RATIONALE: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D 
receptors. It penetrates into the central nervous system and, like other 
5-HT1B/D agonists, its pharmacotherapeutic profile may include significant 
anti-aggressive effects.
OBJECTIVES: To examine whether zolmitriptan has potential anti-aggressive 
effects by studying two kinds of aggressive behavior in mice--species-typical 
and aggression under the influence of alcohol. A second objective was to study 
whether pre- or post-synaptic receptors mediate these anti-aggressive effects.
METHODS: Initially, the anti-aggressive effects of zolmitriptan were studied in 
male CFW mice during 5-min resident-intruder confrontations. To confirm the 
5-HT1B receptor as a critical site of action for the anti-aggressive effects, 
the zolmitriptan dose-effect determinations were repeated after pretreatment 
with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated 
concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) 
in order to compare the effects of this agonist on species-typical and 
alcohol-heightened aggression. Finally, mice were infused with the neurotoxin 
5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and 
presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17 
mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the 
lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and 
prefrontal cortex.
RESULTS: Zolmitriptan exerted behaviorally specific anti-aggressive effects. The 
reduction in aggression was antagonized by GR 127935, indicated by a rightward 
shift in the dose-effect curves of zolmitriptan, showing the specificity for the 
5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with 
equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan 
remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 
5-HT by 60-80%.
CONCLUSIONS: Zolmitriptan proved to be an effective and behaviorally specific 
anti-aggressive agent in situations that engender moderate and 
alcohol-heightened levels of aggression. These effects are potentially due to 
activation of post-synaptic 5-HT1BD receptors.