Pregnenolone sulfate, an endogenous
neurosteroid in the central nervous system, is a positive allosteric modulator of the
NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of
pregnenolone sulfate using the
dopamine transporter knockout (DAT-KO) mice, which exhibit endophenotypes that recapitulate certain symptoms of
schizophrenia, including the
psychomotor agitation, stereotypy, prepulse inhibition (PPI) deficits and
cognitive impairments. We found that acute treatment with
pregnenolone sulfate normalized the hyperlocomotion and stereotypic bouts, and rescued the PPI deficits of DAT-KO mice. In addition, long-term treatment with
pregnenolone sulfate rescued the cognitive deficits of DAT-KO mice in the novel object recognition and social transmission of food preference tests. We also showed that
pregnenolone sulfate normalized behavioral abnormalities in MK801-treated wild-type mice, whereas
pregnenolone, its precursor, only partially rescued MK801-induced behavioral abnormalities. This indicates that there are distinct mechanisms of action between
pregnenolone sulfate and
pregnenolone, and the involvement of
NMDA receptor signaling in the action of
pregnenolone sulfate. Moreover, we found that acute treatment with
pregnenolone sulfate increased the phosphorylation levels of striatal AKT and GSK3β in DAT-KO mice, and that long-term treatment with
pregnenolone sulfate increased expression levels of NR1 subunit of the
NMDA receptor in hippocampus. Thus,
pregnenolone sulfate was able to rescue the behavioral anomalies of DAT-KO mice through the
NMDA receptor-mediated, AKT/GSK3β signaling pathway.