Abstract
Selective breeding for aggressive behavior alters GABA-dependent chloride uptake and behavioral response to benzodiazepine treatment. Pharmacological and biochemical studies examined subjects from three lines of adult male ICR mice selectively bred for either high levels or low levels of aggressive behavior, as well as unselected controls. Selective breeding produced two lines of behaviorally distinct males. During 5-min dyadic confrontations with an outbred stimulus animal, untreated low-aggressive mice spent more time in walking, rearing, and social interaction than untreated high-aggressive mice. The three lines also showed different responsiveness to the aggression increasing and decreasing effects as well as the sedative effects of benzodiazepine treatment. High doses of chlordiazepoxide (17, 30 mg/kg) reduced motor behaviors (walk, rear and groom) in the low-aggressive line without altering these behaviors in the high aggressive line. In the high-aggressive line, the same doses of chlordiazepoxide (17, 30 mg/kg) produced a behavioral shift; aggressive behaviors were reduced while social behaviors increased to levels similar to the untreated low-aggressive line. In contrast, only the unselected line pursued and threatened more after a low dose of chlordiazepoxide (3 mg/kg). The three lines also showed alterations at the GABAA-benzodiazepine receptor complex. Specific uptake of [3H]Ro-15-1788 was increased in cerebral cortex, hypothalamus and hippocampus in the low-aggressive line, and was reduced in these areas in high-aggressive line when compared with unselected controls. Similarly, GABA-dependent chloride uptake in cortical synaptoneurosomes was augmented in low-aggressive mice and decreased in high-aggressive mice when compared to unselected controls. These data suggest a direct relationship between GABAA-benzodiazepine receptor function and the predisposition to initiate aggressive behavior.
Similar content being viewed by others
References
Braestrup C, Squires RF (1977) Brain specific benzodiazepine receptors in rats characterized by high affinity 3H-diazepam binding. Proc Natl Acad Sci USA 74:3805
Brizer DA (1988) Psychopharmacology and the management of violent patients. Psychiatr Clin N Am 11:551–568
Cairns RB, MacCombie DJ, Hood KE (1983) A developmental-genetic analysis of aggressive behavior in mice: I. Behavioral outcomes. J Com Psychol 97:69–89
Cairns RB, Gariepy J-L, Hood KE (1990) Development, micro-evolution, and social behavior. Psychol Rev 97:49–65
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
DaVanzo JP, Daugherty M, Ruckart R, Kang L (1966) Pharmacological and biochemical studies in isolation-induced fighting mice. Psychopharmacologia 9:210–219
DeFeudis FV (1983) GABA binding processes and behavior. Gen Pharmacol 14:313–319
Depaulis A, Vergnes M (1983) Induction of mouse-killing in the rat by intraventricular injection of a GABA-agonist. Physiol Behav 30:383–388
Depaulis A, Vergnes M (1984) GABAergic modulation of mouse-killing in the rat. Psychopharmacology 83:367–372
Depaulis A, Vergnes M (1985) Elicitation of conspecific attack or defense in the male rat by intraventricular injection of a GABA agonist of antagonist. Physiol Behav 35:447–453
Donat P, Krsiak M (1985) Effects of a combination of diazepam and scopolamine in animal model of anxiety and aggression. Act Nerv Super (Praha) 7:307–308
Drugan RC, Holmes PV (1991) Central and peripheral benzodiazepine receptors: Involvement in an organism's response to physical and psychological stress. Neurosci Biobehav Rev 15:277–298
Earley CJ, Leonard BE (1977) The effect of testosterone and cyproterone acetate on the concentration of aminobutyric acid in brain areas of aggressive and non-aggressive mice. Pharmacol Biochem Behav 6:409–413
Haefely W (1988) Endogenous ligands of the benzodiazepine receptor. Pharmacopsychiatry 21:43–46
Haug M, Simler S, Kim L, Mandel P (1980) Studies on the involvement of GABA in the aggression directed by groups of intact or gonadectomized male and female mice towards lactating intruders. Pharmacol Biochem Behav 12:189–193
Haug M, Simler S, Ciesielski L, Mandel P, Moutier R (1984) Influence of castration and brain GABA levels in three strains of mice on aggression towards lactating intruders. Physiol Behav 32:767–770
Heise GA, Boff E (1961) Taming action of chlordiazepoxide. Fed Proc 20:393
Heuschele WP (1961) Chlordiazepoxide for calming zoo animals. J Am Vet Medi Assoc 139:996–998
Hood KE, Cairns RB (1989) A developmental-genetic analysis of aggressive behavior in mice: IV. Genotype-environment interaction. Agress Behav 15:361–380
