Skip to main content
SpringerLink
Log in

Prevention of the pro-aggressive effects of alcohol in rats and squirrel monkeys by benzodiazepine receptor antagonists

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Pharmacological manipulations at the benzodiazepine-GABAA-chloride ionophore receptor complex modify some of the behavioral and physiological actions of alcohol (ethanol). The interactions between alcohol, benzodiazepines and aggression were examined in similar ethopharmacological studies in squirrel monkeys and in rats in confrontations with conspecifics. Dominant male squirrel monkeys were tested (1) within their social groups, and (2) in dyadic confrontations with “rival” males from a different social group, and resident male rats were tested in their home cage in confrontations with an inexperienced male intruder. Low doses of alcohol (0.1–0.3 g/kg) increased aggressive behaviors in dominant squirrel monkeys and a subgroup of resident rats, whereas high doses of alcohol (1–3 g/kg) decreased aggression and produced marked motor incoordination. Individuals that showed alcohol-enhanced aggression were selected, and pretreated with benzodiazepine antagonists (flumazenil, ZK 93426) prior to alcohol administration. Both ZK 93426 (3 mg/kg) and flumazenil (10 mg/kg) blocked the aggression-enhancing effects of alcohol in dominant squirrel monkeys and resident rats in confrontations with conspecifics. Neither compound altered the reductions in aggression and increases in inactivity produced by high doses of alcohol. Interestingly, agonist-like increased feeding and inverse agonist-like reductions in social behaviors were observed simultaneously at the same dose of flumazenil, in the same individual and testing situation. ZK 93426 did not alter feeding but also reduced social behaviors. The two antagonists were also not equipotent in their interactions with alcohol. ZK 93426 reduced alcohol-induced motor incoordination in squirrel monkeys, whereas flumazenil did not. In fact, flumazenil potentiated the effects of low doses of alcohol. Locomotion was reduced, while staggering and time spent sitting were increased in squirrel monkeys pretreated with flumazenil plus low to moderate alcohol doses that previously did not produce these effects when administered alone. The blockade of the motor-incoordinating effects of alcohol may depend on inverse agonist activities of the antagonist acting at the GABAA-benzodiazepine receptor coupled chloride channel.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Altmann J (1974) Observational study of behavior: sampling methods. Behaviour 49:227–267

    PubMed  Google Scholar 

  • Belzung C, Misslin R, Vogel E (1988) Does Ro 15-4513 reverse the anxiolytic effects of alcohol by its intrinsic properties? Pharmacol Biochem Behav 30:867–870

    Article  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Bonetti EP, Burkard WP, Gabl M, Mohler H (1985) The partial inverse benzodiazepine agonist Ro 15-4513 antagonizes acute ethanol effects in mice and rats. Br J Pharmacol 86:463

    Google Scholar 

  • Chan AWK, Langan MC, Schanley DL, Penetrante ML, Leong FW, Aldrich-Castanik L (1988) Differential effects of Ro-15-1788 in actions of chlordiazepoxide and ethanol. Pharmacol Biochem Behav 29:315–320

    Article  PubMed  Google Scholar 

  • Chance MRA, Mackintosh JH, Dixon AK (1973) The effects of ethyl alcohol on social encounters between mice. J Alcohol 8:90–93

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Cooper SJ (1987) Bidirectional changes in the consumption of food produced by beta-carbolines. Brain Res Bull 19:347–358

    Article  PubMed  Google Scholar 

  • Deacon RMJ, Budhram P, Thomson TA, Gardner CR (1990) Differential interactions of Ro 15-4513 with benzodiazepines, ethanol and pentobarbitol. Eur J Pharmacol 180:283–290

    Article  PubMed  Google Scholar 

  • DiMascio A (1973) The effects of benzodiazepines on aggression: reduced or increased? Psychopharmacologia 30:95–102

    Article  PubMed  Google Scholar 

  • Duka T, Stephens DN, Krause W, Dorow R (1987) Human studies on the benzodiazepine receptor antagonist beta-carboline ZK 93 426: preliminary observations on psychotrophic activity. Psychopharmacology 93:421–427

