QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 27, 2007, 27(26):6956-6964; doi:10.1523/JNEUROSCI.2584-06.2007

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Heisler, L. K. Articles by Tecott, L. H. Search for Related Content PubMed PubMed Citation Articles by Heisler, L. K. Articles by Tecott, L. H.

 Previous Article  |  Next Article 

Behavioral/Systems/Cognitive
Serotonin Activates the Hypothalamic–Pituitary–Adrenal Axis via Serotonin 2C Receptor Stimulation

Lora K. Heisler,¹ Nina Pronchuk,² Katsunori Nonogaki,^3,4 Ligang Zhou,¹ Jacob Raber,⁵ Loraine Tung,¹ Giles S. H. Yeo,¹ Stephen O'Rahilly,¹ William F. Colmers,² Joel K. Elmquist,⁶ and Laurence H. Tecott³

¹Department of Clinical Biochemistry, Addenbrooke's Hospital and the University of Cambridge, Cambridge CB2 2QR, United Kingdom, ²Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7, ³Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California at San Francisco, San Francisco, California 94117, ⁴Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan, ⁵Departments of Behavioral Neuroscience and Neurology, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon 97239, and ⁶Departments of Internal Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to either of the following: Dr. Joel K. Elmquist, Departments of Internal Medicine and Pharmacology, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9051, Email: joel.elmquist{at}UTSouthwestern.edu; or Dr. Lora K. Heisler, Department of Clinical Biochemistry, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge CB2 2QQ, UK, Email: lkh30{at}medschl.cam.ac.uk

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_2CRs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild-type rodents and 5-HT_2CR-deficient mice, we determined that 5-HT_2CRs 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_2CR and 5-HT_1DR transcripts were consistently identified as present in the PVH, and of these, the 5-HT_2CR was expressed at a substantially higher level. The abundant expression of 5-HT_2CRs 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_2CR mRNA. We observed that PVH CRH neurons consistently depolarized in the presence of a high-affinity 5-HT_2CR agonist, an effect blocked by a 5-HT_2CR antagonist. Supporting the importance of 5-HT_2CRs in CRH neuronal activity, genetic inactivation of 5-HT_2CRs 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.

Key words: serotonin; 5-HT_2C receptor; mCPP; corticotropin-releasing hormone; paraventricular nucleus of the hypothalamus; corticosterone

---

Received June 20, 2006; revised April 25, 2007; accepted April 25, 2007.

Correspondence should be addressed to either of the following: Dr. Joel K. Elmquist, Departments of Internal Medicine and Pharmacology, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9051, Email: joel.elmquist{at}UTSouthwestern.edu; or Dr. Lora K. Heisler, Department of Clinical Biochemistry, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge CB2 2QQ, UK, Email: lkh30{at}medschl.cam.ac.uk

This article has been cited by other articles:

				H. J. Yu and A. Yamaguchi 5-HT2C-Like Receptors in the Brain of Xenopus laevis Initiate Sex-Typical Fictive Vocalizations J Neurophysiol, August 1, 2009; 102(2): 752 - 765. [Abstract] [Full Text] [PDF]

				L. Asarian Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2009; 296(1): R51 - R56. [Abstract] [Full Text] [PDF]

				A. S. Garfield and L. K. Heisler Pharmacological targeting of the serotonergic system for the treatment of obesity J. Physiol., January 1, 2009; 587(1): 49 - 60. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help