Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation

Lora K. Heisler, Nina Pronchuk, Katsunori Nonogaki, Ligang Zhou, Jacob Raber, Loraine Tung, Giles S.H. Yeo, Stephen O'Rahilly, William F. Colmers, Joel K. Elmquist, Laurence H. Tecott

Research output: Contribution to journalArticle

191 Scopus citations

Abstract

The dynamic interplay between serotonin [5-hydroxytryptamine (5-HT)] neurotransmission and the hypothalamic-pituitary-adrenal (HPA) axis has been extensively studied over the past 30 years, but the underlying mechanism of this interaction has not been defined. A possibility receiving little attention is that 5-HT regulates upstream corticotropin-releasing hormone (CRH) signaling systems via activation of serotonin 2C receptors (5-HT2CRs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild-type rodents and 5-HT2CR-deficient mice, we determined that 5-HT2CRs are necessary for 5-HT-induced HPA axis activation. We used laser-capture PVH microdissection followed by microarray analysis to compare the expression of 13 5-HTRs. Only 5-HT2CR and 5-HT1DR transcripts were consistently identified as present in the PVH, and of these, the 5-HT2CR was expressed at a substantially higher level. The abundant expression of 5-HT2CRs in the PVH was confirmed with in situ hybridization histochemistry. Dual-neurohistochemical labeling revealed that approximately one-half of PVH CRH-containing neurons coexpressed 5-HT2CR mRNA. We observed that PVH CRH neurons consistently depolarized in the presence of a high-affinity 5-HT2CR agonist, an effect blocked by a 5-HT2CR antagonist. Supporting the importance of 5-HT2CRs in CRH neuronal activity, genetic inactivation of 5-HT2CRs produced a downregulation of CRH mRNA and blunted CRH and corticosterone release after 5-HT compound administration. These findings thus provide a mechanistic explanation for the longstanding observation of HPA axis stimulation in response to 5-HT and thereby give insight into the neural circuitry mediating the complex neuroendocrine responses to stress.

Original languageEnglish (US)
Pages (from-to)6956-6964
Number of pages9
JournalJournal of Neuroscience
Volume27
Issue number26
DOIs
StatePublished - Jun 27 2007

Keywords

  • 5-HT receptor
  • Corticosterone
  • Corticotropin-releasing hormone
  • Paraventricular nucleus of the hypothalamus
  • Serotonin
  • mCPP

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Heisler, L. K., Pronchuk, N., Nonogaki, K., Zhou, L., Raber, J., Tung, L., Yeo, G. S. H., O'Rahilly, S., Colmers, W. F., Elmquist, J. K., & Tecott, L. H. (2007). Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. Journal of Neuroscience, 27(26), 6956-6964. https://doi.org/10.1523/JNEUROSCI.2584-06.2007