Modifying effect of the repeated experience of agonistic confrontations on effect of naltrexone in male mice

In mice with different experience of agonistic confrontations: victories or social defeats during 3 and 10 days (T3 and T10 winners and T3 and T10 losers, resp.), T10 winners displayed a lesser aggression and a more hostile behaviour than T3 winners. Naltrexone dose-dependently decreased attacks in the T3 winners and did not affect aggressive grooming, diggings, autogrooming, and exploratory activity. Naltrexone was ineffective in T10 winners. The naltrexone effects were similar in T3 and T10 losers and its high and low doses contrarily affected different parameters of submissive behaviour. The repeated experience of agonistic confrontations seems to modify the naltrexone effects depending on a neurochemical background, differing in winners and losers.     

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.     

Effect of the D1-receptor antagonist SCH-23390 on the individual and aggressive behavior in male mice with various aggression experience

It has been shown that dopaminergic systems are involved in mechanisms of aggressive behavior. Effects of SCH 23390 (dopamine Di receptors antagonist. 0-1 mg/kg, i/p, 30 min) on aggressive and individual behaviors were studied in male C57BL/6J mice with different experience of aggression. SCH 23390 reduced aggressive attacks in animals without preliminary experience of aggression. However total time of hostile behavior (sum of the total time of attacks, aggressive grooming and diggings) didn't changed. No significant effects on behaviors were found in mice with long (20 days) repeated experience of aggression. It was supposed that long aggressive experience produces pharmacological desensitization of Di receptors as a result of enhanced dopaminergic activity shown earlier in aggressive animals.     

Involvement of kappa-opioid receptors in mechanisms of aggressive and submissive types of behavior in male mice

Effects of the kappa-opioid receptor agonist U-50.488H (0.0, 0.6, 1.25, 2.5 mg/kg. s.c., 30 min) on behavior of the winner with repeated experience of victories and the losers with repeated experience of social defeat in 20 daily agonistic confrontations as well as the control mice were investigated in the tests estimating exploratory activity (open-field) and communication (partition test). Different effects of drug on behaviors of animals with different social story were shown in both tests. In the losers, all doses of U-50.488H had anxiolytic effect, increasing the communication in the partition test. In the winners, the drug induced an increase of aggressive motivation. The control mice were less sensitive to the treatment. In the open-field test, U-50.488H increased the locomotor and exploratory activity in high anxious losers. Winners significantly differed in their reaction to drug treatment in most behavioral forms in comparison with the controls and losers. It was concluded that kappa-opioid receptors are specifically involved into mechanisms of formation of aggressive or submissive types of behaviors under positive or negative social experience.     

Effects of repeated experience of aggression on aggressive motivation and development of anxiety in male mice

The sensory contact technique allows an aggressive type of behavior to be formed as a result of repeated experience of social victories in daily agonistic confrontations. In mice of the low-aggressive and high-emotional CBA/Lac strain repeated positive fighting experience increases plus-maze anxiety. Behavioral reactivity of males to other conspecifics in the partition test (which measures aggressive motivation) significantly rises. It is concluded that repeated experience of aggression provokes the development of anxiety in male mice. The results suggest that level of anxiety and its behavioral realization depend on duration of aggressive experience and genetic strain.     

Modulation of anxiety-related behaviors by mu- and kappa-opioid receptor agonists depends on the social status of mice

This study was aimed to determine the effects of mu- and kappa-opioid receptor activation in relation to the social status of mice, being a winner with repeated experience of victories or a loser with repeated experience of social defeats. The behaviors of the animals were assessed in a social encounter test measuring the communicative behavior towards a familiar and an unfamiliar partner behind a perforated transparent partition (partition test) and in an elevated plus-maze test estimating the anxiety level of mice. Placebo and graded doses of the mu-opioid receptor agonist DAMGO (0.5 and 2 mg/kg s.c.) and the kappa-opioid receptor agonist U-50,488H (0.6, 1.25, and 2.5 mg/kg s.c.) were administered to the control mice, winners and losers in two experiments. In the partition test, the winners spent somewhat more time and the losers less time than the controls in the vicinity of their partner probably related to a lower and higher level of anxiety respectively. In the plus-maze test the losers appeared to have a somewhat higher anxiety level than the controls and winners. In both tests DAMGO produced anxiogenic-like effects in the winners and the controls, but not in the losers. Winners hardly responded to treatment with U-50,488H, while the losers responded dose dependently with an anxiolytic-like effect in both tests. It is concluded that anxiety-like responses in mice are differentially affected by stimulation of mu- and kappa-opioid receptors and that the effects depend on the social status of the animals.     

