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 journalArticlepeer-review

220 Scopus citations


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
Issue number26
StatePublished - Jun 27 2007


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

ASJC Scopus subject areas

  • Neuroscience(all)


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