Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

摘要

Neurosteroids represent a class of endogenous compounds that exert rapid,nongenomic effects through neurotransmitter receptor systems such as GABA_A.Two neurosteroids,allopreg-nanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one),possess anxiolytic and sedative properties and show substitution for ethanol,benzodiaz-epines,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 C57BLy6J 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-hy-droxytryptamine (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 preg-nanolone's discriminative stimulus in either sex or strain.Pen-tobarbital and midazolam were more potent in producing preg-nanolone-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.