Change in certain forms of aggressive behavior and the concentration of monoamines in the brain during selection of wild rats for taming

Norway rats have been selected during 20 generations by the absence of aggressive reaction to man (tamed rats). From 7 up to 20th generations of selection, different forms of aggressive behaviour (reaction to glove, intermale, shock-induced aggression and predatory aggression) were studied, and the level of noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid was determined in the brain. In the absence of aggressive reaction to glove in tamed rats, the shock-induced aggression considerably decreased while the predatory aggressiveness (mouse-killing behaviour) and intermale aggressiveness did not change. Beginning from 15-16th generation of selection, a higher level of the 5-hydroxyindoleacetic acid in the hypothalamus was established, in the 20th generation an increased content of serotonin was revealed in the hypothalamus and the midbrain. In some generations of selection an increased level of noradrenaline in the hypothalamus in comparison to wild rats was observed. A conclusion is made that the selection of animals by taming unequally influences different kinds of aggressiveness and is accompanied by inherited consolidated reorganization of the monoamine brain systems.     

Changes in the sexual tendency accompanying selection for aggressiveness in the three-spined stickleback,Gasterosteus aculeatus L.*

Independent selection experiments for reduced juvenile and reduced territorial aggression levels in male three-spined sticklebacks both resulted in reduced courtship aggression levels. In the low juvenile aggression line this is accompanied by an enhanced sexual activity, but in the low territorial aggression line males display a reduced sexual activity. These results are consistent with a mutually inhibitory relationship between the aggressive and sexual tendencies, if selection for juvenile aggressiveness has only affected the aggressive tendency while selection for territorial aggressiveness has simultaneously affected the aggressive and sexual tendencies in the same direction. This is in agreement with the hormonal changes (pituitary-gonadal axis) suggested by the selection studies.     

Further evidence for the role of nitric oxide in maternal aggression: effects of L-NAME on maternal aggression towards female intruders in Wistar rats

It has been shown that nitric oxide (NO) increases aggression in male mice, whereas it decreases aggression in lactating female mice and prairie voles. It is also known that aggression can be exhibited at different levels in rodent species, strain or subtypes. The aims of this study were to investigate the proportion of aggressiveness in Wistar rats, the effect of intraperitoneally administered nonspecific nitric oxide synthase (NOS) inhibitor L-NAME (NG-nitro L-arginine methyl ester) on maternal aggression towards female intruders, and whether these effects are due to NO production or not. Rats were given saline intraperitoneally on the postpartum Day 2 and aggression levels were recorded. The same rats were given 60 mg/kg L-NAME or D-NAME (NG-nitro D-arginine methyl ester) on the postpartum Day 3 and their effects on aggression levels were compared to saline. While L-NAME administration did not cause any differences in the total number of aggressive behavior, aggression duration and aggression intensity, it reduced the proportion of animals showing aggressive behavior. In addition, the latency of the first aggression was significantly increased by L-NAME. In the D-NAME group, however, no significant change was found. Our results have shown that L-NAME reduces maternal aggression towards female intruders in Wistar rats through inhibition of NO production. These results suggest that the role of NO in offensive and defensive maternal aggression shares neural mechanisms.     

The role of dopamine receptors in controlling mouse aggressivity: the genotype dependence]

Significant genotypic differences in shock-induced aggression were found in mice of eight inbred strains. Aggression was evaluated in test with the action of low electric current through the cage floor. Low aggressive strains C3H/He, DD, BALB/c, AKR and highly aggressive strains CBA, DBA/2. CC57Br were singled out by the number of aggressive attacks. Selective stimulation of dopamine D2 receptors by bromocriptine considerably increased the shock-induced aggressiveness in mice of low-aggressive strains. Blockade of D2-receptors by the injection of antagonist sulpiride decreased or prevented the manifestation of aggression in highly-aggressive mice. At the same time selective agonist of dopamine (D1) receptors SKF 38393 and administration of selective antagonist of D1-receptors SCH 23390 did not influence significantly shock-induced aggression. Thus, shock-induced aggression, depends on the animal genotype and activation of D2-receptors.     

Reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice

The importance of AMPA-type glutamate receptors has been demonstrated in neuronal plasticity and in adaptation to drugs of abuse. We studied the involvement of AMPA receptors in social interaction and anxiety and found that in several paradigms of agonistic behavior naïve male mice deficient for the GluR-A subunit- containing AMPA receptors are less aggressive than wild-type littermates. GluR-A deficient mice and wild-type littermates exhibited similar basic behavior and reflexes as monitored by observational Irwin's test, but they tended to be less anxious in elevated plus-maze and light-dark tests. Maternal aggression or male-female encounters were not affected which suggests that male hormones are involved in the expression of suppressed aggressiveness. However, testosterone levels and brain monoamines can be excluded and found to be similar between GluR-A deficient and wild-type littermates. The reduced AMPA receptor levels caused by the lack of the GluR-A subunit, and measured by a 30% reduction in hippocampal [³H]-S-AMPA binding, seem to be the reason for suppressed male aggressiveness. When we analyzed mice with reduced number of functional AMPA receptors mediated by the genomic introduced GluR-A(Q582R) channel mutation, we observed again male-specific suppressed aggression, providing additional evidence for GluR-A subunit-containing AMPA receptor involvement in aggression.     

The involvement of brain 5-HT(1A)-receptors in genetically determined aggressive behavior

The hypothesis was tested that one of the critical mechanisms underlying genetically determined aggressiveness involves brain serotonin 5-HT(1A)-receptors. The expression of 5-HT(1A)-receptor mRNA in brain structures and functional correlate for 5-HT(1A)-receptors identified as 8-OH-DPAT-induced hypothermia were studied in Norway rats bred over the course of 59 generations for the low and high affective (defensive) aggressiveness with respect to man and in highly aggressive (offensive) MAO A-knockout mice (Tg8 strain). Considerable differences between the aggressive and the nonaggressive animals were shown. Agonist of 5-HT(1A)-receptor 8-OH-DPAT (0.5 mg/kg for rats and 2.0 mg/kg for mice, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and mice and did not affect significantly the body temperature in aggressive animals. In aggressive rats, a significant reduction of the expression of 5-HT(1A)-receptor mRNA was found in the midbrain. In Tg8 mice, 5-HT(1A)-receptor mRNA level was increased in the frontal cortex and amygdala and not changed in the hypothalamus and the midbrain. The results provide support for the idea that brain 5-HT(1A)-receptors contribute to the genetically determined individual differences in aggressiveness.     

On the role of brain serotonin system in the pathway from gene to behaviour

This paper concentrates on involvement of protein elements in the brain neurotransmitter serotonin system (key enzymes in serotonin metabolism and 5-HT(1A) receptors) in the genetic control of behaviour. The data were obtained using Norway rats selected for more that 50 generations for lack of aggressive response and for aggressive behaviour towards humans (fear-induced aggression), inbred mouse strains, and MAO A knockout mice. The review provides converging line of evidence that: 1) brain serotonin contributes to critical mechanism underlying genetically defined individual differences in aggressiveness, and 2) genes encoding pivotal enzymes in serotonin metabolism (tryptophan hydroxylase, MAO A) and 5-HT(1A) receptors belong to a group of genes that modulate aggressive behaviour.     

The effect of ablation in the n. medianus raphe on the aggressive and sexual behavior of white rats]

A study was made of a change in the aggressive and sexual behaviour of albino rats under the influence of ablation of the n. medianus raphe whose serotonin-containing units send ascending projections to the forebrain. Ablation of the nucleus produced a drop in the serotonin level in the forebrain, and aggressiveness to mice, which was much more pronounced in the male than in the female animals. Intraspecial aggressiveness between animals of the same sex and the sexual behaviour of the male rats did not change. It has been assumed that n. medianus raphe exerts an inhibitory influence on the manifestation of aggression of the "predatory" animal.     

