Zolmitriptan – a 5-HT_1B/D agonist, alcohol, and aggression in mice

Abstract.

Rationale: Zolmitriptan is an anti-migraine agent with action at 5-HT_1B/D receptors. It penetrates into the central nervous system and, like other 5-HT_1B/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-HT_1B 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 µg) 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-HT_1B 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-HT_1B/D receptors.