Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice
Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA A . Two neurosteroids, allopregnanolone (3α-hydroxy-5α-pregnan-20-one) and pregnanolone (3α-hydroxy-5β-pregnan-20-one), possess anxiolytic and sedat...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 314; no. 2; pp. 675 - 685 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.08.2005
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Subjects | |
Online Access | Get full text |
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Summary: | Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor
systems such as GABA A . Two neurosteroids, allopregnanolone (3α-hydroxy-5α-pregnan-20-one) and pregnanolone (3α-hydroxy-5β-pregnan-20-one), possess
anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination
assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone.
Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone
from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with
the chronic intermittent pregnanolone administration used in drug discrimination. GABA A -positive modulators, neuroactive steroids, N -methyl- d -aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT) 3 agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic
neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT 3 agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital
and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences
in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at
pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of
the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and
are not apparent in a drug discrimination procedure. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.104.082644 |