Elsevier

Hormones and Behavior

Volume 44, Issue 3, September 2003, Pages 199-208
Hormones and Behavior

Regular article
Cerebrospinal fluid monoamine and metabolite concentrations and aggression in rats

https://doi.org/10.1016/S0018-506X(03)00132-6Get rights and content

Abstract

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.

Introduction

The central serotonin (5-HT) system has been linked to aggression in humans and in many species of animals. The CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, has been used as indicator of brain 5-HT activity. It was discovered there is a link between low 5-HIAA levels and high aggressiveness Asberg et al., 1976, Brown et al., 1979, Brown et al., 1982, Higley et al., 1992, suggesting a deficient 5-HT function in high aggressive individuals. In numerous studies this relation has been investigated, with variable outcomes (reviewed in Coccaro, 1989, Kavoussi et al., 1997, Lee and Coccaro, 2001, Miczek et al., 1989, Tuinier et al., 1995. Low 5-HIAA levels appeared to be linked especially to impulsive aggression or impulsivity in general, severe or escalated aggression, and suicide Brown et al., 1982, Coccaro, 1989, Coccaro and Astill, 1990, Fairbanks et al., 2001, Higley et al., 1996a, Kavoussi et al., 1997, Lee and Coccaro, 2001, Reisner et al., 1996, Van Praag, 1998, Westergaard et al., 1999.

The vast majority of these studies have been carried out in humans and other primates, although a similar link between brain 5-HT and aggression is believed to be present in other species as well. Surprisingly, virtually no CSF 5-HIAA correlational studies have been performed in rodents; only postmortem brain tissue levels of 5-HT and/or 5-HIAA have been employed to examine the putative association between brain 5-HT activity and aggression. Though there are studies in which CSF is sampled from unanaesthetised rats Egashira et al., 2000, Qureshi et al., 1989, Wada et al., 1998, to our knowledge Sahakian et al., (1986) were the only ones to report about a relation between aggression and CSF indices of 5-HT transmission. Unfortunately, in that paper the actual 5-HIAA concentrations were not reported.

This lack of data in rodents is surprising, because studies on the neurobiology of aggression using manipulation experiments, either pharmacologically or otherwise, have mostly been carried out in rodents Coccaro, 1989, Miczek et al., 1989. It was never studied, or at least not reported, whether a similar link between CSF 5-HIAA levels and aggression exists in rodents, as derived from clinical data and primate experiments. Therefore our first aim was to investigate in rats the relationship between the individual level of aggressiveness and CSF 5-HT and 5-HIAA concentrations. The rat strain that we used—Wildtype Groningen—is especially suitable for this experiment, because of the large naturally present variation in aggressiveness between individuals. In view of the 5-HT deficiency hypothesis, we expected to find a negative correlation between the 5-HIAA levels and aggression. In addition, norepinephrine (NE), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were analysed in the CSF samples and related to aggression. These neurotransmitter systems have been linked to aggressive behaviour as well, although no consistent relationship between aggression and CSF NE and DA concentrations has been reported Haller, 1995, Kavoussi et al., 1997, Lee and Coccaro, 2001.

In discussing “high aggression” it is important to discern the propensity of an individual to react aggressively in many circumstances (high trait aggression) from the actual display of aggressive behaviour (aggression as a state). Increasing neurobiological evidence supports the view that high aggressive individuals are characterised by a tonically decreased 5-HT transmission compared to low aggressive ones. However, some of our recent studies suggest that, during the act of aggressive behaviour, the 5-HT system is (shortly) activated De Boer et al., 2000, Van der Vegt, et al., 2003. Therefore a second aim was to test whether changes in CSF neurotransmitter or metabolite concentrations could be measured shortly after aggressive behaviour has been carried out. This distinction between possible basal differences between high and low aggressive individuals and (differential) responses during/after the performance of aggressive behaviour is not clearly made in all studies and may be a source of confusion and misinterpretation.

In the last part of this study it was investigated whether pharmacological challenges, known to affect 5-HT neurotransmission and aggressive behaviour, would also be reflected in alterations of CSF monoamine and metabolite levels.

Section snippets

Animals, housing, and aggression tests

All experiments were approved by the animal experiments committee of the University of Groningen.

The subjects used for this study were male Wildtype Groningen rats (Rattus norvegicus). The ancestors were originally wild-trapped animals, subsequently bred in our laboratory for more than 21 generations. These rats not only exhibit a rich repertoire of social behaviour, including aggression, but there is also a high degree of interindividual variation.

Throughout the experiments rats had free

Results

The relationships between the individual level of aggressiveness and basal CSF concentrations of 5-HT, 5-HIAA, the ratio 5-HIAA/5-HT, and concentrations of NE, DA, and DOPAC were analysed. The results, when the relative duration of aggressive behaviour is used as measure of aggressiveness, are shown in Fig. 1 (the average concentration of two baseline samples per animal is plotted). A clear positive correlation was observed between aggressive behaviour and all monoamines and metabolites

Discussion

The main aim of this study was to scrutinise the relationship between aggression and CSF monoamine and metabolite content in rats. Much to our surprise, a clear positive correlation was found between trait-like aggression and levels of 5-HT and 5-HIAA.

This finding in rats seems to be in contrast to a large number of studies in humans and other primates, reporting a negative correlation between indices of 5-HT transmission and aggression. However, this correlation is not always present, and a

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