Brain-derived tumor necrosis factor-α and its involvement in noradrenergic neuron functioning involved in the mechanism of action of an antidepressant
Brain-derived tumor necrosis factor-α and its involvement in noradrenergic neuron functioning involved in the mechanism of action of an antidepressant
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DOI：
10.1124/jpet.104.067835
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发表时间：
2004-09-01
影响因子：
3.5
通讯作者：
Spengler, RN
中科院分区：
文献类型：
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作者：
Reynolds, JL;Ignatowski, TA;Spengler, RN
本研究记录了脑源性肿瘤坏死因子-α（TNF）在抗抑郁药物去甲丙咪嗪（地昔帕明）的作用机制中的作用。为了证实这种作用，采用场刺激和灌流的大鼠海马脑片研究TNF对去甲肾上腺素（NE）释放的调节。慢性地昔帕明给药将TNF介导的NE释放抑制转化为促进，依赖于α（2）-肾上腺素能受体激活。慢性静脉微量输注多克隆TNF抗体（pTNF-Ab）类似地将TNF对NE释放的抑制转变为促进。为了确定这种转化是否是由于地昔帕明诱导的脑中TNF生物活性的抑制，将大鼠单独或与同时腹膜内地昔帕明给药的重组大鼠TNF（rrTNF）i. c. v.微输注14天。从这些大鼠分离的海马切片中NE释放的TNF调节与从单独长期给予地昔帕明的大鼠分离的切片进行比较。虽然同时微量输注rrTNF与慢性地昔帕明管理防止由地昔帕明诱导的转化，rrTNF的微量输注增强NE释放的TNF抑制。这些细胞事件对应于通过强迫游泳试验（FST）分析的不动性的变化。与aCSF微输注大鼠相比，侧脑室微输注rrTNF可增加大鼠在FST中的不动持续时间。地昔帕明长期给药可减少不动持续时间，这可通过i. c. v.微量输注pTNF-Ab模拟，并可通过同时i. c. v.微量输注rrTNF预防。因此，i. c. v.微量输注rrTNF伴随地昔帕明给药对抗神经元相关TNF水平的降低，这是转化突触前对TNF的敏感性所必需的，这是药物有效所必需的。
The present study documents a role for brain-derived tumor necrosis factor-alpha (TNF) in the mechanism of action of the antidepressant drug desmethylimipramine ( desipramine). To establish this role, field stimulation and superfusion of rat hippocampal slices was employed to investigate the regulation of norepinephrine ( NE) release by TNF. Chronic desipramine administration transforms TNF-mediated inhibition of NE release to facilitation, dependent upon alpha(2)-adrenergic receptor activation. Chronic i.c.v. microinfusion of polyclonal TNF antibody (pTNF-Ab) similarly transforms TNF inhibition of NE release to facilitation. To determine whether this transformation is due to desipramine-induced inhibition of TNF bioactivity in the brain, rats were i.c.v. microinfused with recombinant rat TNF (rrTNF) for 14 days, either alone or with simultaneous i.p. desipramine administration. TNF regulation of NE release in hippocampal slices isolated from these rats was compared with slices isolated from rats chronically administered desipramine alone. Although simultaneous microinfusion of rrTNF with chronic desipramine administration prevents the transformation induced by desipramine, microinfusion of rrTNF enhances TNF inhibition of NE release. These cellular events correspond to changes in immobility, analyzed by the forced swim test (FST). Intracerebroventricular microinfusion of rrTNF increases the duration of immobility of rats in the FST, compared with rats microinfused with aCSF. Desipramine administered chronically decreases immobility duration, which is mimicked by i.c.v. microinfusion of pTNF-Ab and prevented by simultaneous i.c.v. microinfusion of rrTNF. Thus, i.c.v. microinfusion of rrTNF with concomitant desipramine administration opposes decreases in neuron-associated TNF levels, required to transform presynaptic sensitivity to TNF, which is necessary for the drug to be efficacious.