PMID- 36532377
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221222
IS  - 2352-2895 (Print)
IS  - 2352-2895 (Electronic)
IS  - 2352-2895 (Linking)
VI  - 21
DP  - 2022 Nov
TI  - Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in 
      the prefrontal cortex.
PG  - 100489
LID - 10.1016/j.ynstr.2022.100489 [doi]
LID - 100489
AB  - 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 GABA(A) receptor 
      activator is synthesized in response to acute stress, we hypothesized its 
      participation in stress-induced PPI deficits. 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 GABA(A) receptor antagonist bicuculline and mimicked by AP infusions in the 
      medial prefrontal cortex (mPFC). Building on these findings, 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). 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. 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.
CI  - (c) 2022 The Authors.
FAU - Cadeddu, Roberto
AU  - Cadeddu R
AD  - Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 
      Salt Lake City, UT, USA.
FAU - Mosher, Laura J
AU  - Mosher LJ
AD  - Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 
      Salt Lake City, UT, USA.
AD  - Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 
      Lawrence, KS, USA.
FAU - Nordkild, Peter
AU  - Nordkild P
AD  - Asarina Pharmaceuticals, Copenhagen, Denmark.
FAU - Gaikwad, Nilesh
AU  - Gaikwad N
AD  - Gaikwad Steroidomics, Davis, CA, USA.
FAU - Ratto, Gian Michele
AU  - Ratto GM
AD  - National Enterprise for NanoScience and NanoTechnology (NEST), Istituto 
      Nanoscienze, Consiglio Nazionale delle Ricerche (CNR), Pisa, Italy.
AD  - Scuola Normale Superiore Pisa, 56127, Pisa, Italy.
FAU - Scheggi, Simona
AU  - Scheggi S
AD  - Department of Molecular and Developmental Medicine, University of Siena, Italy.
FAU - Bortolato, Marco
AU  - Bortolato M
AD  - Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 
      Salt Lake City, UT, USA.
AD  - Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 
      Lawrence, KS, USA.
LA  - eng
PT  - Journal Article
DEP - 20220924
PL  - United States
TA  - Neurobiol Stress
JT  - Neurobiology of stress
JID - 101643409
PMC - PMC9755022
OTO - NOTNLM
OT  - Acute stress
OT  - Allopregnanolone
OT  - Animal models
OT  - Medial prefrontal cortex
OT  - Prepulse inhibition
COIS- 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.
EDAT- 2022/12/20 06:00
MHDA- 2022/12/20 06:01
PMCR- 2022/09/24
CRDT- 2022/12/19 04:12
PHST- 2022/07/18 00:00 [received]
PHST- 2022/09/07 00:00 [revised]
PHST- 2022/09/20 00:00 [accepted]
PHST- 2022/12/19 04:12 [entrez]
PHST- 2022/12/20 06:00 [pubmed]
PHST- 2022/12/20 06:01 [medline]
PHST- 2022/09/24 00:00 [pmc-release]
AID - S2352-2895(22)00064-9 [pii]
AID - 100489 [pii]
AID - 10.1016/j.ynstr.2022.100489 [doi]
PST - epublish
SO  - Neurobiol Stress. 2022 Sep 24;21:100489. doi: 10.1016/j.ynstr.2022.100489. 
      eCollection 2022 Nov.