Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Epilepsy Behav. 2011 Jun;21(2):122-7. doi: 10.1016/j.yebeh.2011.03.010. Epub 2011 Apr 30.
Citalopram, a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of major depressive disorders. In addition to its antidepressant features, citalopram shows some anticonvulsive properties at lower doses, whereas higher doses, ingested in cases of suicide, have been associated with seizures. Moreover, some reports support the enhancing effect of morphine on different responses of SSRIs such as analgesic and anticonvulsant properties. Although the exact mechanisms of these additive effects are not yet fully understood, 5-HT(3) receptor has recently been shown to play an important role in the central effects of SSRIs and morphine. In this regard, we used a model of clonic seizures induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether morphine and citalopram exhibit additive anticonvulsant effects and, if so, whether this effect is mediated through modulation of 5-HT(3) receptors. In our study, citalopram at lower doses (0.5 and 1 mg/kg, ip) significantly increased the seizure threshold (P<0.01) and at a higher dose (50 mg/kg) had proconvulsive effects. Moreover, morphine at low and noneffective doses had additive effects on the anticonvulsive properties of citalopram. This additive effect was prevented by pretreatment with low and noneffective doses of tropisetron (a 5-HT(3) receptor antagonist) and augmented by 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT(3) receptor agonist). Moreover, low doses of morphine (0.1 and 0.5 mg/kg) alone or in combination with potent doses of 5-HT(3) receptor agonist or antagonist could not alter the proconvulsive properties of citalopram at higher dose (50 mg/kg), ruling out the contribution of 5-HT(3) to this effect. In summary, our findings demonstrate that 5-HT(3) receptor mediates the additive anticonvulsant properties of morphine and low-dose citalopram. This could constitute a new approach to augmenting the efficacy and curtailing the adverse effects of citalopram.
西酞普兰，一种选择性 5-羟色胺再摄取抑制剂（SSRI），常用于治疗重度抑郁症。除了抗抑郁作用外，西酞普兰在较低剂量下还具有一定的抗惊厥作用，而较高剂量的西酞普兰在自杀情况下则与癫痫发作有关。此外，一些报告支持吗啡对 SSRI 不同反应（如镇痛和抗惊厥作用）的增强作用。虽然这些附加作用的确切机制尚未完全了解，但 5-HT3 受体最近被证明在 SSRI 和吗啡的中枢作用中发挥重要作用。在这方面，我们使用戊四氮（PTZ）诱导的男性 NMRI 小鼠阵挛性癫痫发作模型，研究吗啡和西酞普兰是否表现出相加的抗惊厥作用，如果是这样，这种作用是否通过调节 5-HT3 受体来介导。在我们的研究中，较低剂量的西酞普兰（0.5 和 1 mg/kg，ip）显著增加了癫痫发作阈值（P<0.01），而较高剂量（50 mg/kg）则具有促惊厥作用。此外，低剂量和无效剂量的吗啡对西酞普兰的抗惊厥作用具有相加作用。这种相加作用可被低剂量和无效剂量的托吡司特（5-HT3 受体拮抗剂）预处理所阻止，并可被 1-（间氯苯基）-双胍（mCPBG，5-HT3 受体激动剂）增强。此外，单独使用低剂量的吗啡（0.1 和 0.5 mg/kg）或与有效剂量的 5-HT3 受体激动剂或拮抗剂联合使用，不能改变较高剂量（50 mg/kg）的西酞普兰的促惊厥作用，排除了 5-HT3 对此作用的贡献。总之，我们的研究结果表明，5-HT3 受体介导了吗啡和低剂量西酞普兰的相加抗惊厥作用。这可能为增强西酞普兰的疗效和减少其不良反应提供一种新方法。
