Differences in the Effects of 5-ht1a Receptor Agonists on Forced Swimming Behaviour and in Brain 5-ht Metabolism between Low and High Aggressive Mice

Wild house mice genetically selected for low (LAL) and high (SAL) aggression show divergent behavioural coping responses in the forced swim test (FST, i.e., immobility by LAL mice versus swimming/climbing by SAL mice). The two mouse lines also differ in structural and functional properties of postsynaptic serotonergic-1A (5-HT1A) receptors. In the present study, it was first investigated whether this difference in 5-HT1A receptors is associated with a difference in brain 5-HT metabolism in LAL and SAL mice. Secondly, the behavioural response of LAL and SAL mice to two different types of 5-HT1A receptor agonists (8-OHDPAT and S-15535) was examined in the FST. In addition, 5-HT metabolism was measured in several brain regions of vehicle treated mice and 8-OH-DPAT treated mice in an attempt to explain behavioural differences in the forced swim test. Results show that in most brain regions, levels of 5-HT, 5-HIAA and 5-HIAA/5HT ratio (index of 5-HT turnover) were not significantly different between LAL and SAL mice. Only in brain stem 5-HT content was higher, and only in striatum and amygdaloid region 5-HT turnover was lower in LAL compared to SAL mice. Hence, it is unlikely that the observed difference in 5-HT1A properties between LAL and SAL mice is an adaptive compensatory reaction to changes in 5-HT metabolism. The full 5-HT1A receptor agonist, 8-OH-DPAT, abolished the behavioural line-differences in the FST by reducing immobility behaviour in LAL mice and reducing climbing behaviour in SAL mice. The somatodendritic 5-HT1A autoreceptor agonist, S-15535, induced a similar behavioural effect as 8-OHDPAT in SAL mice, but did not alter the behaviour of LAL mice. This suggests that the behavioural change was induced by predominant activation of postsynaptic 5-HT1A receptors in LAL mice and of presynaptic 5-HT1A receptors in SAL mice. Enhanced somatodendritic 5-HT1A autoreceptor sensitivity in SAL mice is further supported by the finding that 8-OH-DPAT (5 mg/kg) potently attenuated the forced swimming-enhanced 5-HT turnover in SAL but not in LAL mice. Interestingly, however, forced swimming did not elicit an increase in 5-HT turnover in LAL mice compared to SAL mice. In conclusion, the present study demonstrates that genetic selection for trait aggression in male wild house-mice is associated with region-specific differences in basal 5-HT metabolism that were not related to the region-specific differences in 5-HT1A receptor properties. The anti-immobility effect of 8-OH-DPAT together with signs of lower brain 5-HT responsiveness and previously demonstrated HPA hyperreactivity, suggests that these LAL mice may be of clinical significance for the study of affective disorders. Serotonergic functioning in LAL and SAL mice 117