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Molecular Neurobiology

, Volume 55, Issue 10, pp 7802–7821 | Cite as

PKCδ Knockout Mice Are Protected from Dextromethorphan-Induced Serotonergic Behaviors in Mice: Involvements of Downregulation of 5-HT1A Receptor and Upregulation of Nrf2-Dependent GSH Synthesis

  • Hai-Quyen Tran
  • Youngho Lee
  • Eun-Joo ShinEmail author
  • Choon-Gon Jang
  • Ji Hoon Jeong
  • Akihiro Mouri
  • Kuniaki Saito
  • Toshitaka Nabeshima
  • Hyoung-Chun KimEmail author
Article

Abstract

We investigated whether a specific serotonin (5-HT) receptor-mediated mechanism was involved in dextromethorphan (DM)-induced serotonergic behaviors. We firstly observed that the activation of 5-HT1A receptor, but not 5-HT2A receptor, contributed to DM-induced serotonergic behaviors in mice. We aimed to determine whether the upregulation of 5-HT1A receptor induced by DM facilitates the specific induction of certain PKC isoform, because previous reports suggested that 5-HT1A receptor activates protein kinase C (PKC). A high dose of DM (80 mg/kg, i.p.) induced a selective induction of PKCδ out of PKCα, PKCβI, PKCβII, PKCξ, and PKCδ in the hypothalamus of wild-type (WT) mice. More importantly, 5-HT1A receptor co-immunoprecipitated PKCδ in the presence of DM. Consistently, rottlerin, a pharmacological inhibitor of PKCδ, or PKCδ knockout significantly protected against increases in 5-HT1A receptor gene expression, 5-HT turnover rate, and serotonergic behaviors induced by DM. Treatment with DM resulted in an initial increase in nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation and DNA-binding activity, γ-glutamylcysteine (GCL) mRNA expression, and glutathione (GSH) level. This compensative induction was further potentiated by rottlerin or PKCδ knockout. However, GCL mRNA and GSH/GSSG levels were decreased 6 and 12 h post-DM. These decreases were attenuated by PKCδ inhibition. Our results suggest that interaction between 5-HT1A receptor and PKCδ is critical for inducing DM-induced serotonergic behaviors and that inhibition of PKCδ attenuates the serotonergic behaviors via downregulation of 5-HT1A receptor and upregulation of Nrf2-dependent GSH synthesis.

Keywords

Dextromethorphan Serotonin syndrome Protein kinase C δ knockout mice 5-HT1A receptor Hypothalamus Nuclear factor erythroid-2-related factor 2 

Abbreviations

5-HIAA

5-Hydroxyindoleacetic acid

5-HT

Serotonin

ARE

Antioxidant response element

CNS

Central nervous system

DM

Dextromethorphan

GCL

γ-Glutamylcysteine

GI

Gastrointestinal

GSH

Glutathione

GSSG

Glutathione disulfide

IPANs

Intrinsic primary afferent nerves

Keap1

Kelch ECH associating protein 1

KO

Knockout

L-BSO

l-Buthionine sulfoximine

MAO-A

Monoamine oxidase-A

MDL

MDL11,939

Nrf2

Nuclear factor erythroid-2-related factor 2

PKC

Protein kinase C

Rott

Rottlerin

WAY

WAY100635

WT

Wild-type

Notes

Acknowledgements

This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (#NRF-2017R1A2B1003346 and #NRF-2016R1A1A1A05005201, Republic of Korea, and by a grant (17H04252) from the Japan Society for the Promotion of Science (JSPS), Japan. Hai-Quyen Tran was supported by the BK21 PLUS program, National Research Foundation of Korea, Republic of Korea. The English in this document has been checked by at least two professional editors, both native speakers of English.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National UniversityChunchonRepublic of Korea
  2. 2.Department of Pharmacology, School of PharmacySungkyunkwan UniversitySuwonRepublic of Korea
  3. 3.Department of Pharmacology, College of MedicineChung-Ang UniversitySeoulRepublic of Korea
  4. 4.Advanced Diagnostic System Research LaboratoryFujita Health University Graduate School of Health ScienceToyoakeJapan
  5. 5.Aino UniversityIbarakiJapan
  6. 6.Japanese Drug Organization of Appropriate and ResearchNagoyaJapan

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