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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

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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.

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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

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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.

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  1. Hai-Quyen Tran and Youngho Lee contributed equally to this work.

Authors and Affiliations

  1. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea

    Hai-Quyen Tran, Youngho Lee, Eun-Joo Shin & Hyoung-Chun Kim

  2. Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea

    Choon-Gon Jang

  3. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea

    Ji Hoon Jeong

  4. Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Toyoake, Aichi, 470-1192, Japan

    Akihiro Mouri, Kuniaki Saito & Toshitaka Nabeshima

  5. Aino University, Ibaraki, 576-0012, Japan

    Toshitaka Nabeshima

  6. Japanese Drug Organization of Appropriate and Research, Nagoya, 468-0069, Japan

    Toshitaka Nabeshima

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  1. Hai-Quyen Tran
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Tran, HQ., Lee, Y., Shin, EJ. et al. 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. Mol Neurobiol 55, 7802–7821 (2018). https://doi.org/10.1007/s12035-018-0938-7

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