    Google Scholar 

  • Durcan MJ, Lister RG (1989) Reduction of the intoxicating effects of ethanol by drugs acting at the benzodiazepine-GABA receptor complex. Pharmacol Biochem Behav 32:667–670

    Article  PubMed  Google Scholar 

  • File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 88:1–11

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Foltin RW, Fischman MW, Byrne MF (1989) Food intake in baboons: effects of diazepam. Psychopharmacology 97:443–447

    Article  PubMed  Google Scholar 

  • Glowa JR, Crawley J, Suzdak PD, Paul SM (1989) Ethanol and the GABA receptor complex: studies with the partial inverse benzodiazepine receptor agonist Ro 15-4513. Pharmacol Biochem Behav 31:767–772

    Article  Google Scholar 

  • Goldstein DB (1983) Pharmacology of ethanol. Oxford University Press, New York, pp 48–64

    Google Scholar 

  • Harris RA (1990) Distinct actions of alcohols, barbiturates and benzodiazepines on GABA-activated chloride channels. Alcohol 7:273–275

    Article  PubMed  Google Scholar 

  • Harris RA, Allan AM, Daniell LC, Nixon C (1988) Antagonism of ethanol and pentobarbitol actions by benzodiazepine inverse agonists: neurochemical studies. J Pharmacol Exp Ther 247:1012–1017

    PubMed  Google Scholar 

  • Heise GA, Boff E (1961) Taming action of chlordiazepoxide. Fed Proc 20:393

    PubMed  Google Scholar 

  • Hilakivi LA, Lister RG (1989) Effect of ethanol on the social behavior of group-housed and isolated mice. Alcohol Clin Exp Res 13:622–625

    PubMed  Google Scholar 

  • Hiltunen AJ, Järbe TUC (1988) Ro 15-4513 does not antagonize the discriminative stimulus- or rate-depressant effects of ethanol in rats. Alcohol 5:203–207

    Article  PubMed  Google Scholar 

  • Hopf S, Hartmann-Wiesner E, Kühlmorgen B, Mayer S (1974) The behavioral repertoire of the squirrel monkey (Saimiri). Folia Primatol 21:225–249

    PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Koob GF, Braestrup C, Britton KT (1986) The effects of FG 7142 and RO Ro 15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat. Psychopharmacology 90:173–178

    Google Scholar 

  • Krsiak M (1975) Timid singly-housed mice: their value in prediction of psychotropic activity of drugs. Br J Pharmacol 55:141–150

    PubMed  Google Scholar 

  • Krsiak M (1976) Effect of ethanol on aggression and timidity in mice. Psychopharmacology 51:75–80

    Article  PubMed  Google Scholar 

  • Lagerspetz KMJ, Ekqvist K (1978) Failure to induce aggression in inhibited and in genetically non-aggressive mice through injections of ethyl alcohol. Aggress Behav 4:105–113

    Google Scholar 

  • Lister RG (1987a) The benzodiazepine receptor inverse agonists FG 7142 and RO 15-4513 both reverse some of the behavioral effects of ethanol in a holeboard test. Life Sci 41:1481–1489

    Article  PubMed  Google Scholar 

  • Lister RG (1987b) Reversal of the intrinsic effects of RO 15-4513 on exploratory behavior by two benzodiazepine receptor antagonists. Neurosci Lett 79:306–310

    Article  PubMed  Google Scholar 

  • Lister RG (1987c) Interactions of RO 15-4513 with diazepam, sodiumpentobarbital and ethanol in a holeboard test. Pharmacol Biochem Behav 28:75–79

    Article  PubMed  Google Scholar 

  • Lister RG (1988a) Partial reversal of ethanol-induced reductions in exploration by two benzodiazepine antagonists (flumazenil and ZK 93426). Brain Res Bull 21:765–770

    Article  PubMed  Google Scholar 

  • Lister RG (1988b) Antagonism of the behavioral effects of ethanol, sodiumpentobarbital and RO 15-4513 by the imidazodiazepine RO 15-3505. Neurosci Res Commun 2:85–92

    Google Scholar 

  • Lister RG, Linnoila M (1991) Alcohol, the chloride ionophore and endogenous ligands for benzodiazepine receptors. Neuropharmacology 30:1435–1440

    PubMed  Google Scholar 

  • Lister RG, Nutt DJ (1988) Alcohol antagonists—the continuing quest. Alcohol Clin Exp Res 12:566–569

    PubMed  Google Scholar 

  • Mehta AK, Ticku MK (1988) Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gammaaminobutyric acid A-gated chloride channels. J Pharmacol Exp Ther 246:558–564

    PubMed  Google Scholar 

  • Miczek KA (1974) Intraspecies aggression in rats: effects ofd-amphetamine and chloridazepoxide. Psychopharmacologia 39:275–301

    Article  PubMed  Google Scholar 

  • Miczek KA (1979) A new test for aggression in rats without aversive stimulation: differential effects ofd-amphetamine and cocaine. Psychopharmacology 60:253–259

    Article  PubMed  Google Scholar 

  • Miczek KA (1982) Ethological analysis of drug action on aggression, defense, and defeat. In: Spielgelstein NY, Levy A (Eds) Behavioral models and analysis of drug action. Elsevier, Amsterdam, pp 225–239

    Google Scholar 

  • Miczek KA (1985) Alcohol and aggressive behavior in rats: Interaction with benzodiazepines. Soc Neurosci Abstr 11:1290

    Google Scholar 

  • Miczek KA, Barry H III (1977) Effects of alcohol on attack and defensive-submissive reactions in rats. Psychopharmacology 52:231–237

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Miczek KA, O'Donnell JM (1980) Alcohol and chlordiazepoxide increase suppressed aggression in mice. Psychopharmacology 69:39–44

    Article  PubMed  Google Scholar 

  • Miczek KA, Weerts EM (1987) Seizures in drug-treated animals. Science 235:1127

    PubMed  Google Scholar 

  • Miczek KA, Weerts EM, Tornatzky W, DeBold JF, Vatne TM (1992) Alcohol and aggressive “bursts” in rats: ethological analysis of individual differences. Psychopharmacology 107:551–563

    PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Miczek KA, Woolley J, Schlisserman S, Yoshimura H (1981) Analysis of amphetamine effects on agonistic and affiliative behavior in squirrel monkeys (Saimiri sciureus). Pharmacol Biochem Behav 14 [sup 1]:103–107

    PubMed  Google Scholar 

  • Misslin R, Belzung C, Vogel E (1988) Interaction of RO 15-4513 and ethanol on the behavior of mice: antagonistic or additive effects? Psychopharmacology 94:392–396

    Article  PubMed  Google Scholar 

  • Mos J, Olivier B (1986) RO 15-1788 does not influence postpartum aggression in lactating female rats. Psychopharmacology 90:278–280

    Article  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Nutt DJ, Lister RG, Rusche D, Bonetti EP, Reese RE, Rufener R (1988) RO 15-4513 does not protect rats against the lethal effects of ethanol. Eur J Pharmacol 151:127–129

    Article  PubMed  Google Scholar 

  • Olivier B, Mos J, Miczek KA (1991) Ethopharmacological studies of anxiolytics and aggression. Eur Neuropsychopharmacol 1:97–100

    Article  PubMed  Google Scholar 

  • Rees DC, Balster (1988) Attenuation of the discriminative stimulus properties of ethanol, oxazepam, but not pentobarbital, by Ro 15-4513 in mice. J Pharm Exp Therapeutics 224:592–598

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Sarter M (1990) Elevations of local glucose utilization by the β-carboline ZK 93426. Eur J Pharmacol 177:155–162

    Article  PubMed  Google Scholar 

  • Sarter M, Bruno JP, Dudchenko P (1990) Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification. Psychopharmacology 101:1–17

    Google Scholar 

  • 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

    Google Scholar 

  • Skolnick P, Crawley JN, Glowa JR, Paul SM (1984) Beta-carboline-induced anxiety states. Psychopathology 17:52–60

    PubMed  Google Scholar 

  • Skolnick P, Reed GF, Paul SM (1985) Benzodiazepine-receptor mediated inhibition of isolation-induced aggression in mice. Pharmacol Biochem Behav 23:17–20

