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

J Neurosci. 2007 Jun 27;27(26):6956-64. doi: 10.1523/JNEUROSCI.2584-06.2007.

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-HT(2C)Rs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild-type rodents and 5-HT(2C)R-deficient mice, we determined that 5-HT(2C)Rs 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-HT(2C)R and 5-HT(1D)R transcripts were consistently identified as present in the PVH, and of these, the 5-HT(2C)R was expressed at a substantially higher level. The abundant expression of 5-HT(2C)Rs 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-HT(2C)R mRNA. We observed that PVH CRH neurons consistently depolarized in the presence of a high-affinity 5-HT(2C)R agonist, an effect blocked by a 5-HT(2C)R antagonist. Supporting the importance of 5-HT(2C)Rs in CRH neuronal activity, genetic inactivation of 5-HT(2C)Rs 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / metabolism
  • Animals
  • Corticotropin-Releasing Hormone / metabolism*
  • Down-Regulation / genetics
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurosecretory Systems / drug effects
  • Neurosecretory Systems / metabolism
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / metabolism*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1D / genetics
  • Receptor, Serotonin, 5-HT1D / metabolism
  • Receptor, Serotonin, 5-HT2C / genetics*
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin / metabolism*
  • Serotonin / pharmacology
  • Serotonin 5-HT2 Receptor Agonists
  • Stress, Physiological / genetics
  • Stress, Physiological / metabolism
  • Stress, Physiological / physiopathology

Substances

  • Adrenal Cortex Hormones
  • RNA, Messenger
  • Receptor, Serotonin, 5-HT1D
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin
  • Corticotropin-Releasing Hormone