Gaggi R, D'Allolio R, Santangelo M, Roncada P
Department of Pharmacology, University of Bologna, Italy.
Pharmacol Biochem Behav. 1997 Oct;58(2):299-303. doi: 10.1016/s0091-3057(97)00238-4.
Isradipine and darodipine are dihydropyridine calcium antagonists that affect the serotonergic pathways with a peculiar profile of effects because, at low dose (0.08 and 0.3 mg/kg, respectively) they facilitate, but at high dose (1.60 and 5.0 mg/kg, respectively) they inhibit the serotonergic neurotransmission. To investigate the mechanisms of these effects, the selective 5-HT1A receptor agonist 8-OHDPAT was injected S.C. to rats pretreated I.P. with isradipine (0.04-1.60 mg/kg) or darodipine (0.3-5.0 mg/kg). By stimulating presynaptic 5-HT1A autoreceptor, 8-OHDPAT induced signs of inhibition of the serotonergic neutransmission (i.e., decrease of the 5-HIIA/5-HT ratio), but it also produced behavioral effects by stimulating postsynaptic 5-HT1A receptors (i.e., forepaw treadings). A low dose of isradipine (0.08 mg/kg) or darodipine (0.3 mg/kg) antagonized the presynaptic, but enhanced the postsynaptic effects of 8-OHDPAT, suggesting relief of the autoreceptor-mediated inhibition of the 5-HT release. Thus, the amine released could stimulate postsynaptic receptors, adding its action to that of 8-OHDPAT. A high dose of isradipine (1.60 mg/kg) or darodipine (5.0 mg/kg) left unchanged, or also enhanced, the signs of inhibition of serotonergic neurotransmission displayed by 8-OHDPAT, reducing but not suppressing the increase in the behavioral response to the stimulation of postsynaptic 5-HT1A receptors. It was speculated that the effects of isradipine and darodipine on scrotonergic pathways of rat brain could be due to changes in the back-regulation of the neurotransmission, mediated by 5-HT1A autoreceptors. This mechanism of action could be extended to other dihydropyridine calcium antagonists, because blockade of L-type VSCC by these compounds appears to be involved in their effects on brain 5-HT turnover.
伊拉地平与达罗地平是二氢吡啶类钙拮抗剂，它们对血清素能通路的影响具有独特的效应特征，因为在低剂量（分别为0.08和0.3毫克/千克）时它们促进血清素能神经传递，但在高剂量（分别为1.60和5.0毫克/千克）时则抑制血清素能神经传递。为了研究这些效应的机制，将选择性5-HT1A受体激动剂8-OHDPAT皮下注射给经腹腔注射伊拉地平（0.04 - 1.60毫克/千克）或达罗地平（0.3 - 5.0毫克/千克）预处理的大鼠。通过刺激突触前5-HT1A自身受体，8-OHDPAT诱导血清素能神经传递抑制的迹象（即5-HIIA/5-HT比值降低），但它也通过刺激突触后5-HT1A受体产生行为效应（即前爪踏动）。低剂量的伊拉地平（0.08毫克/千克）或达罗地平（0.3毫克/千克）拮抗突触前效应，但增强8-OHDPAT的突触后效应，提示解除了自身受体介导的5-羟色胺释放抑制。因此，释放的胺可刺激突触后受体，使其作用与8-OHDPAT的作用相加。高剂量的伊拉地平（1.60毫克/千克）或达罗地平（5.0毫克/千克）使8-OHDPAT所显示的血清素能神经传递抑制迹象保持不变或增强，减少但未抑制对突触后5-HT1A受体刺激的行为反应增加。据推测，伊拉地平与达罗地平对大鼠脑血清素能通路的作用可能归因于由5-HT1A自身受体介导的神经传递反馈调节的变化。这种作用机制可能扩展到其他二氢吡啶类钙拮抗剂，因为这些化合物对L型电压门控钙通道的阻断似乎与其对脑5-羟色胺代谢的作用有关。
