5-HT1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox. (January 2019)

• Record Type: Journal Article
• Authors: Tran, Hai-Quyen; Shin, Eun-Joo; Hoai Nguyen, Bao-Chau; Phan, Dieu-Hien; Kang, Min-Ji; Jang, Choon-Gon; Jeong, Ji Hoon; Nah, Seung-Yeol; Mouri, Akihiro; Saito, Kuniaki; Nabeshima, Toshitaka; Kim, Hyoung-Chun
• Is Part Of: Food and chemical toxicology. Volume 123(2019)
• Page Start: 125
• Page End: 141
• Publication Date: 2019-01
• Subjects: Serotonergic behaviors -- 5-HT1A receptor -- PKCδ knockout mice -- p47phox knockout mice -- Interaction between 5HT1A receptor -- PKCδ, and p47phox -- Hypothalamus; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.10.049
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Serotonin syndrome is an adverse reaction due to increased serotonin (5-hydroxytryptophan: 5-HT) concentrations in the central nervous system (CNS). The full 5-HT1A receptor (5-HT1A R) agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) has been recognized to elicit traditional serotonergic behaviors. Treatment with 8-OH-DPAT selectively increased PKCδ expression out of PKC isoforms and 5-HT turnover rate in the hypothalamus of wild-type mice. Treatment with 8-OH-DPAT resulted in oxidative burdens, co-immunoprecipitation of 5-HT1A R and PKCδ, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT1A R or PKCδ in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT1A R antagonism (i.e., WAY100635), PKCδ inhibition (i.e., rottlerin and genetic depletion of PKCδ), or NADPH oxidase/p47phox inhibition (i.e., apocynin and genetic depletion of p47phox). However, WAY100635, apocynin, or rottlerin did not exhibit any additive effects against the protective effect by inhibition of PKCδ or p47phox. Furthermore, apocynin, rottlerin, or WAY100635 also significantly protected from pro-inflammatory/pro-apoptotic changes induced by 8-OH-DPAT. Therefore, we suggest that 8-OH-DPAT-induced serotonergic behaviors requires oxidative stress, pro-inflammatory, and pro-apoptotic changes, that PKCδ or p47phox mediates the serotonergic behaviors induced by 8-OH-DPAT, and that the inhibition of PKCδ-dependent p47phox activation is critical for protecting against serotonergic behaviors. Graphical abstract: Highlights: 8-OH-DPAT significantly increases PKCδ expression and 5-HT turnover rate in the hypothalamus of mice. 8-OH-DPAT induces oxidative burdens and interactions of "5-HT1A R and PKCδ", "5-HT1A R and PKCδ", and "PKCδ and p47phox". Oxidative, inflammatory, apoptotic changes by 8-OH-DPAT are attenuated via inhibition of 5-HT1A R, PKCδ, or PHOX/p47phox. PKCδ or p47phox mediates the increase in 5-HT turnover rate and serotonergic behaviors induced by 8-OH-DPAT. The inhibition of PKCδ-dependent p47phox activation is critical for attenuating against the serotonergic behaviors.