Kalogeras K T, Calogero A E, Kuribayiashi T, Khan I, Gallucci W T, Kling M A, Chrousos G P, Gold P W
Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Endocrinol Metab. 1990 May;70(5):1462-71. doi: 10.1210/jcem-70-5-1462.
We report here a study of the effects of alprazolam on in vivo pituitary-adrenal function in jacketed nonrestrained nonhuman primates and on in vitro CRH release from rat hypothalami and ACTH release from rat dispersed anterior pituicytes. We undertook this study because alprazolam is the only benzodiazepine effective in treating both major depressive and anxiety disorders, and recent data suggest that the hypercortisolism of major depression reflects hypersecretion of CRH. Moreover, the intracerebroventricular administration of CRH can reproduce many of the components of the symptom complex of major depression, including not only hypercortisolism, but also hypothalamic hypogonadism, decreased libido, anorexia, and intense anxiety. As a comparison, we also assessed the effects of diazepam on in vitro CRH release, because in contrast to alprazolam, diazepam is effective in anxiety states but not in depression. Alprazolam (0.01-0.3 mg/kg, iv) produced a dose-dependent inhibition of both plasma ACTH and cortisol secretion in non-restrained adult male rhesus monkeys. Our in vitro studies showed that alprazolam significantly inhibited serotonin (5HT)-induced CRH release in a dose-dependent fashion (10(-10)-10(-5) M). Diazepam also inhibited 5HT-induced CRH release, but was 40 times less potent than alprazolam. Alprazolam was ineffective in blocking basal or CRH-induced ACTH release from rat dispersed anterior pituicytes, suggesting that its in vivo effects are through inhibition of CRH secretion. As expected, the inactive benzodiazepine ligand Ro 15-1788 inhibited the effects of alprazolam on 5HT-induced CRH release, but this occurred only at doses below 10(-7) M. Interestingly, when incubated alone in higher doses with our rat hypothalamic organ culture, Ro 15-1788, like alprazolam, produced a dose-dependent inhibition of 5HT-induced CRH release (10(-7)-10(-5) M), suggesting an agonistic action of Ro 15-1788 at the benzodiazepine receptor at higher concentrations. We conclude that alprazolam is capable of suppressing the primate pituitary-adrenal axis, and that this suppression most likely reflects suppression of the CRH neuron rather than of the pituitary corticotroph cell. We speculate that the enhanced capacity of alprazolam to suppress the CRH neuron relative to other benzodiazepines may contribute to its unique efficacy among this class of drugs in the treatment of major depression. The capacity of Ro 15-1788 to reverse alprazolam-induced suppression of the CRH neuron indicates that the effects of alprazolam are mediated at least in part via its interaction with the benzodiazepine component of the gamma-aminobutyric acidA macromolecular complex.
我们在此报告一项关于阿普唑仑对夹套非束缚非人灵长类动物体内垂体 - 肾上腺功能以及对大鼠下丘脑促肾上腺皮质激素释放激素（CRH）体外释放和大鼠分散的垂体前叶细胞促肾上腺皮质激素（ACTH）释放影响的研究。我们开展这项研究是因为阿普唑仑是唯一一种对治疗重度抑郁症和焦虑症均有效的苯二氮䓬类药物，且近期数据表明重度抑郁症的高皮质醇血症反映了CRH分泌过多。此外，脑室内注射CRH可重现重度抑郁症症状复合体的许多成分，不仅包括高皮质醇血症，还包括下丘脑性腺功能减退、性欲降低、厌食和强烈焦虑。作为对照，我们还评估了地西泮对体外CRH释放的影响，因为与阿普唑仑不同，地西泮对焦虑状态有效，但对抑郁症无效。阿普唑仑（0.01 - 0.3mg/kg，静脉注射）对未束缚的成年雄性恒河猴的血浆ACTH和皮质醇分泌产生剂量依赖性抑制作用。我们的体外研究表明，阿普唑仑以剂量依赖性方式（10⁻¹⁰ - 10⁻⁵M）显著抑制5 - 羟色胺（5HT）诱导的CRH释放。地西泮也抑制5HT诱导的CRH释放，但效力比阿普唑仑低40倍。阿普唑仑对大鼠分散的垂体前叶细胞基础或CRH诱导的ACTH释放无阻断作用，表明其体内作用是通过抑制CRH分泌实现的。正如预期的那样，无活性的苯二氮䓬配体Ro 15 - 1788抑制阿普唑仑对5HT诱导的CRH释放的作用，但仅在剂量低于10⁻⁷M时才会发生。有趣的是，当以较高剂量单独与我们的大鼠下丘脑器官培养物一起孵育时，Ro 15 - 1788与阿普唑仑一样，产生剂量依赖性抑制5HT诱导的CRH释放（10⁻⁷ - 10⁻⁵M），表明Ro 15 - 1788在较高浓度下对苯二氮䓬受体具有激动作用。我们得出结论，阿普唑仑能够抑制灵长类动物的垂体 - 肾上腺轴，且这种抑制很可能反映了对CRH神经元的抑制而非垂体促肾上腺皮质激素细胞的抑制。我们推测，相对于其他苯二氮䓬类药物，阿普唑仑增强的抑制CRH神经元的能力可能有助于其在这类药物中治疗重度抑郁症时具有独特疗效。Ro 15 - 1788逆转阿普唑仑诱导的CRH神经元抑制的能力表明，阿普唑仑的作用至少部分是通过其与γ-氨基丁酸A大分子复合物的苯二氮䓬成分相互作用介导的。
