Natalia N. Kudryavtseva

A Model of Anxious Depression: Persistence of Behavioral Pathology

Chronic psychoemotional stress induced by negative experience of social defeats in intermale confrontations over a period of 30 days was found to lead to the development of anxious-depressive symptomatology in male mice. Cessation of the psychopathogenic conditions and placing of depressed animals in comfortable conditions for 1–2 weeks with females did not lift the pathological state. Individuals continued to show marked anxiety, a behavioral deficit, decreased communicativeness, and a high level of depressivity, as revealed by a variety of behavioral tests. Persistence of the resulting psychoemotional disturbance in these animals is evidence for the development and persistence of the behavioral pathology requiring drug treatment.

Features of the genetically defined anxiety in mice.

The behaviors of male mice of the C57BL/6J (C57), CBA/Lac (CBA) and BALB/c (BALB) strains have been studied in the plus-maze and open field tests for estimation of state anxiety in the stressful novel conditions, and in the cubic box test (exploration of novel cubic box) and the partition test (behavioral reactivity to the unfamiliar partner in the neighboring compartment) for estimation of trait anxiety in the unstressful familiar conditions of the home cage. Plus-maze data suggest that C57 mice are the more anxious than CBA and BALB ones. However, it was revealed the opposite rank order in the open field. The study on the effect of pre-testing in the one of test on the behavior in the other test revealed active behavioral strategy in C57 mice in any situations. The plus-maze behavior of CBA mice was affected to a much lesser extent than in C57 ones after pre-testing in the open field, but expressed changes were observed in open field behavior of CBA mice after pre-testing in the plus-maze. BALB mice displayed low-reactive behavior after any pre-testing exposure under the state anxiety-provoking conditions. Familiar environment revealed a higher level of trait anxiety in C57 than males of other two strains: CBA and BALB mice willingly explore unfamiliar partner and cubic box while C57 mice avoid its. Mainly genetically inherent state anxiety in CBA mice and trait anxiety in C57 mice has been suggested. Lowest state and trait indices of anxiety were revealed in BALB mice in these conditions.

Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience

Tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA levels in the ventral tegmental area (VTA) of midbrain were measured by multiplex RT-PCR in male mice with repeated experience of social victories (winners) and social defeats (losers) in 10 daily agonistic confrontations. Two independent experiments revealed enhanced TH and DAT mRNA levels in VTA of the winners in comparison with the losers and controls (animals after 5 days of individual housing). A positive correlation between DAT and TH mRNA levels was shown.

Repeated experience of social defeats increases serotonin transporter and monoamine oxidase A mRNA levels in raphe nuclei of male mice

Serotonin transporter (SERT) and monoamine oxidase A (MAOA) mRNA levels in the raphe nuclei area of the midbrain were measured by the multiplex reverse transcription-polymerase chain reaction method in male mice with repeated experience of social victories (winners) and defeats (losers) in ten daily agonistic confrontations. Experiments revealed enhanced SERT and MAOA mRNA levels in the losers compared with the winners and controls. It has been supposed that SERT and MAOA genes are involved in enhancement of serotonin inactivation in response to the increase of serotonergic activity shown earlier in the losers. A positive correlation between MAOA and SERT mRNA levels in the raphe nuclei area of the midbrain was shown.

An experimental approach to the study of learned aggression

The sensory contact technique increases aggressiveness in male mice and allows aggressive types of behavior to be formed as a result of the 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 periods of confrontation; intent, measured by increase of the aggressive motivation prior to agonistic confrontation; and decreased emotionality, estimated by parameters of open-field behavior. Relevant situation provokes increases in aggression (boundary aggression). This review summarizes 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 the influence of the repeated experience of aggression. The expression of the neurochemical and behavioral changes observed in winners has been found to depend on the mouse strain and on the duration of their agonistic confrontations. Aggr. Behav. 26:241–256, 2000.

Association between experience of aggression and anxiety in male mice

The sensory contact technique increases aggressiveness in male mice and allows an aggressive type of behavior to be formed as a result of repeated experience of social victories in daily agonistic confrontations. In the low aggressive and high emotional mice of CBA/Lac strain, repeated positive fighting experience leads to increased plus maze anxiety in the winners after 10 days of experience of victories and much more after 20 days. Behavioral reactivity to other conspecifics was significantly increased as revealed by the parameters of partition test, which measures aggressive motivation in the winners. Thus, anxiety as a consequence of repeated experience of aggression is associated with the increase of aggressive motivation in CBA/Lac mice. It is concluded, that: (1) Repeated experience of aggression provokes the development of anxiety in male mice. (2) The level of anxiety as well as its behavioral realization depends on the duration of aggressive experience and genetic strain. Genetically defined features of innate anxiety (trait or state) in individuals may determine the kind of association between aggressive experience, aggressive motivation and anxiety.

