Reduced aggression in mice lacking the serotonin transporter.
BACKGROUND
Dysregulation 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.


OBJECTIVE
To 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.


METHODS
Isolated 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.


RESULTS
5-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.


CONCLUSIONS
Deletion 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.
Holmes
Andrew
A
Section on Behavioral Genomics, National Institute of Mental Health, Building 10 Room 4D11, Bethesda, MD 20892-1375, USA. aholmes@intra.nimh.nih.gov
Murphy
Dennis L
DL
Crawley
Jacqueline N
JN
D000374:Aggression / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics*; D006702:Homing Behavior / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins; D011930:Reaction Time / Q000187:drug effects; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse