Abstract
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 ς1receptors. 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 GABAAmodulation, but not direct agonism, confers a discriminative stimulus effect similar to pregnanolone. Additionally, antagonism of NMDA receptors and activation of 5-HT3 and ς1receptors 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.
Footnotes
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Send reprint requests to: Dr. Kathleen Grant, Department of Physiology and Pharmacology, Medical Center Blvd., Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail:kagrant{at}wfubmc.edu
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This research was supported by National Institutes of Health-National Institute of Alcohol Abuse and Alcoholism Grants RO1 AA09346, T32 AA07565, and P50 11997.
- Abbreviations:
- GABA
- γ-aminobutyric acid
- NMDA
- N-methyl-d-aspartate
- THDOC
- allotetrahydrocorticosterone
- DHEAS
- dehydroepiandrosterone sulfate
- THIP
- 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol
- CPBG
- chlorophenylbiguanide
- FR
- fixed ration
- 2HPCD
- 2-hydroxypropyl-β-cyclodetrin
- Received November 13, 2000.
- Accepted January 23, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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