Synergistic effect of estradiol benzoate and dihydrotestosterone on aggression in mice

Orchiectomized CD-1 mice were treated with several steroids, alone and in combination, and then tested for aggressiveness against group-housed, intact “stimulus” mice. Estradiol benzoate (EB) in combination with dihydrotestosterone (DHT) elicited aggression equivalent to that shown by intact, sham-operated animals and by testosterone-treated subjects. EB alone was less effective than EB with DHT. DHT alone elicited no more aggression than that observed in control animals. The data suggest a synergism between EB and DHT within the central nervous system in the induction of aggressive behavior.     

Territorial Behaviour and Social Organization as a Function of the Level of Aggressiveness in Male Mice

Territoriality and social organization were examined in relation to different genetic dispositions for aggressive behaviour. The animals used in the study were male mice of the 51st and 52nd generation of selection for high (Turku Aggressive, TA) and low (Turku Non-Aggressive, TNA) levels of aggressiveness. The level of aggressiveness of the animals was assessed by means of individual tests with non-aggressive standard opponents, after which they were allowed to form individual territories in a 102 times 204 times 90 cm enclosure. TA and TNA males were placed in different enclosures. After 2 wk, when the partitions between individual pens were removed, the behaviour of the animals was observed for a 7-d period. Excessive fighting between the highly aggressive TA males occurred, resulting in the formation of dominant-subordinate relationships. A great number of attacks inflicted were found to be associated with dominance in the colony, and correlated with a high level of aggressiveness when the animals were individually tested for aggression after having been in colony environments. The level of aggressiveness of the TA males that had become subordinates had significantly decreased. The TNA males fought less and were more often found to stay in their original territory for the entire period of observation. The results suggest that different genotypes for aggression arc related to differences in territoriality and social organization in mice.     

High predisposition to catalepsy decreases intermale aggression and increases acoustic startle reflex amplitude

Reaction of freezing (a pronounced motor inhibition, catalepsy) is suggested to be associated with fear in response to predator appearance or attack of aggressive congener. In order to evaluate association between a kind of behavior such as freezing, aggressiveness and fear, the effects of high predisposition to catalepsy on intermale aggression, acoustic startle response and anxiety-related behavior in the light/dark test were studied. Mice of 14th and 15th generations of selective breeding for high predisposition to catalepsy were characterized by a significant decrease in aggressive behavior. The marked decrease in the percentage of aggressive mice in the catalepsy-prone strain is consistent with the notion that aggression and catalepsy represent two alternative kinds of behavior in intermale conflicts. A positive correlation was found between high predisposition to catalepsy and startle reflex amplitude (but not anxiety-related behavior).     

Cerebrospinal fluid monoamine and metabolite concentrations and aggression in rats

In humans and other primates low cerebrospinal fluid (CSF) levels of the major serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been correlated to high aggressiveness. This finding forms the basis of the 5-HT deficiency hypothesis of aggression. Surprisingly, this correlation has not been confirmed in rodents so far, while manipulation studies aimed to investigate the link between 5-HT and aggressive behaviour are mostly carried out in rodents. In this study the relation between aggression and CSF monoamine and metabolite concentrations was investigated in male Wildtype Groningen rats. In sharp contrast to the hypothesis and our expectation, a clear positive correlation was found between the individual level of trait-like aggressiveness and CSF concentrations of 5-HT, 5-HIAA, norepinephrine (NE), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC). Shortly after the acute display of aggressive behaviour (as a state-like phenomenon), decreased 5-HT levels and an increase in 5-HIAA/5-HT ratio and NE concentrations were found. Surprisingly, pharmacological challenges known to influence 5-HT transmission and aggressive behaviour did not affect CSF 5-HT and 5-HIAA concentrations, only the NE level was increased. Lesioning 5-HT terminals by 5,7-dihydroxytryptamine (5,7-DHT) administration caused a decrease in CSF 5-HT and 5-HIAA, but without affecting aggressive behaviour. The observed positive correlation between CSF 5-HIAA and trait aggressiveness makes it questionable whether a direct extrapolation of neurobiological mechanisms of aggression between species is justified. Interpretation of CSF metabolite levels in terms of activity of neural substrates requires a far more detailed knowledge of the dynamics and kinetics of a neurotransmitter after its release.     

