Zolmitriptan - a 5-HT1B/D agonist, alcohol, and aggression in mice

Rationale: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D r eceptors. It penetrates into the central nervous system and, like other 5-H T1B/D agonists, its pharmacotherapeutic profile may include significant ant i-aggressive effects. Objectives: To examine whether zolmitriptan has poten tial anti-aggressive effects by studying two kinds of aggressive behavior i n mice species-typical and aggression under the influence of alcohol. A sec ond objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. Methods: Initially, the anti-aggressive effe cts of zolmitriptan were studied in male CFW mice during 5-min resident-int ruder confrontations. To confirm the 5-HT1B receptor as a critical site of action for the antiaggressive effects, the zolmitriptan dose-effect determi nations were repeated after pretreatment with GR 127935 (10 mg/kg, i.p.). I n further experiments, mice were treated concurrently with alcohol (1.0 g/k g, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) in order to compare the effect s of this agonist on species-typical and alcohol-heightened aggression. Fin ally, mice were infused with the neurotoxin 5,7-DHT (10 pg) into the raphe area to eliminate somatodendritic and presynaptic autoreceptors. The anti-a ggressive 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: Zolmitrip tan 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 w ith equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitript an remained unaltered by 5,7-DHT lesions that depleted cortical and hippoca mpal 5-HT by 60-80%. Conclusions: Zolmitriptan proved to be an effective an d behaviorally specific anti-aggressive agent in situations that engender m oderate and alcohol-heightened levels of aggression. These effects are pote ntially due to activation of post-synaptic 5-HT1B/D receptors.