Kochansky GE, Salzman C, Shader RI, Harmatz JS, Ogeltree AM (1975) The differential effects of chlordiazepoxide and oxazepam on hostility in a small group setting. Am J Psychiatry 132:861–863
Krsiak M (1975) Timid singly-housed mice: their value in prediction of psychotropic activity of drugs. Br J Pharmacol 55:141–150
Lagerspetz KMJ (1969) Aggression and aggressiveness in laboratory mice. In: Garattini S, Sigg EB (eds) Aggressive Behaviour. Excerpta Medica Foundation, Amsterdam, pp 77–85
Lagerspetz KMJ, Lagerspetz KYH (1974) Genetic determination of aggressive behavior. In: Van Abeelen JHF (ed) The genetics of behaviour. North-Holland, Amsterdam, pp 321–346
Lewis MH, DeVaud LL, Gariepy JL, Southerland SB, Mailman RB, Cairns RB (1992) Dopamine and social behavior in mice bred for high and low levels of aggression. Brain Res Bull (in press)
Mack G, Simler S, Mandel P (1975) Systeme inhibiteur GABAergique dans l'agressivite interspecifique Rat-Souris. J Physiol 71:162a
Mandel P, Mack G, Kempf E (1979) Molecular basis of some models of aggressive behavior In: Sandler M (ed) Psychopharmacology of aggression. Raven Press, New York, pp 95–110
Mandel P, Ciesielski L, Maitre M, Simler S, Kempf E, Mack G (1981) Inhibitory amino acids, aggressiveness, and convulsions. In: DeFeudis FV, Mandel (eds) Amino acid neurotransmitters. Raven Press, New York, pp 1–9
Miczek KA (1974) Intraspecies aggression in rats; effects ofd-amphetamine and chlordiazepoxide. Psychopharmacologia 39:275–301
Miczek KA (1983) 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, O'Donnell JM (1980) Alcohol and chlordiazepoxide increase suppressed aggression in mice. Psychopharmacology 69:39–44
Miller LG, Greenblatt DJ, Paul SM, Shader RI (1987) Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions. J Pharmacol Exp Ther 240:516–522
Miller LG, Greenblatt DJ, Barnhill JG, Shader RI (1988) Chronic benzodiazepine administration. I. Lorazepam administration is associated with down regulation of benzodiazepine receptor binding and gama-aminobutyric acidA receptor function. J Pharmacol Exp Ther 246:170–176
Mohler H, Okada T (1977) Benzodiazepine receptor: demonstration in the central nervous system. Science 198:849–851
Molina V, Ciesielsski L, Gobaille S, Mandel P (1986a) Effects of the potentiation of the GABAergic neurotransmission in the olfactory bulbs on mouse-killing behavior. Pharmacol Biochem Behav 24:657–664
Molina V, Ciesielsski L, Gobaille S, Mandel P (1986b) Effects of the potentiation of the GABAergic neurotransmission in the olfactory bulbs on mouse-killing behavior. Pharmacol Biochem Behav 24:657–664
Olivier B, van Dalen D (1982) Social behaviour in rats and mice: an ethologically based model for differentiating psychoactive drugs. Aggress Behav 8:163–168
Olivier B, van Aken H, Jaarsma I, van Oorshot R, Zethof T, Bradford D (1984) Behavioural effects of psychoactive drugs on agonistic behaviour of male territorial rats (resident-intruder model). In: Miczek KA, Kruk MR, Olivier B (eds) Ethopharmacological aggression research. Liss, New York, pp 137–156
Potegal M, Perumal AS, Barkai AI, Cannova GE, Blau AD (1982) GABA binding in the brains of aggressive and non-aggressive female hamsters. Brain Res 247:315–324
Puglisi-Allegra S, Mandel P (1980) Effects of sodium n-dipropylacetate, muscimol hydrobromide and (R,S)nipecotic acid amide on isolation-induced aggressive behavior in mice. Psychopharmacology 70:287–290
Rickels K, Downing RW (1974) Chlordiazepoxide and hostility in anxious outpatients. Am J Psychiatry 131:442–444
Rodgers RJ, Depaulis A (1982) GABAergic influences on defensive fighting in rats. Pharmacol Biochem Behav 17:451–456
Sheard MH (1983) Psychopharmacology of aggression. In: Hippius H, Winokur G (eds) Clinical psychopharmacology. Excerpta Medica, Amsterdam, pp 188–201
Sheard MH (1984) Clinical pharmacol of aggressive behavior. Clin Neuropharmacol 7:173–183
Simler S, Puglisi-Allegra S, Mandel P (1982) Gamma-aminobutyric acid in brain areas of isolated aggressive or non-aggressive inbred strains of mice. Pharmacol Biochem Behav 16:57–61
Sulcova A, Krsiak M (1980) Effect of piracetam on agonistic behaviour in mice. Acti Nerv Super (Praha) 122:200–201
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 (Praha) 26:255–256
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 (Praha) 28:312–316
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Weerts, E.M., Miller, L.G., Hood, K.E. et al. Increased GABAA-dependent chloride uptake in mice selectively bred for low aggressive behavior. Psychopharmacology 108, 196–204 (1992). https://doi.org/10.1007/BF02245307
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245307