5-HT 1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox

Hai Quyen Tran, Eun Joo Shin, Bao Chau Hoai Nguyen, Dieu Hien Phan, Min Ji Kang, Choon Gon Jang, Ji Hoon Jeong, Seung Yeol Nah, Akihiro Mouri, Kuniaki Saito, Toshitaka Nabeshima, Hyoung Chun Kim

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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-HT 1A receptor (5-HT 1A 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-HT 1A R and PKCδ, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT 1A R or PKCδ in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT 1A 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.

Original languageEnglish
Pages (from-to)125-141
Number of pages17
JournalFood and Chemical Toxicology
Volume123
DOIs
Publication statusPublished - 01-01-2019

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All Science Journal Classification (ASJC) codes

  • Food Science
  • Toxicology

Cite this

Tran, H. Q., Shin, E. J., Hoai Nguyen, B. C., Phan, D. H., Kang, M. J., Jang, C. G., Jeong, J. H., Nah, S. Y., Mouri, A., Saito, K., Nabeshima, T., & Kim, H. C. (2019). 5-HT 1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox Food and Chemical Toxicology, 123, 125-141. https://doi.org/10.1016/j.fct.2018.10.049