Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through
neurotransmitter receptor systems such as
GABA(A). Two
neurosteroids,
allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and
pregnanolone (3alpha-hydroxy-5beta-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.