title: 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.affiliation: Department of Psychology, The University at Albany, SUNY, Albany, NY 12222, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Petralia
authors.forename: V
authors.initials: V
authors.lastname: Jahagirdar
authors.forename: C A
authors.initials: CA
authors.lastname: Frye
mesh_terms: D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D004074:Digitoxin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004971:Estrus / Q000187:drug effects / Q000502:physiology*; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology; D011187:Posture; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000096:biosynthesis; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D011863:Radioimmunoassay; D051381:Rats; D020318:Rats, Long-Evans; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D013238:Stereotaxic Techniques; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D011372:Progestins; C051190:pregnan-3,6-diol-20-one; D018120:Finasteride; D011280:Pregnanolone; D004074:Digitoxin; D002786:Cholesterol Side-Chain Cleavage Enzyme