Anxiety and ethanol consumption in victorious and defeated mice; effect of κ-opioid receptor activation

Alcohol consumption and addiction have been related to anxiety and the anxiolytic effect of ethanol. It has been shown in mice that losers with repeated experience of social defeats are more anxious than winners with repeated experience of victories. Mice with a different social status were tested for their oral ethanol consumption using a free two bottle choice paradigm and for their social approach behaviour after ethanol consumption using the partition test, in which anxiety is an important component. In addition, the sensitivity of the animals for the kappa-opioid receptor agonist U-50,488H (2.5 mg/kg, s.c.) was assessed using the partition test, in which this drug has been shown to induce anxiolytic-like effects. Further, the effect of daily treatment with U-50,488H for 8 days on ethanol consumption was tested in animals that had consumed ethanol and were subjected during these 8 days to a period of 5 days of interruption of ethanol supply and subsequently to a period of 3 days of renewed access to ethanol. Losers consumed more ethanol than winners. Consumption of ethanol was accompanied by a decrease of anxiety level, as evidenced by an increased approach behaviour in the partition test. U-50,488H stimulated ethanol consumption after a period of 5 days of interruption of ethanol supply and drug treatment in the losers, but not in the winners. U-50,488H increased approach behaviour in the losers not consuming ethanol and decreased this behaviour in the winners, especially in those that had consumed ethanol. It is postulated that U-50,488H acts as a partial agonist in this respect. The increased anxiety may be related to the enhanced ethanol consumption in the losers, which may be of relevance for the etiology of alcohol addiction.

Molecular Implications of Repeated Aggression: Th, Dat1, Snca and Bdnf Gene Expression in the VTA of Victorious Male Mice

Background It is generally recognized that recurrent aggression can be the result of various psychiatric disorders. The aim of our study was to analyze the mRNA levels, in the ventral tegmental area (VTA) of the midbrain, of the genes that may possibly be associated with aggression consistently shown by male mice in special experimental settings. Methodology/Principal Findings The genes were Th, Dat1, Snca and Bdnf; the male mice were a group of animals that had each won 20 daily encounters in succession and a group of animals that had the same winning track record followed by a no-fight period for 14 days. Increased Th, Dat1 and Snca mRNA levels were in the fresh-from-the-fight group as compared to the controls. Increased Th and Dat1 mRNA levels were in the no-fight winners as compared to the controls. Significant positive correlations were found between the level of aggression and Th and Snca mRNA levels. Conclusions Repeated positive fighting experience enhances the expression of the Th, Dat1 and Snca genes, which are associated with brain dopaminergic systems. The expression of the Th and Dat1 genes stays enhanced for a long time.

Correlation between tryptophan hydroxylase activity in the brain and predisposition to pinch-induced catalepsy in mice.

Pinch-induced catalepsy and activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, in brain structures have been studied in mice of six inbred strains. A pronounced predisposition to catalepsy was found in the CBA mouse strain. It was shown that the CBA mice had the highest tryptophan hydroxylase activity in the neostriatum compared to mice of other noncataleptic strains. The experience of repeated victories in intermale encounters producing highly aggressive CBA mice resulted in the inhibition of the genetically determined predisposition to pinch-induced catalepsy and in the simultaneous decrease of tryptophan hydroxylase activity in the neostriatum down to the level found in noncataleptic mice. The inhibitor of tryptophan hydroxylase, p-chloromethamphetamine, significantly decreased the enzyme activity in the neostriatum of CBA mice and completely inhibited their genetically determined predisposition to catalepsy. These findings indicate the key role of the striatal serotonergic system in the catalepsy-inducing mechanism.

Effects of Repeated Experience of Aggression on the Aggressive Motivation and Development of Anxiety in Male Mice

The sensory contact model allowed aggressive behavior to be formed in male mice as a result of repeated experience of victory in daily social confrontations. In individuals of the low aggressivity, high emotionality line CBA/Lac, repeated experience of aggression led to the development of anxiety, assessed in the elevated cross maze test. Males showed increases in aggressive motivation, measured in terms of increases in behavioral reactions to conspecifics in the partition test. It is concluded that repeated experience of aggression provokes the development of anxiety in male mice and that the level of developing anxiety, like its behavioral correlates, depends on the duration of aggressive experience and the mouse line studied.The sensory contact model allowed aggressive behavior to be formed in male mice as a result of repeated experience of victory in daily social confrontations. In individuals of the low aggressivity, high emotionality line CBA/Lac, repeated experience of aggression led to the development of anxiety, assessed in the elevated cross maze test. Males showed increases in aggressive motivation, measured in terms of increases in behavioral reactions to conspecifics in the partition test. It is concluded that repeated experience of aggression provokes the development of anxiety in male mice and that the level of developing anxiety, like its behavioral correlates, depends on the duration of aggressive experience and the mouse line studied.