title: Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens.
abstract: 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.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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jean
authors.forename: Grégory
authors.initials: G
authors.lastname: Conductier
authors.forename: Christine
authors.initials: C
authors.lastname: Manrique
authors.forename: Constantin
authors.initials: C
authors.lastname: Bouras
authors.forename: Philippe
authors.initials: P
authors.lastname: Berta
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Yves
authors.initials: Y
authors.lastname: Charnay
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Valérie
authors.initials: V
authors.lastname: Compan
mesh_terms: D000818:Animals; D000856:Anorexia Nervosa / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D004435:Eating; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044422:Receptors, Serotonin, 5-HT4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D044422:Receptors, Serotonin, 5-HT4; D018817:N-Methyl-3,4-methylenedioxyamphetamine