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


OBJECTIVE
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.
de Almeida
R M
RM
Department of Psychology, Tufts University, Medford, MA 02155, USA
Nikulina
E M
EM
Faccidomo
S
S
Fish
E W
EW
Miczek
K A
KA
D000374:Aggression / Q000187:drug effects* / Q000502:physiology / Q000523:psychology; D000428:Alcohol Drinking / Q000523:psychology; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D023303:Oxazolidinones / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014363:Tryptamines
D002492:Central Nervous System Depressants; D023303:Oxazolidinones; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; D000431:Ethanol