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

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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

Fingerprint

Receptor, Serotonin, 5-HT2C
Paraventricular Hypothalamic Nucleus
Corticotropin-Releasing Hormone
Hypothalamus
Serotonin
Neurons
Microdissection
Messenger RNA
Microarray Analysis
Corticosterone
Synaptic Transmission
In Situ Hybridization
Rodentia
Lasers
Down-Regulation
Observation

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Heisler, L. K., Pronchuk, N., Nonogaki, K., Zhou, L., Raber, J., Tung, L., ... 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

Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. / Heisler, Lora K.; Pronchuk, Nina; Nonogaki, Katsunori; Zhou, Ligang; Raber, Jacob; Tung, Loraine; Yeo, Giles S H; O'Rahilly, Stephen; Colmers, William F.; Elmquist, Joel K.; Tecott, Laurence H.

In: Journal of Neuroscience, Vol. 27, No. 26, 27.06.2007, p. 6956-6964.

Research output: Contribution to journalArticle

Heisler, LK, Pronchuk, N, Nonogaki, K, Zhou, L, Raber, J, Tung, L, Yeo, GSH, O'Rahilly, S, Colmers, WF, Elmquist, JK & Tecott, LH 2007, 'Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation', Journal of Neuroscience, vol. 27, no. 26, pp. 6956-6964. https://doi.org/10.1523/JNEUROSCI.2584-06.2007
Heisler, Lora K. ; Pronchuk, Nina ; Nonogaki, Katsunori ; Zhou, Ligang ; Raber, Jacob ; Tung, Loraine ; Yeo, Giles S H ; O'Rahilly, Stephen ; Colmers, William F. ; Elmquist, Joel K. ; Tecott, Laurence H. / Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 26. pp. 6956-6964.
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