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.