Journal
MOLECULAR NEUROBIOLOGY
Volume 55, Issue 10, Pages 7802-7821Publisher
SPRINGER
DOI: 10.1007/s12035-018-0938-7
Keywords
Dextromethorphan; Serotonin syndrome; Protein kinase C delta knockout mice; 5-HT1A receptor; Hypothalamus; Nuclear factor erythroid-2-related factor 2
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Funding
- Korea Food and Drug Administration [14182MFDS979]
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT, Republic of Korea [NRF-2017R1A2B1003346, NRF-2016R1A1A1A05005201]
- Japan Society for the Promotion of Science (JSPS), Japan [17H04252]
- BK21 PLUS program, National Research Foundation of Korea, Republic of Korea
- Grants-in-Aid for Scientific Research [17H04252] Funding Source: KAKEN
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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 PKC delta out of PKC alpha, PKC beta I, PKC beta II, PKC xi, and PKC delta in the hypothalamus of wild-type (WT) mice. More importantly, 5-HT1A receptor co-immunoprecipitated PKC delta in the presence of DM. Consistently, rottlerin, a pharmacological inhibitor of PKC delta, or PKC delta 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, gamma-glutamylcysteine (GCL) mRNA expression, and glutathione (GSH) level. This compensative induction was further potentiated by rottlerin or PKC delta knockout. However, GCL mRNA and GSH/GSSG levels were decreased 6 and 12 h post-DM. These decreases were attenuated by PKC delta inhibition. Our results suggest that interaction between 5-HT1A receptor and PKC delta is critical for inducing DM-induced serotonergic behaviors and that inhibition of PKC delta attenuates the serotonergic behaviors via downregulation of 5-HT1A receptor and upregulation of Nrf2-dependent GSH synthesis.
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