Inhibiting biosynthesis and/or metabolism of progestins in the ventral tegmental area attenuates lordosis of rats in behavioural oestrus.

Abstract

In the ventral tegmental area (VTA), lordosis of rats is facilitated by 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Central 3alpha,5alpha-THP results from metabolism of peripheral progesterone, from the ovaries and/or adrenals, by sequential enzymatic activity of 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR). In addition, in glial cells, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (P450scc), which is then metabolized to progesterone by 3beta-hydroxysteroid dehydrogenase, and subsequently reduced to 3alpha,5alpha-THP. We hypothesize that, in the VTA, formation of 3alpha,5alpha-THP by both metabolism and biosynthesis is necessary for facilitation of lordosis of female rats. In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 microg/side); a 5alpha-reductase inhibitor, finasteride (10 microg/side); digitoxin (1 microg/side)+finasteride (10 microg/side); or vehicle and were tested 3 h later for lordosis. In Experiment 2, the effects of VTA infusions of digitoxin, finasteride, digitoxin+finasteride, or vehicle on lordosis and midbrain and plasma 3alpha,5alpha-THP levels were examined. In Experiment 3, we investigated whether infusions of 3alpha,5alpha-THP to the VTA reinstated lordosis and midbrain 3alpha,5alpha-THP levels following administration of inhibitors. VTA infusions of digitoxin, finasteride, or digitoxin+finasteride, significantly and similarly reduced lordosis and midbrain, but not plasma 3alpha,5alpha-THP levels, compared to vehicle. Following receipt of inhibitor infusions, 3alpha,5alpha-THP to the VTA restored lordosis and midbrain 3alpha,5alpha-THP levels. These data suggest that, in the VTA, both central biosynthesis of progesterone and metabolism of progesterone (from central and/or peripheral sources) to 3alpha,5alpha-THP are important for mediating lordosis of rats.

• Authors: S M Petralia, V Jahagirdar, C A Frye
• Journal: Journal of neuroendocrinology (J Neuroendocrinol) Vol. 17 Issue 9 Pg. 545-52 (Sep 2005) ISSN: 0953-8194 [Print] United States
• PMID: 16101892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Progestins
• pregnan-3,6-diol-20-one
• Finasteride
• Pregnanolone
• Digitoxin
• Cholesterol Side-Chain Cleavage Enzyme

Topics

• Animals
• Cholesterol Side-Chain Cleavage Enzyme (antagonists & inhibitors)
• Digitoxin (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Estrus (drug effects, physiology)
• Female
• Finasteride (pharmacology)
• Mesencephalon (drug effects, physiology)
• Posture
• Pregnanolone (analogs & derivatives, biosynthesis)
• Progestins (antagonists & inhibitors, biosynthesis)
• Radioimmunoassay
• Rats
• Rats, Long-Evans
• Sexual Behavior, Animal (drug effects)
• Stereotaxic Techniques
• Ventral Tegmental Area (drug effects, metabolism)