3H][D-Ala2,NMePhe4,Gly-ol5]-enkephalin (mu-opioid) binding in beige-J mice

Tritiated [D-Ala2,NMePhe4,Gly-ol5]-enkephalin ([3H]DAGO) was used to examine mu-opioid receptor number and mu-ligand binding in brain synaptic membranes (P2 fraction) from C57BL/6J-bgJ/bgJ (beige-J) mice, a strain with combined deficiencies in immunological function (resembling Chediak-Higashi syndrome) and analgesic response to mu-opioid agonists such as morphine and DAGO. As controls, white mice, beige-J littermates (normally responsive to mu-opioid agonists), and a known mu-deficient strain (CXBK) were also examined. Neither the KD (0.47 to 0.49 nM) nor the Bmax (153 to 168 fmol/mg protein) determined for beige-J mice was significantly different from values determined for littermates or white mice. In contrast, the Bmax of CXBK mice (66 fmol/mg protein) was clearly less than that of the other strains. The analgesic defect of beige-J mice, therefore, is not likely due to an insufficient number of mu-opioid receptors, as it presumably is in CXBK mice. Carbachol (200 micrograms/ml), which partly corrects the analgesic defect of beige-J mice, had no effect on [3H]DAGO binding either acutely in vitro or chronically ex vivo after administration to beige-J mice for three weeks. Hence, the analgesic defect of beige-J mice appears to be due to some defect in the mu-opioid receptor-effector coupling mechanism or to some endogenous substance that inhibits binding of mu-opioid ligands to otherwise functional receptors.     

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.     

Lorenz was right, or does aggressive energy accumulate?

Evidence supporting the fact that inherited 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.     

The development of catatonic reactions in male mice of CBA/Lac strain: the effect of repeated experience of aggression and submission

The development of catatonic reactions with rigid muscle tension due to stimulation of the skin at the scruff (catatonia-"pinch" test) and wax muscle plasticity (repeated pinch-induced catalepsy displayed on the parallel bars--BAR-test) was investigated in aggressive and submissive CBA/Lac male mice with repeated experiences of social victories (winners) or defeats (losers), accordingly. The expression of catatonic-like state in "pinch" test was significantly more in the losers after 20 daily agonistic confrontations in comparison with the winners. The catalepsy in the BAR-test was increased in animals with experience of agonistic confrontation in comparison with the controls, however expression of catalepsy reaction depended on kind and duration of agonistic interactions. The pronounced freezing predominated in the free behavior of the losers and, on the contrary, the winners demonstrated the abnormal undirected jumping. It was suggested that two contrast forms of catatonic syndrome accompanying by development of akinesia- or hiperkinesia-like states, are developed in the defeated and victorious (accordingly) mice of cataleptic CBA/Lac strain.     

Effects of repeated aggressive encounters on approach to a female and plasma testosterone in male mice

Effects of repeated experience of aggression accompanied by social victories or social defeat in 10 daily agonistic confrontations on testosterone levels in and the behavioral response of CBA/Lac male mice exposed to a receptive female from behind a perforated transparent partition have been examined. Testosterone levels were not changed significantly in the mice that had consistently been victorious over 10 days (winners) or in the mice that had consistently been defeated over 10 days (losers). Losers and controls (mice that had been caged individually for 5 days) responded with increased levels of behavioral activity near the partition and elevated testosterone. Winners showed a significantly poorer behavioral and hormonal response. It is concluded that the repeated display of aggression by male mice led to a reduction in both their behavioral and neuroendocrine responses to an estrous female.     

