Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression

Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT1A) receptors, both in receptor binding and in mRNA levels, in the aggressive line. The aim of this experiment was to study whether similar differences in 5-HT1A receptors exist in individuals from a random-bred rat strain, varying in aggressiveness. In addition, because little is known about the functional consequences of these receptor differences, a response mediated via postsynaptic 5-HT1A receptors (i.e., hypothermia) was studied both in the selection lines of mice and in the randomly bred rats. The difference in receptor binding, as demonstrated in mice previously, could not be shown in rats. However, both in rats and mice, the hypothermic response to the 5-HT1A agonist alnespirone was larger in aggressive individuals. So, in the rat strain as well as in the mouse lines, there is, to a greater or lesser extent, an enhanced sensitivity of postsynaptic 5-HT1A receptors in aggressive individuals. This could be a compensatory up-regulation induced by a lower basal 5-HT neurotransmission, which is in agreement with the serotonin deficiency hypothesis of aggression.

Individual Variation in Aggression of Feral Rodent Strains: A Standard for the Genetics of Aggression and Violence?

This article summarizes the broad individual differences in aggressiveness and its relationship with several other behavioral, physiological, and neurobiological characteristics that exist in an outbred laboratory strain of male feral rats. Based on the observations that the individual level of offensive aggressive behavior (i.e., the tendency to defend the home territory) is strongly related to the way they react to various other environmental challenges, it is argued that the individual’s level of offensiveness is an important indicator and component of a more traitlike behavioral physiological response pattern (coping strategy) to environmental demands. The coping style of aggressive animals is principally aimed at a (pro)active prevention or manipulation of a stressor, whereas the nonaggressive individuals tend to passively accept or react to it. The (pro)active and reactive/passive behavioral coping styles are clearly associated with distinct patterns of autonomic/endocrine (re)activity and underlying neurobiological correlates and determinants. Consequently, these individual differences in aggression/coping style may not only determine the individual vulnerability to stress-related disease, and hence be an important factor in the population dynamics of the species, but may also determine responsivity to pharmacotherapeutic treatments. From an animal modeling point of view, it is argued that the aggressive extremes of this variation may, under the proper testing conditions, have an enhanced propensity to develop pathological forms of aggression and/or coping, for example, antisocial traits, violence, or impulsivity disorders. Finally, it is proposed that the use of these feral animals as base “material” for genetic association (i.e., QTL search, mRNA differential expression, nucleic acid microarray analysis) and manipulation (i.e., gene silencing or amplification by antisense ODN, siRNA, and/or viral gene-transfer methodologies) studies would most likely be the best option for dissecting successfully the genetic basis of both normal and pathological forms of aggression and/or coping.

Social environment determines the long-term effects of social defeat

A single social defeat by a dominant conspecific induces long-term changes in several physiological and behavioral parameters in rats. These changes may represent an increased vulnerability to subsequent stress and stress-related pathology. Environmental factors, in particular possibilities for social interactions, could modulate these effects. Therefore, we assessed the influence of social environment on susceptibility for the long-term effects of social defeat. Socially housed males of an unselected strain of wild-type rats were equipped with radio-telemetry transmitters that recorded heart rate, temperature and activity. They were individually subjected to defeat and subsequently either housed alone or returned to their group. Behavioral and physiological responses to various novelty stressors were determined during a three-week period after the social defeat. Furthermore, changes in baseline behavior and physiology following defeat were studied in the rat’s homecage. The results show a complex interaction between defeat and housing conditions. Depending on the parameters measured, effects were caused by both isolation alone, defeat alone or a combination of both defeat and isolation. Individual housing alone caused a characteristic hyperactive response to novelty stress. Though defeat did not affect behavioral responses, it amplified the physiological response to novelty and social housing did not attenuate this effect. However, social housing did reduce the effects of defeat on heart rate, temperature and activity in the home cage and completely prevented defeat-induced weight loss. Together these results indicate that social housing may indeed positively affect the animal’s capacity to cope with stressors.

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.

Activation of Serotonergic Neurotransmission During the Performance of Aggressive Behavior in Rats

High aggression is often linked to lowered serotonin (5-HT) neurotransmission. Although this may hold for high aggression as a trait characteristic of an individual, serotonergic activity is probably increased during performance of aggressive behavior. To test this hypothesis, first, the 5-HT1A agonist alnespirone and gamma aminobutyric acid-A agonist muscimol were administered into the dorsal raphe nucleus. These treatments, which inhibit 5-HT neuronal activity, were shown to decrease performance of aggressive behavior. Second, after a resident–intruder test, the activation of 5-HT neurons (measured by c-fos expression) was increased in high-aggressive rats, compared with low-aggressive rats or control rats that were not subjected to a social confrontation. Results show that performance of aggressive behavior increases 5-HT neuronal activity and that preventing this activation inhibits expression of aggressive behavior.