Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone

Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone ar e potent neuromodulators able to affect a number of membrane receptors, inc luding gamma -aminobutyric acid (GABA)(A), N-methyl-D-aspartate (NMDA), 5-h ydroxytryptamine (5-HT)(3), and sigma (1) 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 pregnanolon e from saline in a two-lever operant task maintained by food reinforcement. The opiate agonist morphine and the negative GABAA modulator dehydroepiand rosterone sulfate did not substitute for pregnanolone. All of the GABAA pos itive modulators tested (allopregnanolone, epipregnanolone, androsterone, p entobarbital, midazolam, and zolpidem) dose dependently substituted for pre gnanolone. The direct GABA-site agonists 4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridin-3-ol and muscimol failed to substitute for pregnanolone. Ethanol a nd the sigma (1) receptor agonist SKF 10047 fully substituted for pregnanol one, and the NMDA antagonist MK-801 partially substituted for pregnanolone. The 5-HT3 antagonist tropisetron did not substitute at any dose tested. Th e 5-HT3 agonist SR 57227A reached full substitution, whereas the other 5-HT 3 agonist tested, m-chlorophenylbiguanide, produced partial substitution. T hese results suggest that positive GABA(A) modulation, but not direct agoni sm, confers a discriminative stimulus effect similar to pregnanolone. Addit ionally, antagonism of NMDA receptors and activation of 5-HT3 and sigma (1) receptors modulate stimulus effects similar to the pregnanolone cue. Overa ll, the data suggest that pregnanolone produces discriminative stimulus eff ects representative of a wide-spectrum sedative hypnotic.