Disruption of the vasopressin 1b receptor gene impairs the attack component of aggressive behavior in mice

Vasopressin affects behavior via its two brain receptors, the vasopressin 1a and vasopressin 1b receptors (Avpr1b). Recent work from our laboratory has shown that disruption of the Avpr1b gene reduces intermale aggression and reduces social motivation. Here, we further characterized the aggressive phenotype in Avpr1b -/- (knockout) mice. We tested maternal aggression and predatory behavior. We also analyzed the extent to which food deprivation and competition over food increases intermale aggression. We quantified defensive behavior in Avpr1b -/- mice and later tested offensive aggression in these same mice. Our results show that attack behavior toward a conspecific is consistently reduced in Avpr1b -/- mice. Predatory behavior is normal, suggesting that the deficit is not because of a global inability to detect and attack stimuli. Food deprivation, competition for food and previous experience increase aggression in both Avpr1b +/+ and -/- mice. However, in these circumstances, the level of aggression seen in knockout mice is still less than that observed in wild-type mice. Defensive avoidance behaviors, such as boxing and fleeing, are largely intact in knockout mice. Avpr1b -/- mice do not display as many 'retaliatory' attacks as the Avpr1b +/+ mice. Interestingly, when territorial aggression was measured following the defensive behavior testing, Avpr1b -/- mice typically show less initial aggressive behavior than wild-type mice, but do show a significant increase in aggression with repeated testing. These studies confirm that deficits in aggression in Avpr1b -/- mice are limited to aggressive behavior involving the attack of a conspecific. We hypothesize that Avpr1b plays an important role in the central processing that couples the detection and perception of social cues (which appears normal) with the appropriate behavioral response.     

Salivary testosterone and aggression, delinquency, and social dominance in a population-based longitudinal study of adolescent males

Testosterone (T) has been found to have a stimulating effect on aggressive behavior in a wide range of vertebrate species. There is also some evidence of a positive relationship in humans, albeit less consistently. In the present study we investigated the relationship between T and aggression, dominance and delinquency over time, covering a period from early adolescence to adulthood. From a large population-based sample (n = 1.161) a subgroup of 96 boys was selected whose behavior had been assessed repeatedly by different informants from age 12 to 21 years, and who had provided multiple T samples over these years of assessment. On the whole, a decrease in aggressive and delinquent behavior was observed in a period in which T rises dramatically. Boys who developed a criminal record, had higher T levels at age 16. In addition, positive associations were observed between T and proactive and reactive aggression and self-reported delinquent behavior. Over the pubertal years different forms of aggressive and delinquent behavior were positively related to T, which may indicate that specific positive links are dependent on the social setting in which this relationship is assessed.     

Effects of opiate ligands on intraspecific aggression in crickets

In the cricket Gryllus bimaculatus, the opiate antagonist naloxone, 30 microg in 50 microl into hemolymph per animal, caused a release of intraspecific aggression in male-losers and in females. Naloxone had no significant effect on the aggression of winners and isolated males. The agonist of mu-opiate receptors DAGO, 45 microg, suppressed aggression in male winners and decreased the percentage and duration of contact fights between previously isolated males. The results suggest that, during social contacts, the activity of the endogenous opioid system may contribute to suppressing aggression in subordinate males, as well as in females.     

What can animal research tell us about the link between androgens and social competition in humans?

A contribution to a special issue on Hormones and Human Competition.The relationship between androgenic hormones, like testosterone (T), and aggression is extensively studied in human populations. Yet, while this work has illuminated a variety of principals regarding the behavioral and phenotypic effects of T, it is also hindered by inherent limitations of performing research on people. In these instances, animal research can be used to gain further insight into the complex mechanisms by which T influences aggression. Here, we explore recent studies on T and aggression in numerous vertebrate species, although we focus primarily on males and on a New World rodent called the California mouse (Peromyscus californicus). This species is highly territorial and monogamous, resembling the modern human social disposition. We review (i) how baseline and dynamic T levels predict and/or impact aggressive behavior and disposition; (ii) how factors related to social and physical context influence T and aggression; (iii) the reinforcing or “rewarding” aspects of aggressive behavior; and (iv) the function of T on aggression before and during a combative encounter. Included are areas that may need further research. We argue that animal studies investigating these topics fill in gaps to help paint a more complete picture of how androgenic steroids drive the output of aggressive behavior in all animals, including humans.     

