Anticonvulsant effect of the selective 5-HT1B receptor agonist CP 94253 in mice

The effect of the selective 5-hydroxytryptamine1B (5-HT1B) receptor agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP 94253) and the 5-HT1A/1B/1D receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) in maximal electroshock- and pentylenetetrazol-induced seizures in mice was examined. CP 94253 (10-40 mg/kg) afforded no protection against maximal electroshock-evoked convulsions, but produced anticonvulsant action in the pentylenetetrazol-induced seizures (ED50 = 29 mg/kg). The anticonvulsant effect of CP 94253 was abolished by the selective 5-HT1B receptor antagonist N-[3-(2-dimethylamino)ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641; 20 mg/kg) but it was maintained following the p-chlorophenylalanine (p-CPA; 3 x 300 mg/kg)-induced 5-HT depletion. Interestingly, CP 94253 potentiated the anticonvulsant activity of diazepam in the pentylenetetrazol test; on the other hand, the benzodiazepine receptor antagonist, flumazenil (10 mg/kg), did not modify the anticonvulsant effect of CP 94253. RU 24969 (5 mg/kg) evoked no effect in the maximal electroshock model, but it produced anticonvulsant activity in the pentylenetetrazol assay, the latter effect being attenuated by the selective 5-HT1A receptor antagonist N-(2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl)-N-(2-pyridyl)-cyclohexanecarboxamide (WAY 100635; 0.3 mg/kg) and SB 216641 (10-20 mg/kg). The obtained results suggest that CP 94253 exerts anticonvulsant activity on pentylenetetrazol-induced seizures in mice, as a consequence of stimulation of 5-HT1B receptors (probably located postsynaptically and/or as heteroreceptors); the antiseizure activity of RU 24969 seems to depend on the stimulation of both 5-HT1A and 5-HT1B receptors.