PMID- 34339750 OWN - NLM STAT- MEDLINE DCOM- 20220207 LR - 20230330 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 197 DP - 2021 Oct 1 TI - Different roles of T-type calcium channel isoforms in hypnosis induced by an endogenous neurosteroid epipregnanolone. PG - 108739 LID - S0028-3908(21)00294-X [pii] LID - 10.1016/j.neuropharm.2021.108739 [doi] AB - BACKGROUND: Many neuroactive steroids induce sedation/hypnosis by potentiating gamma-aminobutyric acid (GABA(A)) currents. However, we previously demonstrated that an endogenous neuroactive steroid epipregnanolone [(3beta,5beta)-3-hydroxypregnan-20-one] (EpiP) exerts potent peripheral analgesia and blocks T-type calcium currents while sparing GABA(A) currents in rat sensory neurons. This study seeks to investigate the behavioral effects elicited by systemic administration of EpiP and to characterize its use as an adjuvant agent to commonly used general anesthetics (GAs). METHODS: Here, we utilized electroencephalographic (EEG) recordings to characterize thalamocortical oscillations, as well as behavioral assessment and mouse genetics with wild-type (WT) and different knockout (KO) models of T-channel isoforms to investigate potential sedative/hypnotic and immobilizing properties of EpiP. RESULTS: Consistent with increased oscillations in slower EEG frequencies, EpiP induced an hypnotic state in WT mice when injected alone intra-peritoneally (i.p.) and effectively facilitated anesthetic effects of isoflurane (ISO) and sevoflurane (SEVO). The Ca(V)3.1 (Cacna1g) KO mice demonstrated decreased sensitivity to EpiP-induced hypnosis when compared to WT mice, whereas no significant difference was noted between Ca(V)3.2 (Cacna1h), Ca(V)3.3 (Cacna1i) and WT mice. Finally, when compared to WT mice, onset of EpiP-induced hypnosis was delayed in Ca(V)3.2 KO mice but not in Ca(V)3.1 and Ca(V)3.3 KO mice. CONCLUSION: We posit that EpiP may have an important role as novel hypnotic and/or adjuvant to volatile anesthetic agents. We speculate that distinct hypnotic effects of EpiP across all three T-channel isoforms is due to their differential expression in thalamocortical circuitry. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Coulter, Ian AU - Coulter I AD - Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA. FAU - Timic Stamenic, Tamara AU - Timic Stamenic T AD - Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA. FAU - Eggan, Pierce AU - Eggan P AD - Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA. FAU - Fine, Brier R AU - Fine BR AD - Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA. FAU - Corrigan, Timothy AU - Corrigan T AD - Department of Pediatrics, Division of Neurology, Translational Epilepsy Research Program, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA. FAU - Covey, Douglas F AU - Covey DF AD - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Yang, Lingling AU - Yang L AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, USA. FAU - Pan, Jen Q AU - Pan JQ AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, USA. FAU - Todorovic, Slobodan M AU - Todorovic SM AD - Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA; Neuroscience and University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA; Pharmacology Graduate Programs, University of Colorado, Anschutz Medical Campus, Aurora, 80045, USA. Electronic address: slobodan.todorovic@cuanschutz.edu. LA - eng GR - R01 GM102525/GM/NIGMS NIH HHS/United States GR - P30 NS048154/NS/NINDS NIH HHS/United States GR - R01 GM123746/GM/NIGMS NIH HHS/United States GR - R01 MH115045/MH/NIMH NIH HHS/United States GR - R35 GM141802/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210731 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Adjuvants, Anesthesia) RN - 0 (Anesthetics, Inhalation) RN - 0 (Cacna1g protein, mouse) RN - 0 (Cacna1i protein, mouse) RN - 0 (Calcium Channels, T-Type) RN - 0 (Hypnotics and Sedatives) RN - 38LVP0K73A (Sevoflurane) RN - BXO86P3XXW (Pregnanolone) RN - CYS9AKD70P (Isoflurane) SB - IM MH - Adjuvants, Anesthesia/pharmacology MH - Anesthetics, Inhalation/pharmacology MH - Animals MH - Behavior, Animal/drug effects MH - Calcium Channels, T-Type/*drug effects/genetics MH - Electroencephalography/drug effects MH - Hypnotics and Sedatives/*pharmacology MH - Isoflurane/pharmacology MH - Isomerism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Pregnanolone/*pharmacology MH - Sevoflurane/pharmacology PMC - PMC8478885 MID - NIHMS1731270 OTO - NOTNLM OT - Calcium OT - Isoflurane OT - Low-voltage-activated OT - Righting reflex OT - Thalamus OT - Withdrawal reflex COIS- Conflict of interest The authors received no compensation nor do they have any conflicting financial interests in regards to the work described in this manuscript. EDAT- 2021/08/03 06:00 MHDA- 2022/02/08 06:00 PMCR- 2022/10/01 CRDT- 2021/08/02 20:13 PHST- 2021/03/19 00:00 [received] PHST- 2021/07/09 00:00 [revised] PHST- 2021/07/29 00:00 [accepted] PHST- 2021/08/03 06:00 [pubmed] PHST- 2022/02/08 06:00 [medline] PHST- 2021/08/02 20:13 [entrez] PHST- 2022/10/01 00:00 [pmc-release] AID - S0028-3908(21)00294-X [pii] AID - 10.1016/j.neuropharm.2021.108739 [doi] PST - ppublish SO - Neuropharmacology. 2021 Oct 1;197:108739. doi: 10.1016/j.neuropharm.2021.108739. Epub 2021 Jul 31.