    Article  PubMed  Google Scholar 

  • Smoothy R, Berry MS (1983) Effects of ethanol on behavior of aggressive mice from two different strains: a comparison of simple and complex behavioral assessments. Pharmacol Biochem Behav 19:645–653

    Article  PubMed  Google Scholar 

  • Sulcova A, Krsiak M (1984) The benzodiazepine-receptor antagonist Ro 15-1788 antagonizes effects of diazepam on aggressive and timid behaviour in mice. Act Nerv Super 26:255–256

    Google Scholar 

  • Sulcova A, Krsiak M (1986) Beta-carbolines (beta-CCE, FG 7142) and diazepam: synergistic effects on aggression and antagonistic effects on timidity in mice. Act Nerv Super 28:312–316

    Google Scholar 

  • Suzdak PD, Glowa JR, Crawley JN, Schwartz RD, Skolnick P, Paul SM (1986a) A selective imidazobenzodiazepine antagonist of ethanol in the rat. Science 234:1243–1247

    PubMed  Google Scholar 

  • Suzdak PD, Schwartz RD, Skolnick P, Paul SM (1986b) Ethanol stimulates gamma-aminobutyric acid receptor-mediated chloride transport in rat brain synptoneurosomes. Proc Natl Acad Sci USA 83:4071–4075

    PubMed  Google Scholar 

  • Syapin PJ, Jones BL, Kobayashi LS, Finn DA, Alkana RL (1990) Interactions between benzodiazepine antagonists, inverse agonists, and acute behavioral effects of ethanol in mice. Brain Res Bull 24:705–709

    Article  PubMed  Google Scholar 

  • Thorington RW Jr. (1985) The taxonomy and distribution of squirrel monkeys (Saimiri). In: Rosenblum LA, Coe CL (eds) Handbook of squirrel monkey research. Plenum Press, New York, pp 1–32

    Google Scholar 

  • Ticku MK, Kulkarni SK (1988) Molecular interactions of ethanol with GABAergic system and potential of Ro 15-4513 as an ethanol antagonist. Pharmacol Biochem Behav 30:501–510

    Article  PubMed  Google Scholar 

  • Weerts E, Tornatzky W, Miczek KA (1988) Alcohol-benzodiazepine receptor interactions: Aggressive behavior and motor activity in rats and squirrel monkeys. Soc Neurosci Abstr 14 [2]:1261

    Google Scholar 

  • Weerts EM, Tornatzky W, Miczek KA (1992) “Anxiolytic” and “anxiogenic” benzodiazepines and β-carbolines: effects on aggressive behavior in rats and squirrel monkeys. 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

    Article  PubMed  Google Scholar 

  • Winslow JT, Miczek KA (1988) Androgen dependency of alcohol effects on aggressive behavior: a seasonal rhythm in high-ranking squirrel monkeys. psychopharmacology 95:92–98

    PubMed  Google Scholar 

  • Yoshimura H, Ogawa N (1983) Pharmaco-ethological analysis of agonistic behavior between resident and intruder mice: effects of ethyl alcohol. Folia Pharmacol Japon 81:135–141

    Google Scholar 

  • Yu S, Ho IK (1990) Effects of acute barbiturate administration, tolerance and dependence on brain GABA system: comparison to alcohol and benzodiazepines. Alcohol 7:261–272

    Article  PubMed  Google Scholar 

  • Zumpe D, Michael RP (1986) Dominance index: a simple measure of relative dominance status in primates. Am J Primatol 10:291–300

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychology, Research Building, Tufts University, 490 Boston Avenue, 02155, Medford, MA, USA

    Elise M. Weerts, Walter Tornatzky & Klaus A. Miczek

Authors
  1. Elise M. Weerts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Walter Tornatzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaus A. Miczek
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weerts, E.M., Tornatzky, W. & Miczek, K.A. Prevention of the pro-aggressive effects of alcohol in rats and squirrel monkeys by benzodiazepine receptor antagonists. Psychopharmacology 111, 144–152 (1993). https://doi.org/10.1007/BF02245516

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02245516

Key words

Search

Navigation