Reul J M, Labeur M S, Grigoriadis D E, De Souza E B, Holsboer F
Max-Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Neuroendocrinology. 1994 Nov;60(5):509-19. doi: 10.1159/000126788.
The effects of the reversible monoamine oxidaseA (MAOA) inhibitor moclobemide on the rat hypothalamic-pituitary-adrenocortical (HPA) axis were studied. The time-course experiments showed that moclobemide, given via the drinking water (4.5 mg/kg/day), produces significant decreases (p < 0.05) in adrenal weight after 5 (-23%) and 7 weeks (-16%) of treatment. It was found that long-term moclobemide treatment had neuroanatomically distinct effects on corticosteroid receptor expression. Hippocampal mineralocorticoid receptor (MR) levels were upregulated at 2 (+65%), 5 (+76%) and 7 (+19%) weeks of treatment. Glucocorticoid receptor (GR) levels in this limbic brain structure were slightly up-regulated by 10% at 5 weeks, and indistinguishable from controls after 2 and 7 weeks of treatment. After 5 weeks of treatment, MR levels were unchanged in the hypothalamus, and increased by 44, 24 and 28% in the neocortex, amygdala and anterior pituitary, respectively. GR concentrations were elevated by 24 and 14% in the hypothalamus and anterior pituitary, respectively, whereas neocortical and amygdaloid receptor levels were not altered. After 5 weeks of moclobemide treatment, marked decreases in [125I]Tyr0-ovine corticotropin-releasing hormone ([125I])-oCRH binding capacity and proopiomelanocortin (POMC) mRNA content were observed in the anterior pituitary. Regarding the functional implications of long-term anti-depressant treatment, moclobemide treatment (5 weeks, 4.5 mg/kg/day) significantly attenuated stress (30-min novel environment)-induced plasma ACTH (-35%) and corticosterone (-29%) levels; no changes were observed in basal plasma ACTH and corticosterone levels. In conclusion, this study shows that moclobemide has a concerted influence on multiple elements of the HPA axis manifesting functionally as a reduced neuroendocrine responsiveness to stress. In previous experiments, it was found that the structurally and pharmacologically distinct antidepressant amitriptyline after long-term administration also attenuated HPA axis activity. We postulate that an adjustement of HPA axis activity may be regarded as a common denominator for clinically efficacious antidepressant drugs.
研究了可逆性单胺氧化酶A（MAOA）抑制剂吗氯贝胺对大鼠下丘脑-垂体-肾上腺皮质（HPA）轴的影响。时程实验表明，通过饮水给予吗氯贝胺（4.5毫克/千克/天），在治疗5周（-23%）和7周（-16%）后，肾上腺重量显著降低（p<0.05）。发现长期给予吗氯贝胺对皮质类固醇受体表达具有神经解剖学上不同的影响。在治疗2周（+65%）、5周（+76%）和7周（+19%）时，海马盐皮质激素受体（MR）水平上调。在这个边缘脑结构中，糖皮质激素受体（GR）水平在5周时略有上调10%，在治疗2周和7周后与对照组无差异。治疗5周后，下丘脑的MR水平未改变，新皮质、杏仁核和垂体前叶的MR水平分别增加44%、24%和28%。下丘脑和垂体前叶的GR浓度分别升高24%和14%，而新皮质和杏仁核受体水平未改变。给予吗氯贝胺治疗5周后，垂体前叶中[125I]酪氨酸0-羊促肾上腺皮质激素释放激素（[125I]-oCRH）结合能力和阿黑皮素原（POMC）mRNA含量显著降低。关于长期抗抑郁治疗的功能意义，给予吗氯贝胺治疗（5周，4.5毫克/千克/天）可显著减轻应激（30分钟新环境）诱导的血浆促肾上腺皮质激素（-35%）和皮质酮（-29%）水平；基础血浆促肾上腺皮质激素和皮质酮水平未观察到变化。总之，本研究表明吗氯贝胺对HPA轴的多个元素具有协同影响，在功能上表现为对应激的神经内分泌反应性降低。在先前的实验中，发现结构和药理上不同的抗抑郁药阿米替林长期给药后也减弱了HPA轴活性。我们推测，HPA轴活性的调节可能被视为临床有效抗抑郁药的一个共同特征。
