Vol. 297, Issue 2, 489-495, May 2001

Characterization of Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone

S. R. Engel, R. H. Purdy and K. A. Grant

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (S.R.E., K.A.G.); and Veterans Medical Research Foundation and the Department of Veterans Affairs Medical Center, San Diego, California (R.H.P.)

Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone are potent neuromodulators able to affect a number of membrane receptors, including -aminobutyric acid (GABA)_A, N-methyl-D-aspartate (NMDA), 5-hydroxytryptamine (5-HT)₃, and 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 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 ₁ 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 ₁ 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.