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TITLE:
The neurosteroid tetrahydroprogesterone
attenuates the endocrine response to stress and exerts glucocorticoid-like effects on
vasopressin gene transcription in the rat hypothalamus.
AUTHOR:
Patchev VK; Hassan AH; Holsboer DF; Almeida OF
AUTHOR AFFILIATION:
Department of Neuroendocrinology, Max Planck
Institute of Psychiatry, Munich, Germany. patchev@mpipsykl.mpg.de
SOURCE:
Neuropsychopharmacology 1996 Dec;15(6):533-40
NLM CIT. ID:
97101909
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.
When my office
lease expired at the end of 2004, I decided to turn it into a
"sabbatical" from my private practice. Many years ago, in my
grandfather's 89th year of life, he told me, "John, it is important
to smell the roses while you can still smell them." His life
gave living a very good reputation. It is also true that the
pursuit of that philosophy required my grandfather to to re-open his
assay office/ore market in Wickenburg, Arizona as a 75-year-old because
he had run a little short of retirement money. Thus, if blessed with his
luck and health, I'll be back.. --jjh
