title: Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation.
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.
authors.affiliation: Department of Clinical Biochemistry, Addenbrooke's Hospital and the University of Cambridge, Cambridge CB2 2QR, United Kingdom. lkh30@medschl.cam.ac.uk
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
authors.forename: Nina
authors.initials: N
authors.lastname: Pronchuk
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nonogaki
authors.forename: Ligang
authors.initials: L
authors.lastname: Zhou
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.forename: Loraine
authors.initials: L
authors.lastname: Tung
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Tecott
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044346:Receptor, Serotonin, 5-HT1D / Q000235:genetics / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics* / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000305:Adrenal Cortex Hormones; D012333:RNA, Messenger; D044346:Receptor, Serotonin, 5-HT1D; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D012701:Serotonin; D003346:Corticotropin-Releasing Hormone