THE NEUROSTEROID TETRAHYDROPROGESTERONE ATTENUATES THE ENDOCRINE RESPONSE TO STRESS AND EXERTS GLUCOCORTICOID-LIKE EFFECTS ON VASOPRESSIN GENE-TRANSCRIPTION IN THE RAT HYPOTHALAMUS

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 o f CRH release and gene transcription. Those observations indicated tha t, besides its sedative and analgesic activity, THP may also affect th e neuroendocrine response to stress in a made resembling that of corti costeroids. To examine this possibility, we compared the ability of TH P, its precursor progesterone (P-4), and the glucocorticoids dexametha sone (DEX) and corticosterone (CORT) to influence the pituitary-adrena l response to acute emotional stress and the adrenalectomy-induced inc rease in the gene transcription gf the stress-related peptide arginine vasopressin (AVP) and of corticosteroid receptors (MX and GR) in the brain. Pretreatment of rats with a single dose of THP or P-4 (50 mu g/ kg) significantly attenuated the elevation of plasma adrenocorticotrop in (ACTH) and serum corticosterone after emotional stress, both steroi ds were, however, less potent than a similar dose of DEX. Administrati on of 1 mg of THP, CORT, or P-4 to adrenalectomized (ADX) rats attenua ted the increase in AVP mRNA levels in the ventromedial subdivision of the hypothalamic paraventricular nucleus (PVN), as compared with vehi cle-treated ADX rats. However, whereas CORT and P-4 influenced the ADX -induced increase in the transcription of both types of corticosteroid receptors in the hippocampus, these were unaffected by THP. In contra st to the glucocorticoids, THP and P-4 failed to decrease plasma ACTH levels in rats deprived of endogenous steroids. These results demonstr ate that the neurosteroid THP and its precursor P-4 resemble glucocort icoids in their suppression of the pituitary-adrenal response to emoti onal stress; however, THP influences the transcription of glucocortico id-responsive genes in brain structures involved in the regulation of the hypothalamo-pituitary-adrenal system in a fashion that is quite di stinct from that obtained with glucocorticoids. (C) 1996 American Coll ege of Neuropsychopharmacology