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.     

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.     

The effect of DAGO,selective milli-opioid receptor agonist,on hostile and anxious behaviors in male mice with different experience of aggression

Effects of mu-opioid receptor agonist DAGO (2.0 mg/kg, s.c.) on anxioUs, hostile, and aggressive behaviors of male mice with repeated 3- and 20-day experience of aggression accompanied by victories (T3 and T20 winners, respectively) were stUdied. T20 winners showed lower aggression (attacking and biting) and hostile behavior and were more anxioUs (estimated by plUs-maze test) than T3 winners. In the plUs-maze test DAGO prodUced anxiogenic effects in intact males and was ineffective in T3 and T20 winners testifying to a decrease in mu-receptor sensitivity Under the inflUence of repeated aggression. In agonistic confrontation test, DAGO increased aggressive grooming in T20 winners, decreased hostile behavior (digging and throwing partner's litter) in T3 winners, and did not inflUence attacks in both groUps. It is sUggested that mu-opioid receptors are involved into forming the aggressive behavioral type in mice, and DAGO effects may be conditioned by emotional backgroUnd of these behavioral forms.     

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.     

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.     

Extinction and amnesia in aggressive and submissive mice with various terms of agonistic interaction

Dependence of the passive avoidance retrieval on the duration of agonistic interactions was analyzed in C57BL/6J mice in procedures of extinction and amnesia during formation of aggressive and submissive behavioral stereotypes. The resistance to amnestic stimulation was lower in aggressive mice with 10-day experience of victories than in aggressive animals after 20 daily confrontations. Prolongation of extinction in aggressive mice and fast extinction in submissive animals did not depend on the number of agonistic interactions.     

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.     

Changes in the Expression of Monoaminergic Genes under the Influence of Repeated Experience of Agonistic Interactions: From Behavior to Gene

The role of genetic and environmental factors as well as brain neurochemistry in regulating aggressive and submissive behaviors in animals are considered. We present a review of data on changes in brain monoaminergic activity (synthesis, catabolism, receptors) and on the expression of monoaminergic genes under repeated daily agonistic confrontations in male mice. A repeated experience of aggression was shown to result in the total activation of the dopaminergic systems and the inhibition of the serotonergic one. This was accompanied by a decrease in the mRNA level of the cathecol-O-methyltransferase gene in the midbrain and an increase of the mRNA level of the dopamine transporter and tyrosine hydroxylase genes in the ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced dynamic changes in the serotonergic system of some brain areas and an increase of the mRNA level of the serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Theoretical and methodological possibilities of the proposed ethological approach for studying molecular mechanisms of agonistic behavior are discussed in the context of the fundamental problem of investigating the ways of regulation from behavior to gene.     

Is dehydroepiandrosterone sulfate an anxiolytic agent?

Effects of dehydroepiandrosterone sulfate (DHEAS, 30 mg/kg, i.p., 4 and 28 hours after the injection) were studied in CBA/Lac male mice different in the level of anxiety resulting from repeated social victories (winners) or social defeats (losers) in 10 daily agonistic confrontations. The losers demonstrated high level of anxiety estimated by the "partition" test. The DHEAS and saline injections had different effects on winners, losers, and intact mice. DHEAS prevented the development of anxiety in losers 28 hours after the injection. In these experimental conditions DHEAS exerted no effect on winners. It was concluded that the DHEAS effect depends on the psychoemotional state of an animal. The anxiolytic effect of the exogenous DHEAS may be also characteristic of the endogenous hormone secreted by the adrenal glands and in the central nervous system.     

The study of exploratory behavior in CBA/Lac male mice under influence of positive and negative social interactions

The exploratory activity towards a new object placed in the home cage was studied in CBA/Lac male mice after their repeated daily social victories and defeats. After 10 daily social defeats, submissive mice displayed a significantly declined exploration of a new object, whereas aggressive mice with experience of 10 daily victories expressed only a mild decrease in exploratory activity (as compared to control). Twenty daily social defeats almost completely abolished exploratory behavior in submissive mice, whereas 20 daily victories resulted in the increased exploration of a new object in aggressive mice. It is suggested that repeated social defeats associated with the negative psychoemotional state lead to the development of a pronounced exploratory motivational deficit. On the other hand, the experience of repeated daily aggression forms the enhanced motivational excitement that prevents a relevant response to a neutral stimulus.     

Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: from behavior to gene

The role of genetic and environmental factors as well as brain neurochemistry in regulating aggressive and submissive behaviors in animals are considered. We present a review of data on changes in brain monoaminergic activity (synthesis, catabolism, receptors) and on the expression of monoaminergetic genes under repeated daily agonistic confrontations in male mice. A repeated experience of aggression was shown to result in the total activation of the dopaminergic system and the inhibition of the serotonergic one. This was accompanied by a decrease in the mRNA level of the catechol-O-methyltransferase gene in the midbrain and an increase of the mRNA level of the dopamine transporter and tyrosine hydroxylase genes in the ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced dynamic changes in the serotonergic system of some brain areas and an increase of the mRNA level of the serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Theoretical and methodological possibilities of the proposed ethological approach for studying molecular mechanisms of agonistic behavior are discussed in the context of the fundamental problem of investigating the ways of regulation from behavior to gene.     

