Wesołowska Anna, Nikiforuk Agnieszka, Chojnacka-Wójcik Ewa
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, Kraków, PL 31-343, Poland.
Eur J Pharmacol. 2006 Jul 10;541(1-2):57-63. doi: 10.1016/j.ejphar.2006.04.049. Epub 2006 May 7.
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.
研究了选择性5-羟色胺1B（5-HT1B）受体激动剂5-丙氧基-3-（1,2,3,6-四氢-4-吡啶基）-1H-吡咯并[3,2-b]吡啶（CP 94253）和5-HT1A/1B/1D受体激动剂5-甲氧基-3-（1,2,3,6-四氢-4-吡啶基）-1H-吲哚（RU 24969）对小鼠最大电休克和戊四氮诱发惊厥的影响。CP 94253（10 - 40毫克/千克）对最大电休克诱发的惊厥没有保护作用，但在戊四氮诱发的惊厥中产生抗惊厥作用（半数有效剂量=29毫克/千克）。选择性5-HT1B受体拮抗剂N-[3-（2-二甲基氨基）乙氧基-4-甲氧基苯基]-2'-甲基-4'-（5-甲基-1,2,4-恶二唑-3-基）-（1,1'-联苯）-4-甲酰胺（SB 216641；20毫克/千克）可消除CP 94253的抗惊厥作用，但在对氯苯丙氨酸（p-CPA；3×300毫克/千克）诱导的5-羟色胺耗竭后，其抗惊厥作用仍得以维持。有趣的是，在戊四氮试验中，CP 94253增强了地西泮的抗惊厥活性；另一方面，苯二氮䓬受体拮抗剂氟马西尼（10毫克/千克）并未改变CP 94253的抗惊厥作用。RU 24969（5毫克/千克）在最大电休克模型中未产生作用，但在戊四氮试验中产生抗惊厥活性，后一种作用被选择性5-HT1A受体拮抗剂N-（2-[4-（2-甲氧基苯基）哌嗪-1-基]乙基）-N-（2-吡啶基）-环己烷甲酰胺（WAY 100635；0.3毫克/千克）和SB 216641（10 - 20毫克/千克）减弱。所得结果表明，CP 94253通过刺激5-HT1B受体（可能位于突触后和/或作为异受体）对小鼠戊四氮诱发的惊厥发挥抗惊厥活性；RU 24969的抗癫痫活性似乎取决于对5-HT1A和5-HT1B受体的刺激。
