Document Detail


Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens.
MedLine Citation:
PMID:  17913892     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT(4)R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT(4)R antagonist or siRNA-mediated 5-HT(4)R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT(4)R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT(4)R. Using 5-HT(4)R knockout mice, we demonstrate that 5-HT(4)R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT(4)R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT(4)R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy.
Authors:
Alexandra Jean; Grégory Conductier; Christine Manrique; Constantin Bouras; Philippe Berta; René Hen; Yves Charnay; Joël Bockaert; Valérie Compan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-03
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  104     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-10-16     Completed Date:  2007-11-28     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16335-40     Citation Subset:  IM    
Affiliation:
Centre National de Recherche Scientifique, Unité Mixte de Recherche 5203, Institut National de Santé et de Recherche Médicale, U661, Université Montpellier I and II, Institut de Génomique Fonctionnelle, Département de Neurobiologie, Montpellier, France.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anorexia Nervosa / etiology,  genetics,  metabolism*
Base Sequence
Eating
Male
Mice
Mice, Knockout
N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
Nerve Tissue Proteins / antagonists & inhibitors,  genetics,  metabolism*
Nucleus Accumbens / drug effects,  metabolism*
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / genetics
Receptors, Serotonin, 5-HT4 / deficiency,  genetics,  metabolism*
Signal Transduction
Chemical
Reg. No./Substance:
0/Nerve Tissue Proteins; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/cocaine- and amphetamine-regulated transcript protein; 158165-40-3/Receptors, Serotonin, 5-HT4; 42542-10-9/N-Methyl-3,4-methylenedioxyamphetamine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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