Maternal aggression and intermale social aggression: a behavioral comparison

The aggressive behavior of alpha male rats and lactating females were each examined toward an intact adult male rat, a castrated adult male rat, an anesthetized adult male rat, a nonlactating adult female rat, an adult albino guinea pig (male or female), or an albino mouse (male or female). When in their living colony, females displayed high levels of aggressiveness toward all stimulus objects except a mouse. The aggression toward the intruding males occurred whether the female's pups were present or not. Alpha males were aggressive toward the same stimuli except an intruding female rat and a mouse. When tested in an unfamiliar colony, the males but not the females (with or without pups present) were aggressive toward an adult male rat. Half of the females but none of the males displayed defensive burying toward an anesthetized intruder. It is suggested that the attack on an adult female, the absence of attack outside of the resident colony, and the tendency to display defensive burying are features of the aggressiveness of lactating females that are fundamentally different from the aggressiveness of alpha males. The form of the aggression (lateral attack vs. lunge attack) was only quantitatively different in males and females.     

Neurobiological correlates premeditated (learned) aggression: seeking new experimental approaches]

Theoretical possibility of experimental modeling of learned (premediated) aggression developing in human after experience of aggression is considered. The sensory contact technique increases aggressiveness in male mice and allows aggressive type of behavior to be formed as a result of repeated experience of victories in daily agonistic confrontations. Some behavioral domains confirm the development of learned aggression in males similar to those in humans. The features are: repeated experience of aggression reinforced by victories; elements of learned behavior after period of confrontations; intent, measured by increase of the aggressive motivation prior agonistic confrontation; decreased emotionality estimated by parameters of open field behavior. Relevant stimuli provoke demonstration of aggression. This review summarized data on the influence of positive fighting experience in daily intermale confrontations on the behavior, neurochemistry and physiology of aggressive mice (winners). This sort of experience changes many characteristics in individual and social behaviors, these having been estimated in different tests and in varied situations. Some physiological parameters are also changed in the winners. Neurochemical data confirm the activation of brain dopaminergic systems and functional inhibition of serotonergic system in winners under influence of repeated experience of aggression. The expression of the neurochemical and behavioral changes observed in winners has been found dependent on the mouse strain and on the duration of their agonistic confrontations. Similarities in mechanisms of learned aggression in humans and mice are considered.     

Changes in male odours and urinary marking patterns due to inhibition of aggression in male mice

The effects of active inhibition of aggression on male odours and urinary marking patterns were studied in mice belonging to a highly aggressive strain the TA (Turku Aggressive), which has been developed by selective breeding through 37 generations. These males were defeated by trained fighters until they showed no aggression. Individually housed TA males served as controls. Mice from the parental or Normal Strain, which is intermediate in aggression, were exposed to the odours. The males from the Normal Strain were tested for aggression against male castrates to which urine from the two types of TA males or water had been applied. The urine from the highly aggressive control TA males evoked most aggression. The Normal males were later tested against castrates on soiled sawdust. Fewer attacks occured on sawdust soiled by the urine from the control TA males. The preferences for areas covered with soiled sawdust were also assessed. The males from the Normal Strain preferred areas soiled by the TA males trained to nonaggressiveness while the females preferred areas soiled by the highly aggressive control TA males. Subsequently the size and number of urinary marks deposited were examined. The TA males trained to nonaggressiveness voided urine in fewer but larger pools. The differences showed the same direction as those previously found between the TA and TNA strains, selectively bred for aggression and non-aggression, respectively. In mice the odour signals and urinary marking patterns seem to be correlated with the level of aggressiveness, either hereditarily determined or acquired through learning.     

