Ethanol-like discriminative stimulus effects of endogenous neuroactive steroids: Effect of ethanol training dose and dosing procedure

Carrie A. Bowen, Robert H. Purdy, Kathleen (Kathy) Grant

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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 (GABA(A)) and N-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 GABA(A) 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 GABA(A)-positive modulatory steroids allopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone substituted for ethanol, as did the low-efficacy steroid 3β,5β-P. GABA(A)-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.

Original languageEnglish (US)
Pages (from-to)405-411
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number1
StatePublished - 1999
Externally publishedYes

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Pregnanolone
Ethanol
Steroids
Dehydroepiandrosterone Sulfate
Sulfates
N-Methyl-D-Aspartate Receptors
gamma-Aminobutyric Acid
Aminobutyrates
Pregnenolone
Long Evans Rats
N-Methylaspartate
GABA-A Receptors
Central Nervous System

ASJC Scopus subject areas

  • Pharmacology

Cite this

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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 (GABA(A)) and N-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 GABA(A) 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 GABA(A)-positive modulatory steroids allopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone substituted for ethanol, as did the low-efficacy steroid 3β,5β-P. GABA(A)-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.",
author = "Bowen, {Carrie A.} and Purdy, {Robert H.} and Grant, {Kathleen (Kathy)}",
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AU - Bowen, Carrie A.

AU - Purdy, Robert H.

AU - Grant, Kathleen (Kathy)

PY - 1999

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N2 - 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 (GABA(A)) and N-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 GABA(A) 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 GABA(A)-positive modulatory steroids allopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone substituted for ethanol, as did the low-efficacy steroid 3β,5β-P. GABA(A)-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.

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