The hyperphagic effect of 3α-hydroxylated pregnane steroids in male rats

Abstract

Like benzodiazepines receptor (BDZR) ligands, 3α-hydroxylated, 5α, or 5β 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 3α-hydroxylated pregnane steroids — Pregnanolone (3α-hydroxy-5β-pregnan-20-one), allopregnanolone (3α-hydroxy-5α-pregnan-20-one), alphaxalone (3α-hydroxy-5α-pregnan-11,20-dione), and 5β-pregnanediol (5β-pregnan-3α,20α-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 (3β-hydroxy-5α-pregnan-20-one) (10 mg/kg) and pregnenolone sulfate (2 mg/kg), and the BDZ antagonist, Rol5-1788 (20 mg/kg), did not reverse the hyperphagic effect of pregnanolone. Picrotoxin, a GABA A 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 5β-pregoanediol-induced hyperphagia. These results indicate that the hyperphagic effects of pregnanolone and alphaxalone are mediated by the GABA A receptor but not by direct interaction with BDZ receptors. However, allopregnanolone- and 5β-pregnanediol-induced hyperphagia may be mediated by other receptor systems. Because some 3α-hydroxylated pregnane steroids are endogenous progesterone metabolites, they may play an important role in appetite control.