The effects of castration and Silastic implants of testosterone on intermale aggression in the mouse

Castration and testosterone (T) replacement were used to study developmental changes in aggressive behavioral responsiveness to androgenic stimulation. Male mice castrated at birth were less sensitive to circulating T than were prepubertal or adult castrates, but fighting was induced in neonatal castrates with a dose of androgen that produced hypertrophy of the accessory organ system in adult castrates. Gonadectomy shortly prior to pubertal increases in serum T concentration also reduced behavioral responsiveness to androgen administration. Intermale aggression was induced in prepubertal castrates only with T treatment that maintained accessory organ growth in adult castrates. The aggressive behavior of males castrated after the pubertal surge in serum T was supported with circulating levels of androgen that failed to stimulate the accessory organ system above that of oil-treated castrates. It was concluded that T stimulation during neonatal or pubertal life is not totally crucial for organization of neural substrates that mediate the ultimate expression of intermale aggression, but exposure to androgen from birth throughout pubertal development is normally required to produce maximal aggressive behavioral responsiveness to circulating T encountered in adulthood.     

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.     

Neonatal buspirone modulates the intermale aggression in adult mice

Mice of two strains with different levels of male aggression (RSB and RLB) were subjected to daily injections of 5-HT1A receptor agonist buspirone (25 microg) on the 2nd - 6th postnatal days. This neonatal treatment augmented the aggressive behavior (tested in the dyadic contests with non-aggressive A/Sn males) in aggressive RSB mice and reduced aggression in less aggressive RLB. Correlations with different signs were found between the 5-HT and 5-HIAA levels in the neocortex, hippocampus, and hypothalamus and behavioral indices of aggression in RSB and RLB males. The remote effects of neonatal buspirone in these two mice strains presumably depend on genotype-related features of ontogeny of the 5-HT system.     

Involvement of dopaminergic systems in the functional specialization of brain areas during formation of aggressive and submissive behavior in mice

In addition to its common activating action, the DA system is involved in the functional specialization of the brain areas which participate in the expression of discrete behavioral components. The evidence for different levels of activity of the mesocortical DA system in aggressive and submissive mice were obtained. In C57BL/6J mice, confrontations produced simultaneous increase in the extracellular DA content and its release from the nerve terminals in the nucleus accumbens and frontal cortex, while an elevation of the HVA concentration in these structures was found only in submissive mice. After 20 encounters, the habituation of animals to the repeated stress exposures and conditioning developed. Activation of the DA metabolism (increase in the DOPAC level and DOPAC/DA ratio) in the hippocampus was observed only in aggressive mice after 20 days of confrontation, when the extinction of the information novelty leading to aggression had been already accomplished. Our findings suggest the predominance of the role of the mesolimbic DA system, in particular, of its mesoaccumbens link, in the extinction of the information novelty in aggressors. A role of the mesocortical DA system in realization of the submissive behavior patterns, stress reactions, conditioned defensive behavior, anxiety-related behavior, and in modulation of the anxiety response to social stimuli is considered.     

Multimetric statistical analysis of behavior in mice selected for high and low levels of isolation-induced male aggression

Behavioral observations as a matrix of probabilistic changes of postures and acts are multiple measurements that could introduce variability to statistical analysis. We propose the multimetric statistical algorithm that supplements the linear analysis of variance by pair correlation, factor and discriminant function analyses. Although these methods were utilized mostly in behavioral studies, the combined use in frame of one behavioral test was not done before. In present study statistical techniques were applied to analyze social behavior in Turku aggressive (TA) and Turku non-aggressive (TNA) mouse lines, bidirectional selected for offensive aggression towards an unknown male. Each statistical technique amplified new details of mouse behavioral profiles that give possibility to describe TA and TNA subjects in terms of Cloninger's model of personality. Also, it was identified that TA mice displayed fighting-biting aggression while TNA mice demonstrated immobile defensive strategy. Hypothetical discriminant formula was found for each mouse behavioral genotype that might be used to identify behavioral profile and line affiliation of unknown subjects.