Antidepressants reverse corticosterione-mediated decrease in brain-derived neurotrophic factor expression: Differential regulation of specific exons by antidepressants and corticosterone
Antidepressants reverse corticosterione-mediated decrease in brain-derived neurotrophic factor expression: Differential regulation of specific exons by antidepressants and corticosterone
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DOI：
10.1016/j.neuroscience.2005.12.058
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Pandey, G. N.
中科院分区：
文献类型：
--
作者：
Dwivedi, Y.;Rizavi, H. S.;Pandey, G. N.
早期研究表明脑源性神经营养因子与压力和抗抑郁药的作用机制有关。研究表明，抗抑郁药上调大鼠脑中脑源性神经营养因子的表达，而皮质酮则下调。各类抗抑郁药是否能逆转皮质酮介导的脑源性神经营养因子的下调尚不清楚。同样未知的是抗抑郁药或皮质酮如何调节脑源性神经营养因子的表达。为了澄清这一点，我们检查了各类抗抑郁药和皮质酮（单独或联合使用）对大鼠脑中总脑源性神经营养因子和单个脑源性神经营养因子外显子 mRNA 表达的影响。正常或皮质酮颗粒植入（100 mg，21天）大鼠腹腔注射不同类别的抗抑郁药、氟西汀、地昔帕明或苯乙肼，持续21天，并在最后一次注射后2小时处死。测量额叶皮层和海马中总脑源性神经营养因子和外显子 I-IV 的 mRNA 表达。给予正常大鼠，氟西汀仅增加海马中的总脑源性神经营养因子 mRNA，而地昔帕明或苯乙嗪则增加额叶皮层和海马中的脑源性神经营养因子 mRNA。当检查特定的外显子时，地昔帕明增加了两个大脑区域中外显子 I 和 III 的表达，而苯乙肼增加了额叶皮质和海马中外显子 I 的表达，但仅增加了海马中外显子 IV 的表达。另一方面，氟西汀仅增加海马中的外显子 11。正常大鼠的皮质酮治疗降低了两个脑区总脑源性神经营养因子 mRNA 的表达，特别是降低了外显子 11 和 IV。对植入皮质酮颗粒的大鼠进行地昔帕明或苯乙肼治疗，逆转了皮质酮诱导的两个脑区总脑源性神经营养因子表达的减少；然而，氟西汀仅部分逆转了海马体的减少。有趣的是，对植入皮质酮颗粒的大鼠进行抗抑郁治疗仅增加了那些在用每种特定抗抑郁药治疗正常大鼠时增加的特定外显子。我们发现，虽然皮质酮和抗抑郁药都调节脑源性神经营养因子的表达，并且抗抑郁药可以逆转皮质酮诱导的脑源性神经营养因子的减少，但抗抑郁药和皮质酮在调节脑源性神经营养因子外显子表达的方式上有所不同。 (c) 2006 年由 Elsevier Ltd 代表 IBRO 出版。
Earlier studies have implicated brain-derived neurotrophic factor in stress and in the mechanism of action of antidepressants. It has been shown that antidepressants upregulate, whereas corticosterone downregulates, brain-derived neurotrophic factor expression in rat brain. Whether various classes of antidepressants reverse corticosterone-mediated downregulation of brain-derived neurotrophic factor is unclear. Also not known is how antidepressants or corticosterone regulates brain-derived neurotrophic factor expression. To clarify this, we examined the effects of various classes of antidepressants and corticosterone, alone and in combination, on the mRNA expression of total brain-derived neurotrophic factor and of individual brain-derived neurotrophic factor exons, in rat brain. Normal or corticosterone pellet-implanted (100 mg, 21 days) rats were injected with different classes of antidepressants, fluoxetine, desipramine, or phenelzine, intraperitoneally for 21 days and killed 2 h after the last injection. mRNA expression of total brain-derived neurotrophic factor and of exons I-IV was measured in frontal cortex and hippocampus. Given to normal rats, fluoxetine increased total brain-derived neurotrophic factor mRNA only in hippocampus, whereas desipramine or phenelzine increased brain-derived neurotrophic factor mRNA in both frontal cortex and hippocampus. When specific exons were examined, desipramine increased expression of exons I and III in both brain areas, whereas phenelzine increased exon I in both frontal cortex and hippocampus but exon IV only in hippocampus. On the other hand, fluoxetine increased only exon 11 in hippocampus. Corticosterone treatment of normal rats decreased expression of total brain-derived neurotrophic factor mRNA in both brain areas, specifically decreasing exons 11 and IV. Treatment with desipramine or phenelzine of corticosterone pellet-implanted rats reversed the corticosterone-induced decrease in total brain-derived neurotrophic factor expression in both brain areas; however, fluoxetine reversed the decrease only partially in hippocampus. Interestingly, antidepressant treatment of corticosterone pellet-implanted rats increased only those specific exons that are increased during treatment of normal rats with each particular antidepressant. We found that although corticosterone and antidepressants both modulate brain-derived neurotrophic factor expression, and antidepressants reverse the corticosterone-induced brain-derived neurotrophic factor decrease, antidepressants and corticosterone differ in how they regulate the expression of brain-derived neurotrophic factor exon(s). (c) 2006 Published by Elsevier Ltd on behalf of IBRO.