5-HT 2A receptor-mediated PKCδ phosphorylation is critical for serotonergic impairments induced by p-chloroamphetamine in mice.

Autor: Phan DH; Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea; School of Medicine and Pharmacy - Hoa Quy Ward, The University of Da Nang, Da Nang 550000, Viet Nam., Shin EJ; Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea., Sharma N; Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea., Hoang Yen TP; Faculty of Pharmacy, University of Medicine and Pharmacy of Ho Chi Minh City, 710000, Viet Nam., Dang DK; Pharmacy Faculty, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Viet Nam., Lee YS; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea., Lee YJ; Clinical Pharmacy, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea., Nah SY; Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, 05029, Republic of Korea., Cheong JH; Department of Pharmacy, Sahmyook University, Seoul, 01795, Republic of Korea., Jeong JH; Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea., Kim HC; Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea. Electronic address: kimhc@kangwon.ac.kr.
Jazyk: angličtina
Zdroj: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association [Food Chem Toxicol] 2020 Jul; Vol. 141, pp. 111395. Date of Electronic Publication: 2020 May 11.
DOI: 10.1016/j.fct.2020.111395
Abstrakt: p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT 1A receptor gene expression, but significantly increased 5-HT 2A receptor gene expression. Furthermore, 5-HT 2A receptor antagonist MDL11939, but not 5-HT 1A receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT 2A receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT 2A receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT 2A receptor-mediated serotonergic effects. Our results suggest that 5-HT 2A receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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