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.     

Development of anhedonia under negative experience of social confrontations in male mice

Possible development of anhedonia in male mice under chronic stress produced by social confrontations was investigated. Cheese, instead of traditional sucrose solution, was used as a positive reinforcement. It has been shown that the controls, the winners with repeated experience of aggression accompanied by victories and the losers with repeated experience of social defeats, irrespective of their social status, preferred to eat cheese, but not pellets, under the free choice conditions--80% of total food. After three days of cheese deprivation, the least food motivation and the least level of cheese consumption were observed in the losers as compared with the controls and winners. Influence of social stress as well as negative psychoemotional state produced by social defeats, on development of anhedonia as a symptom of major depression, is discussed.     

The neurochemical control of aggression and submission]

Neurochemical mechanisms of agonistic behaviour in different models of aggression are discussed. The effects of aggression and submission experience in 10 mice intermale confrontations under conditions of sensory contact on the levels of brain neurotransmitters and their metabolites were investigated in 7 brain areas. The values obtained in aggressive and control, or submissive and control, animals were compared. In this comparison neurochemical alterations specific for aggressive or submissive behaviours, or nonspecific became apparent. The long experience of victories leads to activation of dopaminergic system through DA catabolism which leads to DOPAC formation. The long experience of defeats increases the 5HT metabolism and decreases NA level in some brain areas. The dopaminergic system of Nucleus accumbens and midbrain are nonspecifically activated in both aggressive and submissive animals. The investigation of values obtained in animals with conversion of behavioural type (after defeat of previously aggressive animals and/or display of aggressive reaction by previously submissive mice) allowed to find many significant differences between aggressive, submissive and "converted" males; in particular the amygdala is the site of opposite changes in 5HT system during inversion of aggressive or submissive behaviours. The above data evidence for the specific role of transmitter systems and brain structures in maintaining or inversion of different types of agonistic behaviour.     

The animal model of anxious depression: persistence of behavior pathology

It has been shown that chronic psychoemotional stress caused by repeated experience of defeats in agonistic interactions during 30 days led to development of the anxiety depression--like state accompanied by pronounced anxiety, behavioral deficit, decreased communication, and increased depressiveness as estimated by various behavioral tests in male mice. This psychopathological state still existed after 1-2 weeks living with females in comfortable conditions (without confrontations with other males), that testified to persistence of behavior pathology.     

Agonistic behavior: model, experiment, perspectives]

Repeated experiences of social victories or defeats in daily agonistic confrontations led to different changes of the brain neurotransmitter activities in male mice with alternative types of social behaviour. Total activation of the brain dopamine metabolism was found in winners. Chronic defeats were accompanied by specific changes in serotonin and noradrenaline metabolism in limbic areas of the brain. Between losers and winners, significant differences were found in emotionality, exploratory activity, locomotion, level of anxiety, communicative behaviour, and alcohol consumption, as well as in immune responses and susceptibility to transplanted Krebs-2 tumour growth, gonadal function, and gastric mucosa damage. A sensory contact technique is proposed for studying the neurophysiological consequences of social conflicts.     

Effect of the activation of GABA A, benzodiazepine, and D2 dopamine receptors on the passive avoidance extinction in submissive and aggressive mice

The effect of activation of GABAA, benzodiazepine, and D2 dopamine receptors on extinction of passive avoidance and their dependence on the initial state of aggressive and submissive C57BL/6J mice were studied. It was found that in mice with the submissive stereotype of behavior produced by experience of defeats in daily agonistic confrontations, extinction of the conditioned reaction occurred faster than in control mice. The activation of D2 receptors by quinpirole and of benzodiazepine receptors by medasepam before training restored the retrieval of the memory trace. A prolongation of extinction was observed in aggressive mice in comparison with control and submissive animals, and activation of GABAA by muscimol and benzodiazepine receptors by medazepam led to acceleration of extinction. Activation of D2 receptors was ineffective. Thus, the difference in initial behavioral strategy determined both the development of extinction of the passive avoidance and variability of participation of D2, GABAA, and benzodiazepine receptors in the maintenance of availability of the memory trace to retrieval.     

The effect of the animals' emotional state on ethanol consumption under free-choice conditions

Voluntary ethanol consumption (20% solution) in mice of C57BL/6J strain with different experience in social agonistic confrontations was studied. It has been shown, that aggressive males daily winning other individuals did not change the level of ethanol consumption, while the submissive mice with daily experience of defeat in intermale encounters dramatically increased that level. Ethanol enhanced the behavioural reactivity of submissive animals to other individuals. It was supposed that emotionally positive or negative states differentiate the ethanol motivations in mice.