PMID- 31228750 OWN - NLM STAT- MEDLINE DCOM- 20200601 LR - 20201002 IS - 1873-3360 (Electronic) IS - 0306-4530 (Print) IS - 0306-4530 (Linking) VI - 108 DP - 2019 Oct TI - Allopregnanolone is required for prepulse inhibition deficits induced by D(1) dopamine receptor activation. PG - 53-61 LID - S0306-4530(19)30172-6 [pii] LID - 10.1016/j.psyneuen.2019.06.009 [doi] AB - INTRODUCTION: The extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5alpha-reductase (5alphaR). The specific 5alphaR isoenzyme and steroids implicated in these effects, however, remain unknown. METHODS: The effects of the selective D(1) dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D(2) receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5alphaR type 1 (5alphaR1) or type 2 (5alphaR2). Furthermore, we established whether these effects may be modified by the 5alpha-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), or androsterone. To test the mechanisms whereby 5alphaR products may alter the PPI-disrupting properties of D(1) agonists, we studied the involvement of GABA-A and PXR, two receptors targeted by neuroactive steroids. Specifically, we tested the effects of SKF in combination with the GABA-A antagonist bicuculline, as well as in KO mice for the GABA-A delta subunit and PXR. RESULTS: 5alphaR1, but not 5alphaR2, knockout (KO) mice were insensitive to the PPI-disrupting effects of SKF. This sensitivity was reinstated by AP (3 mg/kg, IP), but not other 5alpha-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, delta-subunit KO mice and PXR KO mice. CONCLUSIONS: These results collectively suggest that 5alphaR1 enables the negative effects of D(1) dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D(1) receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Mosher, Laura J AU - Mosher LJ AD - Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City UT United States; Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence KS United States. FAU - Cadeddu, Roberto AU - Cadeddu R AD - Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City UT United States. FAU - Yen, Sabrina AU - Yen S AD - Department of Neuroscience, School of Medicine, Tufts University, Boston MA United States. FAU - Staudinger, Jeffrey L AU - Staudinger JL AD - Department of Basic Science, Kansas City University, School of Osteopathic Medicine, Joplin MO United States. FAU - Traccis, Francesco AU - Traccis F AD - Department of Biomedical Sciences, University of Cagliari, Monserrato CA, Italy. FAU - Fowler, Stephen C AU - Fowler SC AD - Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence KS United States. FAU - Maguire, Jamie L AU - Maguire JL AD - Department of Neuroscience, School of Medicine, Tufts University, Boston MA United States. FAU - Bortolato, Marco AU - Bortolato M AD - Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City UT United States. Electronic address: marco.bortolato@utah.edu. LA - eng GR - F31 NS093939/NS/NINDS NIH HHS/United States GR - R21 NS108722/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190614 PL - England TA - Psychoneuroendocrinology JT - Psychoneuroendocrinology JID - 7612148 RN - 0 (Benzazepines) RN - 0 (Receptors, Dopamine) RN - 0 (Receptors, Dopamine D1) RN - 0 (Receptors, Dopamine D2) RN - 20OP60125T (Quinpirole) RN - 80751-65-1 (SK&F 82958) RN - BXO86P3XXW (Pregnanolone) RN - EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase) RN - VTD58H1Z2X (Dopamine) SB - IM MH - 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/*metabolism/physiology MH - Animals MH - Benzazepines/pharmacology MH - Dopamine/metabolism/pharmacology MH - Male MH - Mice MH - Mice, Knockout MH - Pregnanolone/*pharmacology MH - Prepulse Inhibition/drug effects MH - Quinpirole/pharmacology MH - Receptors, Dopamine/metabolism MH - Receptors, Dopamine D1/drug effects/*metabolism MH - Receptors, Dopamine D2/drug effects/metabolism MH - Reflex, Startle/drug effects MH - Sensory Gating/physiology PMC - PMC6773911 MID - NIHMS1532602 OTO - NOTNLM OT - 5alpha-reductase OT - Allopregnanolone OT - Behavioral studies OT - D(1)receptors OT - Dopamine OT - Sensorimotor gating COIS- Conflict of Interest No conflicts declared. EDAT- 2019/06/23 06:00 MHDA- 2020/06/02 06:00 PMCR- 2020/10/01 CRDT- 2019/06/23 06:00 PHST- 2019/02/24 00:00 [received] PHST- 2019/06/08 00:00 [revised] PHST- 2019/06/12 00:00 [accepted] PHST- 2019/06/23 06:00 [pubmed] PHST- 2020/06/02 06:00 [medline] PHST- 2019/06/23 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - S0306-4530(19)30172-6 [pii] AID - 10.1016/j.psyneuen.2019.06.009 [doi] PST - ppublish SO - Psychoneuroendocrinology. 2019 Oct;108:53-61. doi: 10.1016/j.psyneuen.2019.06.009. Epub 2019 Jun 14.