LONG-TERM ANTIDEPRESSANT ADMINISTRATION ALTERS CORTICOTROPIN-RELEASING HORMONE, TYROSINE-HYDROXYLASE, AND MINERALOCORTICOID RECEPTOR GENE-EXPRESSION IN RAT-BRAIN - THERAPEUTIC IMPLICATIONS
LONG-TERM ANTIDEPRESSANT ADMINISTRATION ALTERS CORTICOTROPIN-RELEASING HORMONE, TYROSINE-HYDROXYLASE, AND MINERALOCORTICOID RECEPTOR GENE-EXPRESSION IN RAT-BRAIN - THERAPEUTIC IMPLICATIONS
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DOI：
10.1172/jci115086
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发表时间：
1991-03-01
影响因子：
15.9
通讯作者：
HERKENHAM, M
中科院分区：
文献类型：
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作者：
BRADY, LS;WHITFIELD, HJ;HERKENHAM, M
丙咪嗪是典型的三环类抗抑郁药，用于治疗抑郁症，并发挥其治疗效果后，才延长给药。 我们报告了一项研究的影响，短期（2周）和长期（8周）管理丙咪嗪对中枢神经系统基因的表达被认为是在丙咪嗪反应性抑郁症失调。 如通过原位杂交所评估的，每日丙咪嗪处理（5 mg/kg，i. p.）在大鼠的下丘脑室旁核（PVN）中，促肾上腺皮质激素释放激素（CRH）mRNA水平降低了37%，蓝斑（LC）中酪氨酸羟化酶（TH）mRNA水平降低了40%。 这些变化与海马盐皮质激素受体（MR，I型）mRNA水平增加70%相关，该受体被认为在介导低水平类固醇对下丘脑-垂体-肾上腺（HPA）轴的负反馈效应中起重要作用。 丙咪嗪还降低了垂体前叶中阿黑皮素原（POMC）mRNA水平38%和糖皮质激素受体（GR，II型）mRNA水平51%。 除了丙咪嗪给药2周后LC中TH mRNA降低20%外，短期给药的结果均不明显。 根据资料表明，抑郁症与脑CRH和LC NE系统的激活有关，长期丙咪嗪给药对降低下丘脑CRH和LC TH基因表达的时间依赖性效应可能与该药物治疗抑郁症的疗效有关。
Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression.