The Neurosteroid Tetrahydroprogesterone Attenuates the Endocrine Response to Stress and Exerts Glucocorticoid-like Effects on Vasopressin Gene Transcription in the Rat Hypothalamus

Abstract

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.

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

“…Interestingly, progesterone elevations in this study preceded allopregnanolone elevations by approximately 30 min, suggesting that CRF challenge may result in progesterone metabolism to allopregnanolone in the adrenal. This sequence of events may be highly relevant to the regulation of the stress response, since rodent data suggest that allopregnanolone negatively modulates the HPA axis (Guo et al, 1995;Patchev et al, 1994Patchev et al, , 1996. Recent evidence in human subjects demonstrating that allopregnanolone and cortisol levels are inversely related both at baseline and following mental stress also supports this possibility (Girdler et al, 2001).…”

“…It is therefore possible that antipsychotic-induced HPA axis alterations may be relevant to stress modulation in schizophrenia and antipsychotic treatment response. Accompanying elevations in cerebral cortical allopregnanolone may function to modulate this corticosterone response and ultimately suppress the HPA axis , since allopregnanolone inhibits corticosterone release in rodents (Patchev et al, 1996;Guo et al, 1995).…”

“…It is possible that clozapine-or olanzapine-induced cerebral cortical allopregnanolone may play a role in modulating acute corticosterone elevations and ensure the eventual return to lower levels of this steroid with prolonged antipsychotic treatment. Evidence that allopregnanolone decreases corticotropin-releasing factor (CRF) and adrenocorticotropin hormone (ACTH) in rodents supports this possibility (Patchev et al, 1994(Patchev et al, , 1996.…”

Neurosteroids in the context of stress: Implications for depressive disorders

“…Specifically, neurosteroids appear to serve as endogenous homeostatic mechanisms restoring both normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following acute stress (Guo et al, 1995;Patchev et al, 1996;Barbaccia et al, 1998;Strous et al, 2006). Animal models indicate that acute stress results in a rapid decrease in GABAergic neurotransmission and that this reduction in inhibitory neurotransmission with stress is mediated by the GABA A receptor (Concas et al, 1988;Drugan et al, 1989;Biggio et al, 1990).…”

“…Additionally, allopregnanolone and allotetrahydroDOC counteract the anxiogenic activity of corticotrophinreleasing factor (CRF) and attenuate methoxamine-stimulated CRF release in vitro in a dosedependent fashion (Patchev et al, 1994). Several laboratories have also shown that the pretreatment of rats with allopregnanolone, allotetrahydroDOC, or progesterone significantly attenuates stress-induced increases in plasma ACTH and cortisol (Owens et al, 1992;Patchev et al, 1996) and that allopregnanolone affects the gene transcription of arginine vasopressin (AVP) in the paraventricular nucleus (PVN) of the hypothalamus in a pattern similar to that seen with glucocorticoids (Patchev et al, 1996). Increased GABAergic tone also inhibits hypophysiotropic CRF neurons (Owens et al, 1992).…”