Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Synapse. 2011 May;65(5):357-67. doi: 10.1002/syn.20853. Epub 2010 Sep 24.
Escitalopram, the S-enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R-citalopram antagonizes this positive allosteric modulation. Escitalopram's effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R-citalopram on dopamine cell firing in the ventral tegmental area, using single-cell recording in vivo and on NMDA receptor-mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40-640 μg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 μg/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 μg/kg) had no significant effects. R-citalopram (320 μg/kg) antagonized the effects of escitalopram (320 μg/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R-citalopram (5 nM), potentiated NMDA-induced currents in pyramidal neurons. Escitalopram's effect was antagonized by R-citalopram and blocked by the dopamine D(1) receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on its cognitive-enhancing effect and superior efficacy compared to other SSRIs in major depression.
依他普仑，西酞普兰的 S-对映体，在治疗重度抑郁症方面比其他选择性 5-羟色胺再摄取抑制剂（SSRIs）具有更好的疗效。依他普仑与 5-羟色胺转运体的变构位点结合，进一步增强了对 5-羟色胺再摄取的抑制作用，而 R-西酞普兰拮抗这种正变构调节。依他普仑对 5-羟色胺以外的神经递质，例如多巴胺和谷氨酸的作用尚未得到很好的研究。因此，我们在这里使用体内单细胞记录和体外在体电生理学研究了依他普仑、西酞普兰和 R-西酞普兰对腹侧被盖区多巴胺细胞放电的影响，并使用新物体识别测试比较了依他普仑和西酞普兰的认知作用。依他普仑（40-640μg/kg 静脉注射）增加了多巴胺能神经元的放电频率和爆发放电，而西酞普兰（80-1280μg/kg）对放电频率没有影响，仅在高剂量时增加爆发放电。R-西酞普兰（40-640μg/kg）没有显著影响。R-西酞普兰（320μg/kg）拮抗了依他普仑（320μg/kg）的作用。依他普仑的浓度非常低（5 nM），但不是西酞普兰（10 nM）或 R-西酞普兰（5 nM），可增强在体培养的锥体神经元上 NMDA 诱导的电流。依他普仑的作用被 R-西酞普兰拮抗，并被多巴胺 D1 受体拮抗剂 SCH23390 阻断。依他普仑，而不是西酞普兰，改善了识别记忆。我们的数据表明，依他普仑对多巴胺能和 NMDA 受体介导的神经传递的兴奋作用可能与其认知增强作用以及在重度抑郁症中优于其他 SSRIs 的疗效有关。
