Urani Alexandre, Romieu Pascal, Portales-Casamar Elodie, Roman François J, Maurice Tangui
Département de Biochimie/Enzymologie, Pfizer GRD-Fresnes, 3/9, rue de la Loge, BP 100, 94265 Fresnes Cedex, France.
Psychopharmacology (Berl). 2002 Aug;163(1):26-35. doi: 10.1007/s00213-002-1150-y. Epub 2002 Jun 29.
Activation of the neuronal sigma(1) (sigma(1)) receptor potentiates calcium mobilization, leading to effective modulation of postsynaptic responses to neurotransmitters. At the behavioral level, sigma(1) agonists modulate learning, response to stress and depression. In particular, the selective sigma(1) agonist igmesine reduced immobility in the forced swimming test.
We investigated the effect of modulators of Ca(2+) influx and mobilization, administered intracerebroventricularly at doses ineffective alone, on the igmesine effect. The tricyclic antidepressant desipramine was also studied for comparison.
The calcium chelator EGTA blocked both igmesine and desipramine-induced decreases of immobility duration, indicating the importance of extracellular Ca(2+) influx in the initial action of each compound. Both L- and N-type voltage-dependent calcium channel (VDCC) appeared involved in the sigma(1) agonist effect. Verapamil, an L-type VDCC antagonist or omega-conotoxin GVI, a N-type VDCC antagonist, blocked whereas (-)-Bay K8644, a L-type VDCC agonist, potentiated the igmesine effect. Mobilization of intracellular Ca(2+) stores is involved selectively in the effect mediated by the sigma(1) receptor, since the membrane permeable intracellular Ca(2+) chelator EGTA/AM affected only the igmesine effect. Inositol 1,4,5-trisphosphate (InsP(3)) receptor-sensitive Ca(2+) pools appeared primarily involved, rather than Ca(2+)/caffeine-sensitive Ca(2+) pools. Indeed, the InsP(3) receptor positive modulator bradykinin potentiated, whereas the InsP(3) receptor antagonist xestospongin C blocked the igmesine effect. The ryanodine receptor agonist caffeine failed to affect the efficacy of igmesine, whereas the antagonist ryanodine reduced it.
The sigma(1) receptor-mediated behavioral effect is dependent not only on rapid Ca(2+) influx, as observed for a classical antidepressant, but also on intracellular Ca(2+) mobilization.
神经元西格玛-1（σ1）受体的激活可增强钙动员，从而有效调节突触后对神经递质的反应。在行为层面，σ1激动剂可调节学习、对应激的反应及抑郁状态。特别是，选择性σ1激动剂伊格美新可减少强迫游泳试验中的不动时间。
我们研究了单独给药无效剂量的脑室内注射钙内流和动员调节剂对伊格美新作用的影响。还研究了三环类抗抑郁药地昔帕明以作比较。
钙螯合剂乙二醇双四乙酸（EGTA）可阻断伊格美新和地昔帕明诱导的不动时间减少，表明细胞外钙内流在每种化合物的初始作用中具有重要性。L型和N型电压依赖性钙通道（VDCC）似乎都参与了σ1激动剂的作用。L型VDCC拮抗剂维拉帕米或N型VDCC拮抗剂ω-芋螺毒素GVI可阻断该作用，而L型VDCC激动剂（-）-Bay K8644可增强伊格美新的作用。细胞内钙库的动员选择性地参与了由σ1受体介导的作用，因为膜通透性细胞内钙螯合剂EGTA/AM仅影响伊格美新的作用。肌醇1,4,5-三磷酸（InsP3）受体敏感的钙库似乎起主要作用，而非钙/咖啡因敏感的钙库。实际上，InsP3受体阳性调节剂缓激肽可增强该作用，而InsP3受体拮抗剂西司他汀C可阻断伊格美新的作用。兰尼碱受体激动剂咖啡因未能影响伊格美新的疗效，而拮抗剂兰尼碱则降低了其疗效。
σ1受体介导的行为效应不仅像经典抗抑郁药那样依赖于快速的钙内流，还依赖于细胞内钙动员。