Participation of 5-HT1A-receptors in regulating various types of aggressive behavior

We studied the effects of selective agonists of 5-HT1A receptors 8-OH-DPAT and flesinoxan on aggressive behavior of C57BL/6 male mice in the "resident-intruder" test and on defensive aggression of Norway rats toward man. 8-OH-DPAT (0.4 mg/kg, i.p.) significantly reduced the intermale aggression in mice and defensive aggression in rats (0.1-0.5 mg/kg, i.p.). In the dose of 0.5 mg/kg, flesinoxan inhibited the aggressive behavior in mice. These results suggest that activation of 5-HT1A receptors reduces different kinds of affective aggression. The results are discussed in terms of interaction between the well-known anxiolytic effects of 5-HT1A agonists and their antiaggressive properties.     

The role of parasite-induced immunodepression,rank and social environment in the modulation of behaviour and hormone concentration in male laboratory mice (Mus musculus).

Peripheral immune responsiveness in male laboratory mice was reduced by infection with the trichostrongyloid nematode Heligmosomoides polygyrus. Responsiveness was also lower among high-ranking (aggressive) males regardless of infection status. Reduced responsiveness in both infected animals and high rankers was associated with elevated serum corticosterone concentration (a potential immunodepressant) and was compounded among high-ranking males by subsequent high aggressiveness. As in previous experiments, only low rankers modulated testosterone secretion in relation to current immunocompetence and corticosterone concentration. The lack of any downregulation of aggression in response to parasite-induced immunodepression contrasted with previous results using antithymocyte serum and may be due to the more localized nature of immunodepression during H. polygyrus infection. However, the additional increase in corticosterone concentration resulting from exposure to female odour and destabilized aggressive social relationships did result in downregulation of aggression among high rankers and of testosterone among mice generally, suggesting that modulation rules of thumb are at least partly dependent on the proximate cues associated with immunodepression.     

Mice: progesterone stimulates aggression in pregnancy-terminated females

Three experiments were conducted in order to assess the role of progesterone (P) in the aggressive behavior displayed by late pregnant Rockland-Swiss mice toward adult male intruders. In Experiment 1, hysterectomy on the 15th day of gestation reduced the aggressive behavior normally displayed by pregnant mice toward male intruders. In Experiment 2, Silastic implants of P stimulated aggression in hysterectomized mice but did not fully restore the behavior to the level of fighting normally observed in pregnant animals. In Experiment 3, aggressive behavior in P-treated hysterectomized animals was inhibited by simultaneous exposure to estradiol (E). Also, treatment with E alone did not stimulate aggression in hysterectomized mice. While pregnancy-induced aggression is promoted by P, other neuroendocrine factors may act in concert with the steroid to fully stimulate aggression in gravid mice.     

Aggressiveness and size: a model and two tests

Individual variation in aggressive behavior in animals might be caused by adaptive covariation with body size. We developed a model that predicts the benefits of aggressiveness as a function of body size. The model indicated that individuals of intermediate sizes would derive the greatest benefits from being aggressive. If we assume that the cost of aggression is approximately uniform with respect to body size, selection should favor higher aggression in intermediate-sized individuals than in large or small individuals. This prediction was tested by stimulating male Madagascar hissing cockroaches, Gromphadorhina portentosa, with disembodied antennae and recording the males' aggressive responses. Antennae from larger males evoked weaker responses in subjects, suggesting that males obtained information about their opponents' size from the opponents' antennae alone. After accounting for this effect, we found support for the key prediction of our model: aggressiveness peaked at intermediate sizes. Data from actual male-male interactions validated that the antenna assay accurately measured aggressiveness. Analysis of an independent data set generated by staging male-male interactions also supported the prediction that intermediate-sized males were most aggressive. We conclude that adaptive covariation between body size and aggressiveness explains some interindividual variation in aggressiveness.     

Lorenz Was Right! Or Does Aggressive Energy Accumulate?

Evidence supporting the fact that innate mechanisms of regulation of aggressive behavior as a result of a repeated experience of aggression ending in victories are transformed into pathological mechanisms based on accumulation of neurochemical shifts in the brain, enhancing aggressiveness, and forming aggressive motivation in aggressive winners. This confirms the concept by Lorenz on the existence of a mechanism (but not instinct) of a spontaneous accumulation of aggressive energy that needs a discharge and formation of permanent attraction to manifestation of aggression.