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 GABAA modulator dehydroepiandrosterone sulfate did not substitute for pregnanolone. All of the GABAA 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 GABAA 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.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - May 8 2001|
ASJC Scopus subject areas
- Molecular Medicine