Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex

Background and purpose Ample evidence indicates that environmental stress impairs information processing, yet the underlying mechanisms remain partially elusive. We showed that, in several rodent models of psychopathology, the neurosteroid allopregnanolone (AP) reduces the prepulse inhibition (PPI) of the startle, a well-validated index of sensorimotor gating. Since this GABAA receptor activator is synthesized in response to acute stress, we hypothesized its participation in stress-induced PPI deficits. Experimental approach We studied whether and how AP influences PPI in mice and rats; thereafter, we tested AP’s implication in the PPI deficits produced by several complementary regimens of acute and short-term stress (footshock, restraint, predator exposure, and sleep deprivation). Key results Systemic AP administration reduced PPI in C57BL/6J mice and Long-Evans, but not Sprague-Dawley, rats. These effects were reversed by isoallopregnanolone (isoAP), an endogenous AP antagonist, and the GABAA receptor antagonist bicuculline and mimicked by AP infusions in the medial prefrontal cortex (mPFC). PPI was reduced by acute footshock, sleep deprivation as well as the combination of restraint and predator exposure in a time- and intensity-dependent fashion. Acute stress increased AP concentrations in the mPFC, and its detrimental effects on PPI were countered by systemic and intra-mPFC administration of isoAP. Conclusions and implications These results collectively indicate that acute stress impairs PPI by increasing AP content in the mPFC. The confirmation of these mechanisms across distinct animal models and several acute stressors strongly supports the translational value of these findings and warrants future research on the role of AP in information processing. ### Competing Interest Statement PN and MB are the Chief Executive Officer and a Scientific Advisory Board member of Asarina Pharma AB, respectively. The other authors declare no conflict of interest.