Patchev V K, Hassan A H, Holsboer D F, Almeida O F
Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
Neuropsychopharmacology. 1996 Dec;15(6):533-40. doi: 10.1016/S0893-133X(96)00096-6.
The neurosteroid tetrahydroprogesterone (5 alpha-pregnan-3 alpha-ol-20-one, allopregnanolone, THP), has been previously shown to counteract the anxiogenic effects of corticotropin-releasing hormone (CRH) and to interfere with noradrenergic and corticosteroid-mediated regulation of CRH release and gene transcription. Those observations indicated that, besides its sedative and analgesic activity, THP may also affect the neuroendocrine response to stress in a mode resembling that of corticosteroids. To examine this possibility, we compared the ability of THP, its precursor progesterone (P4), and the glucocorticoids dexamethasone (DEX) and corticosterone (CORT) to influence the pituitary-adrenal response to acute emotional stress and the adrenalectomy-induced increase in the gene transcription of the stress-related peptide arginine vasopressin (AVP) and of corticosteroid receptors (MR and GR) in the brain. Pretreatment of rats with a single dose of THP or P4 (50 micrograms/kg) significantly attenuated the elevation of plasma adrenocorticotropin (ACTH) and serum corticosterone after emotional stress; both steroids were, however, less potent than a similar dose of DEX. Administration of 1 mg of THP, CORT, or P4 to adrenalectomized (ADX) rats attenuated the increase in AVP mRNA levels in the ventromedial subdivision of the hypothalamic paraventricular nucleus (PVN), as compared with vehicle-treated ADX rats. However, whereas CORT and P4 influenced the ADX-induced increase in the transcription of both types of corticosteroid receptors in the hippocampus, these were unaffected by THP. In contrast to the glucocorticoids, THP and P4 failed to decrease plasma ACTH levels in rats deprived of endogenous steroids. These results demonstrate that the neurosteroid THP and its precursor P4 resemble glucocorticoids in their suppression of the pituitary-adrenal response to emotional stress; however, THP influences the transcription of glucocorticoid-responsive genes in brain structures involved in the regulation of the hypothalamo-pituitary-adrenal system in a fashion that is quite distinct from that obtained with glucocorticoids.
神经甾体四氢孕酮（5α-孕烷-3α-醇-20-酮，别孕烷醇酮，THP），先前已被证明可对抗促肾上腺皮质激素释放激素（CRH）的致焦虑作用，并干扰去甲肾上腺素能和皮质类固醇介导的CRH释放及基因转录调控。这些观察结果表明，除了其镇静和镇痛活性外，THP还可能以类似于皮质类固醇的方式影响对应激的神经内分泌反应。为了检验这种可能性，我们比较了THP、其前体孕酮（P4）以及糖皮质激素地塞米松（DEX）和皮质酮（CORT）影响垂体-肾上腺对应激情绪反应的能力，以及肾上腺切除诱导的应激相关肽精氨酸加压素（AVP）和脑内皮质类固醇受体（MR和GR）基因转录增加的情况。用单剂量THP或P4（50微克/千克）预处理大鼠，可显著减轻应激情绪后血浆促肾上腺皮质激素（ACTH）和血清皮质酮的升高；然而，这两种甾体的效力均低于相同剂量的DEX。与给予赋形剂的肾上腺切除（ADX）大鼠相比，给肾上腺切除的大鼠注射1毫克THP、CORT或P4可减轻下丘脑室旁核（PVN）腹内侧亚区AVP mRNA水平的升高。然而，虽然CORT和P4影响肾上腺切除诱导的海马中两种皮质类固醇受体转录增加，但THP对其无影响。与糖皮质激素不同，THP和P4未能降低缺乏内源性甾体大鼠的血浆ACTH水平。这些结果表明，神经甾体THP及其前体P4在抑制垂体-肾上腺对应激情绪反应方面类似于糖皮质激素；然而，THP影响下丘脑-垂体-肾上腺系统调节相关脑结构中糖皮质激素反应性基因转录的方式与糖皮质激素截然不同。
