The hyperphagic effect of 3 alpha-hydroxylated pregnane steroids in male rats.
Like benzodiazepines receptor (BDZR) ligands, 3 alpha-hydroxylated, 5 alpha, or 5 beta pregnane steroids are sedative, anticonvulsant, and anxiolytic. BDZR ligands also modulate the feeding response. Therefore, in this study we have investigated the effects of four 3 alpha-hydroxylated pregnane steroids-Pregnanolone (3 alpha-hydroxy-5 beta-pregnan-20-one), allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one), alphaxalone (3 alpha-hydroxy-5 alpha-pregnan-11,20-dione), and 5 beta-pregnanediol (5 beta-pregnan-3 alpha,20 alpha-diol) on food intake. In non-food deprived male rats, all four steroids increased the consumption of a palatable diet. For pregnanolone (1-10 mg/kg), hyperphagia was found at lower doses than its anxiolytic effect (5-10 mg/kg) as determined using the elevated plus maze test. The presumed steroid antagonists, isopregnanolone (3 beta-hydroxy-5 alpha-pregnan-20-one) (10 mg/kg) and pregnenolone sulfate (2 mg/kg), and the BDZ antagonist, Ro15-1788 (20 mg/kg), did not reverse the hyperphagic effect of pregnanolone. Picrotoxin, a GABAA receptor antagonist, dose dependently and at a subconvulsive dose (1.5 mg/kg), reversed the hyperphagic effect of pregnanolone and alphaxalone, but had no effect on allopregnanolone- and 5 beta-pregnanediol-induced hyperphagia. These results indicate that the hyperphagic effects of pregnanolone and alphaxalone are mediated by the GABAA receptor but not by direct interaction with BDZ receptors. However, allopregnanolone- and 5 beta-pregnanediol-induced hyperphagia may be mediated by other receptor systems. Because some 3 alpha-hydroxylated pregnane steroids are endogenous progesterone metabolites, they may play an important role in appetite control.
Chen
S W
SW
Molecular Research Institute, Palo Alto, CA 94304, USA.
Rodriguez
L
L
Davies
M F
MF
Loew
G H
GH
D000818:Animals; D001007:Anxiety / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects*; D005442:Flumazenil / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D011278:Pregnanes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D005442:Flumazenil; D018756:GABA Antagonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D010852:Picrotoxin; D011278:Pregnanes; D011280:Pregnanolone