• Andrew Holmes, Dennis L Murphy, and Jacqueline N Crawley.
• Section on Behavioral Genomics, National Institute of Mental Health, Building 10 Room 4D11, Bethesda, MD 20892-1375, USA. aholmes@intra.nimh.nih.gov
• Psychopharmacology (Berl.). 2002 May 1; 161 (2): 160-7.

RationaleDysregulation of the brain serotonergic system has been implicated in the pathophysiology of violence and aggression. As a key regulator of central serotonergic activity, dysfunction of the serotonin transporter (5-HTT) represents a potential mechanism mediating pathological aggression.ObjectivesTo assess aggressive behavior in 5-HTT knockout (KO) mice. To examine home cage activity and 5-HT(1A/1B) receptor function in 5-HTT KO mice as factors contributing to an aggressive phenotype.MethodsIsolated male 5-HTT KO mice were compared to +/+ control mice using the resident-intruder test for aggression over two encounters. Locomotor activity was measured in the home cage over a 24-h period. 5-HT(1A/1B) receptor function was assessed via the pharmacological effects of the 5-HT(1A/1B) receptor agonist, RU24969, on locomotion.Results5-HTT -/- mice were slower to attack the intruder and attacked with less frequency than +/+ littermates, but showed equivalent social investigation. 5-HTT +/- mice were as quick to attack, but made fewer overall attacks, as compared to +/+ controls. Aggression increased with repeated exposure to an intruder in 5-HTT +/- and +/+ mice, but not in 5-HTT -/- mice. 5-HTT -/- mice showed a normal circadian pattern of home cage activity, but less activity overall, as compared to 5-HTT +/- and +/+ mice. RU24969 (5 mg/kg) produced hyperlocomotor effects in 5-HT +/- and +/+, but not 5-HTT -/- mice.ConclusionsDeletion of the 5-HTT gene produces a reduction in aggressive behavior and home cage activity. Desensitization of 5-HT(1A/1B) receptor function may contribute to reduced aggression in 5-HTT KO mice.

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