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Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone.
J Pharmacol Exp Ther. 2001 May; 297(2):489-95.JP

Abstract

Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone are potent neuromodulators able to affect a number of membrane receptors, including gamma-aminobutyric acid (GABA)(A), N-methyl-D-aspartate (NMDA), 5-hydroxytryptamine (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 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 sigma(1) receptor agonist SKF 10047 fully substituted for pregnanolone, and the NMDA antagonist MK-801 partially substituted for pregnanolone. The 5-HT(3) antagonist tropisetron did not substitute at any dose tested. The 5-HT(3) agonist SR 57227A reached full substitution, whereas the other 5-HT(3) 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-HT(3) and sigma(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.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11303034

Citation

Engel, S R., et al. "Characterization of Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone." The Journal of Pharmacology and Experimental Therapeutics, vol. 297, no. 2, 2001, pp. 489-95.
Engel SR, Purdy RH, Grant KA. Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone. J Pharmacol Exp Ther. 2001;297(2):489-95.
Engel, S. R., Purdy, R. H., & Grant, K. A. (2001). Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone. The Journal of Pharmacology and Experimental Therapeutics, 297(2), 489-95.
Engel SR, Purdy RH, Grant KA. Characterization of Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone. J Pharmacol Exp Ther. 2001;297(2):489-95. PubMed PMID: 11303034.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone. AU - Engel,S R, AU - Purdy,R H, AU - Grant,K A, PY - 2001/4/17/pubmed PY - 2001/5/25/medline PY - 2001/4/17/entrez SP - 489 EP - 95 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 297 IS - 2 N2 - Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone are potent neuromodulators able to affect a number of membrane receptors, including gamma-aminobutyric acid (GABA)(A), N-methyl-D-aspartate (NMDA), 5-hydroxytryptamine (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 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 sigma(1) receptor agonist SKF 10047 fully substituted for pregnanolone, and the NMDA antagonist MK-801 partially substituted for pregnanolone. The 5-HT(3) antagonist tropisetron did not substitute at any dose tested. The 5-HT(3) agonist SR 57227A reached full substitution, whereas the other 5-HT(3) 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-HT(3) and sigma(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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11303034/Characterization_of_discriminative_stimulus_effects_of_the_neuroactive_steroid_pregnanolone_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11303034 DB - PRIME DP - Unbound Medicine ER -