Differences in the effects of 5-HT1A receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice

Veenema, Alexa H. ; Cremers, Thomas I. F. H. ; Jongsma, Minke E. ; Steenbergen, Peter J. ; de Boer, Sietse F. ; Koolhaas, Jaap M.

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Rationale: Male wild house- mice genetically selected for long attack latency ( LAL) and short attack latency ( SAL) differ in structural and functional properties of postsynaptic serotonergic- 1A ( 5- HT1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming test ( FST, i. e., higher immobility by LAL versus SAL mice). Objectives: We investigated whether the line difference in 5- HT1A receptors is associated with a difference in brain 5- HT metabolism, and whether acute administration of a 5- HT1A receptor agonist could differentially affect the behavioral responses of LAL and SAL mice. Methods: 5- HT and 5- hydroxyindoleacetic acid ( 5- HIAA) levels were measured in homogenates of several brain regions using high- performance liquid chromatography. The behavioral effect of the full 5- HT1A receptor agonist, 8- OH- DPAT, and of the somatodendritic 5- HT1A autoreceptor agonist, S- 15535, was examined in the FST. The effect of 8- OH- DPAT on forced swimming- induced 5- HT metabolism in brain homogenates was determined. Results: In most brain regions, 5- HT and 5- HIAA levels and 5- HT turnover were not significantly different between LAL and SAL mice. 8-OH- DPAT abolished the behavioral line difference in the FST by reducing immobility in LAL mice and reducing climbing in SAL mice. S- 15535 induced a similar behavioral effect to 8- OH- DPAT in SAL mice, but did not alter the behavior of LAL mice. Compared with LAL, forced swimming elicited in SAL mice a higher brain 5-HT turnover, which was potently attenuated by 8- OHDPAT. Conclusions: It is unlikely that the difference in 5-HT1A properties between LAL and SAL mice is an adaptive compensatory reaction to changes in 5- HT metabolism. Although unspecific motor effects, at least in SAL mice, cannot be ruled out, it is suggested that the behavioral effects of 8- OH- DPAT and S- 15535 may be mediated by predominant activation of postsynaptic 5-HT1A receptors in LAL mice and by presynaptic 5- HT1A receptors in SAL mice.

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