Differential effects of the tricyclic antidepressant desipramine on the density of adrenergic receptors in juvenile and adult rats
Differential effects of the tricyclic antidepressant desipramine on the density of adrenergic receptors in juvenile and adult rats
复制标题
DOI：
10.1124/jpet.106.118935
复制
发表时间：
2007-05-01
影响因子：
3.5
通讯作者：
Bylund, David B.
中科院分区：
文献类型：
--
作者：
Deupree, Jean D.;Reed, Abbey L.;Bylund, David B.
虽然三环类抗抑郁药，如地昔帕明（Desipramine，简称DSI），是治疗成人抑郁症最有效的药物之一，但它们对治疗儿童和青少年抑郁症无效。由于肾上腺素能神经系统直到青春期后期才完全发育，我们假设调节受体密度的机制在年轻哺乳动物中可能尚未成熟。为了检验这一假设，在幼年和成年大鼠中比较了利多卡因治疗对皮质α-1-、α-2-和β-肾上腺素能受体的影响。通过对出生后第9 - 13天（4和7 mg/kg/天）和成年（20 mg/kg/天）大鼠每天两次注射4天，或通过对出生后第21-35天（15 mg/kg/天）和成年（10 mg/kg/天）大鼠连续输注2周（渗透性微型泵），给予地塞米松。这些交付模式给青少年大脑浓度的多巴胺类似于成年大鼠。在幼龄和成年大鼠中，两种给药模式均下调了β-肾上腺素能受体。相比之下，在出生后第9天至13天的大鼠，有一个剂量依赖性的上调α-1在皮质和α-2-肾上腺素能受体在前额叶皮质，而没有变化的密度在成年大鼠。这些差异α-肾上腺素能受体的调节后的治疗表明，三环类抗抑郁药治疗儿童抑郁症疗效的缺乏可能与这些受体的不成熟的调节机制。
Although the tricyclic antidepressants, such as desipramine (DMI), are among the most efficacious treatments for adult depression, they are not effective in treating childhood and adolescent depression. Because the adrenergic nervous system is not fully developed until late adolescence, we hypothesized that the mechanisms regulating receptor density may not yet be mature in young mammals. To test this hypothesis, the effects of DMI treatment on cortical alpha-1-, alpha-2-, and beta-adrenergic receptors were compared in juvenile and adult rats. DMI was delivered either by 4 days of twice daily injections to postnatal day 9 to 13 ( 4 and 7 mg/kg/day) and adult ( 20 mg/kg/day) rats, or by 2 weeks of continual drug infusion ( osmotic minipumps) to postnatal day 21-35 (15 mg/kg/day) and adult 10 mg/kg/day) rats. These delivery paradigms gave juvenile brain concentrations of DMI similar to those in adult rats. The beta-adrenergic receptor was down-regulated with both treatment paradigms in both juvenile and adult rats. By contrast, in the postnatal day 9 to 13 rats, there was a dose-dependent upregulation of the alpha-1 in the cortex and alpha-2-adrenergic receptor in the prefrontal cortex, whereas there was no change in density in adult rats. These differences in the alpha-adrenergic receptor regulation after DMI treatment suggest that the lack of efficacy of tricyclic antidepressants in treating childhood depression may be related to immature regulatory mechanisms for these receptors.