Abstract
A number of endogenous steroids exhibit rapid, nongenomic effects on the central nervous system and are called neuroactive steroids. The rapid mechanisms of action include modulation of γ-aminobutyric acid type A (GABAA) andN-methyl-d-aspartate (NMDA) receptors, which are two receptors implicated in the behavioral effects of ethanol. It was hypothesized that neuroactive steroids that positively modulate GABAA receptors or negatively modulate NMDA receptors, analogous to the actions of ethanol, would produce discriminative stimulus effects similar to ethanol. Two groups of male Long-Evans rats (n = 6–8/group) were trained to discriminate between 1.0 or 2.0 g/kg ethanol (i.g.) and water (i.g.). The neuroactive steroids allopregnanolone, pregnanolone, epipregnanolone, allotetrahydrodeoxycorticosterone, pregnanolone sulfate, epipregnanolone sulfate, dehydroepiandrosterone, dehydroepiandrosterone sulfate, pregnenolone, and pregnenolone sulfate (PS), all administered i.p., were tested for substitution with acute and cumulative dosing procedures (n = 4–8/steroid). The GABAA-positive modulatory steroids allopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone substituted for ethanol, as did the low-efficacy steroid 3β,5β-P. GABAA-negative modulators, such as dehydroepiandrosterone sulfate and PS, and all of the NMDA modulators tested, including PS, pregnanolone sulfate, and epipregnanolone sulfate, did not substitute for ethanol. These results show that certain endogenously occurring neuroactive steroids produce discriminative stimulus effects similar to those of ethanol.
Footnotes
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Send reprint requests to: Kathleen A. Grant, Ph.D., Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083. E-mail: kagrant{at}wfubmc.edu.
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↵1 This research was supported by Grants RO1 AA09346 and F31 AA05455 to Wake Forest University School of Medicine, and Grant AA06420 to The Scripps Research Institute, from the National Institute on Alcohol Abuse and Alcoholism. These data were collected in partial fulfillment of the requirements for a doctoral degree. Portions of this research were presented at the 1998 Research Society on Alcoholism meeting.
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↵2 Present address: Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02178.
- Abbreviations:
- CNS
- central nervous system
- 3α
- 5α-P, 3α-hydroxy-5α-pregnan-20-one (allopregnanolone)
- 3α
- 5β-P, 3α-hydroxy-5β-pregnan-20-one (pregnanolone)
- 3α
- 5α-THDOC, 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydrodeoxycorticosterone)
- 3β
- 5β-P, 3β-hydroxy-5β-pregnan-20-one (epipregnanolone)
- GABA
- γ-aminobutyric acid
- NMDA
- N-methyl-d-aspartate
- 3α
- 5β-PS, 3α-hydroxy-5β-pregnan-20-one sulfate (pregnanolone sulfate)
- 3β
- 5β-PS, 3β-hydroxy-5β-pregnan-20-one sulfate (epipregnanolone sulfate)
- PS
- 3β-hydroxy-pregn-5-en-20-one sulfate (pregnenolone sulfate)
- DHEAS
- 3β-hydroxy-androst-5-en-17-one sulfate (dehydroepiandrosterone sulfate)
- pregnenolone
- 3β-hydroxy-pregn-5-en-20-one
- DHEA
- 3β-hydroxy-androst-5-en-17-one (dehydroepiandrosterone)
- FR20
- Fixed ratio 20
- Received August 10, 1998.
- Accepted November 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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