213–227
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
Scheckel CL, Boff E (1968) The effects of drugs on conditioned avoidance and aggressive behavior. In: Vagtborg H (ed) Use of nonhuman primates in drug evaluation. University of Texas Press, Austin, Texas, pp 301–312
Skolnick P, Reed GF, Paul SM (1985) Benzodiazepine-receptor mediated inhibition of isolation-induced aggression in mice. Pharmacol Biochem Behav 23:17–20
Sofia RD (1969) Effects of centrally active drugs on four models of experimentally-induced aggression in rodents. Life Sci 8:705–716
Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 226:732–734
Stephens DN, Kehr W, Duka T (1986) 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 91–106
Stutzmann J, Bohme A, Cochan M, Roux M, Blanchard J (1987) Proconflict and electrocorticographic effects of drugs modulating GABAergic neurotransmission. GABAergic Neurotransmission 91:74–91
Sulcova A, Krsiak M (1984) The benzodiazepine-receptor antagonist Ro 15-1788 antagonizes effects of diazepam on aggressive and timid behaviour in mice. Activ Nerv Super 26:255–256
Sulcova A, Krsiak M (1986) Beta-carbolines (beta-CCE, FG 7142) and diazepam: synergistic effects on aggresion and antagonistic effects on timidity in mice. Activ Nerv Super 28:312–316
Suzdak PD, Glowa JR, Crawley JN, Schwartz RD, Skolnick P, Paul SM (1986) A selective imidazobenzodiazepine antagonist of ethanol in the rat. Science 234:1243–1247
Ticku MK (1983) Benzodiazepine-GABA receptor-ionophore complex. Current concepts. Neuropharmacology 22:1459–1470
Tompkins EC, Clemento AJ, Taylor DP, Perhach JL Jr. (1980) Inhibition of aggressive behavior in rhesus monkeys by buspirone. Res Commun Psychol Psychiatr Behav 5:337–352
von Blankenfeld G, Sontheimer H, Pritchett DB, Ewert M, Seeburg P, Kettenmann H (1990) Differential benzodiazepine pharmacology of recombinant GABAA receptors. Neuroscience Letters 115:269–273
Weerts EM, Tornatzky W, Miczek KA (1992) Prevention of the proaggressive effects of alcohol in rats and squirrel monkeys by benzodiazepine receptor antagonists. Psychopharmacology (in press)
Winslow JT, Miczek KA (1985) Social status as determinant of alcohol effects on aggressive behavior in squirrel monkeys (Saimiri sciureus). Psychopharmacology 85:167–172
Winslow JT, Miczek KA (1988a) Androgen dependency of alcohol effects on aggressive behavior: a seasonal rhythm in high-ranking squirrel monkeys. Psychopharmacology 95:92–98
Winslow JT, Miczek KA (1988b) Naltrexone blocks amphetamine-induced hyperactivity, but not disruption of social and agonistic behavior in mice and squirrel monkeys. Psychopharmacology 96:493–499
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
Zumpe D, Michael RP (1986) Dominance index: a simple measure of relative dominance status in primates. Am J Primatol 10:291–300
Zwirner PP, Porsolt RD, Loew DM (1975) Inter-group aggression in mice. A new method for testing the effects of centrally active drugs. Psychopharmacologia 45:133–138
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Weerts, E.M., Tornatzky, W. & Miczek, K.A. “Anxiolytic” and “anxiogenic” benzodiazepines and β-carbolines: effects on aggressive and social behavior in rats and squirrel monkeys. Psychopharmacology 110, 451–459 (1993). https://doi.org/10.1007/BF02244652
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DOI: https://doi.org/10.1007/BF02244652