Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone

Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone are potent neuromodulators able to affect a number of membrane receptors, including γ-aminobutyric acid (GABA)_A, N-methyl-D-aspartate (NMDA), 5-hydroxytryptamine (5-HT)₃ and σ₁ receptors. The present study used a drug discrimination procedure to assess further the receptor effects of pregnanolone in vivo. Rats were trained to discriminate 5 mg/kg pregnanolone from saline in a two-lever operant task maintained by food reinforcement. The opiate agonist morphine and the negative GABA_A modulator dehydroepiandrosterone sulfate did not substitute for pregnanolone. All of the GABA_A positive modulators tested (allopregnanolone, epipregnanolone, androsterone, pentobarbital, midazolam, and zolpidem) dose dependently substituted for pregnanolone. The direct GABA-site agonists 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol and muscimol failed to substitute for pregnanolone. Ethanol and the σ₁ receptor agonist SKF 10047 fully substituted for pregnanolone, and the NMDA antagonist MK-801 partially substituted for pregnanolone. The 5-HT₃ antagonist tropisetron did not substitute at any dose tested. The 5-HT₃ agonist SR 57227A reached full substitution, whereas the other 5-HT₃ agonist tested, m-chlorophenylbiguanide, produced partial substitution. These results suggest that positive GABA_A modulation, but not direct agonism, confers a discriminative stimulus effect similar to pregnanolone. Additionally, antagonism of NMDA receptors and activation of 5-HT₃ and σ₁ receptors modulate stimulus effects similar to the pregnanolone cue. Overall, the data suggest that pregnanolone produces discriminative stimulus effects representative of a wide-spectrum sedative hypnotic.