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Anorexia Induced by Activation of Serotonin 5-HT4 Receptors Is Mediated by Increases in CART in the Nucleus Accumbens

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Anorexia Induced by Activation of Serotonin 5-HT4 Receptors Is Mediated by Increases in CART in the Nucleus Accumbens Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens Alexandra Jean*†, Gre´ gory Conductier*†, Christine Manrique‡, Constantin Bouras§, Philippe Berta†, Rene´ Hen¶, Yves Charnay§, Joe¨ l Bockaert*, and Vale´ rie Compan*†ʈ *Centre National de la Recherche Scientifique (CNRS), Unite´Mixte de Recherche (UMR)5203, Institut National de la Sante´et de la Recherche Me´dicale, U661, Universite´Montpellier I and II, Institut de Ge´nomique Fonctionnelle, De´partement de Neurobiologie, 141 Rue de la Cardonille, F-34094 Montpellier Cedex 5, France; †Universite´Nîmes (JE2425, Team 1, Anorexie, De´pendance, Obe´site´de Nîmes: ADONîmes), Rue Docteur Georges Salan, F-30021 Nîmes, France; ‡CNRS, UMR6149, Universite´Aix-Marseille I, Neurobiologie Inte´grative et Adaptative, 3 Place Victor Hugo, F-13331 Marseille Cedex 3, France; §Hoˆpitaux Universitaires de Gene`ve, Division de Neuropsychiatrie, CH-1225 Cheˆne-bourg, Switzerland; and ¶Center of Neurobiology and Behavior, Columbia University, New York, NY 10032 Edited by Wylie Vale, The Salk Institute for Biological Studies, La Jolla, CA, and approved August 22, 2007 (received for review February 20, 2007) Anorexia nervosa is a growing concern in mental health, often over, 5-HT1BR and 5-HT2CR knockout (KO) mice are less inducing death. The potential neuronal deficits that may underlie sensitive to fenfluramine (4, 5). abnormal inhibitions of food intake, however, remain largely Stress and anxiety can also induce anorexia (13), and increases unexplored. We hypothesized that anorexia may involve altered in 5-HT neuromodulation are known to participate in the signaling events within the nucleus accumbens (NAc), a brain decreased food intake caused by stress (14–16). We have dem- structure involved in reward. We show here that direct stimulation onstrated that 5-HT4R KO displays attenuated responses to of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT4R) in stress-induced hypophagia (17). Because MDMA is a rewarding the NAc reduces the physiological drive to eat and increases CART drug that reduces the intake of food despite an energy demand (cocaine- and amphetamine-regulated transcript) mRNA levels in (8), mimicking anorexia-like behavior, we reasoned that the fed and food-deprived mice. It further shows that injecting 5-HT4R activation of 5-HT4R into the nucleus accumbens (NAc) may be antagonist or siRNA-mediated 5-HT4R knockdown into the NAc essential for MDMA-induced anorexia. Indeed, the NAc, as a induced hyperphagia only in fed mice. This hyperphagia was not brain reward center, may influence the physiological drive to eat associated with changes in CART mRNA expression in the NAc in (18–21), which also contains high densities of 5-HT4R (22). fed and food-deprived mice. Results include that 5-HT4R control To address this possibility, we examined the effects on food CART mRNA expression into the NAc via a cAMP/PKA signaling intake of directly stimulating or inactivating 5-HT4R in the NAc, pathway. Considering that CART may interfere with food- and and we also investigated whether these receptors are further drug-related rewards, we tested whether the appetite suppressant involved in the anorectic effect of MDMA by using a combina- properties of 3,4-N-methylenedioxymethamphetamine (MDMA, tion of pharmacological, biochemical, immunocytochemical, and molecular biology techniques that include intracerebral injection ecstasy) involve the 5-HT4R. Using 5-HT4R knockout mice, we of siRNA-mediated 5-HT4R (si5-HT4R) knockdown into the demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART NAc. Using 5-HT4R KO mice, we further determined that mRNA expression in the NAc. Directly injecting CART peptide or 5-HT4R contribute to the appetite-suppressant effect of CART siRNA into the NAc reduces or increases food consumption, MDMA. Additional experiments revealed that the activation of accumbal 5-HT4R increases the mRNA level of the satiety factor respectively. Finally, stimulating 5-HT4R- and MDMA-induced an- cocaine- and amphetamine-regulated transcript (CART) via a NEUROSCIENCE orexia were both reduced by injecting CART siRNA into the NAc. cAMP/PKA signaling pathway. Finally, we provide evidence that Collectively, these results demonstrate that 5-HT R-mediated up- 4 increased CART mRNA expression mediates the appetite- regulation of CART in the NAc triggers the appetite-suppressant suppressant effects of both accumbal 5-HT R stimulation and effects of ecstasy. 4 MDMA, the psychogenic compound of ecstasy. eating ͉ knockout ͉ siRNA ͉ 3,4-methylenedioxymethamphetamine Results (MDMA) Stimulation of Accumbal 5-HT4R Inhibits Food Intake and Increases the Level of CART mRNA. Food intake was measured over 2 h, starting norexia nervosa is one of the mental diseases exhibiting 1 h after intraaccumbal injections of NaCl or endo-N-8-methyl- A the highest mortality rates in industrialized countries (1, 2). No effective strategies for treating this disorder are avail- able. If one defines anorexia as self-imposed deprivation Author contributions: A.J. and G.C. contributed equally to this work; V.C. designed re- search; A.J., G.C., C.M., Y.C., and V.C. performed research; C.B., P.B., R.H., J.B., and V.C. despite an energy demand, similar behavior can be provoked contributed new reagents/analytic tools; A.J., G.C., and V.C. analyzed data; and V.C. wrote by treatments that increase serotonin (5-hydroxytryptamine, the paper. 5-HT) neuromodulation (3). For instance, fenfluramine, The authors declare no conflict of interest. which increases synaptic 5-HT levels, lowers the consumption This article is a PNAS Direct Submission. of food in humans and rodents (4, 5). Similarly, amphetamine Abbreviations: BIMU8, endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3- and 3,4-N-methylenedioxymethamphetamine (MDMA, ec- isopropyl-2-oxo-1H-benzimidazol-1-carboxamide hydrochloride; CART, cocaine- and stasy) diminish food consumption in humans (6) and rats (7) amphetamine-regulated transcript; H89, N-(2-[p-bromocinnamylamino]ethyl)-5- isoquinoline-sulfonamide hydrochloride; 5-HT, serotonin; 5-HT4R, serotonin receptor; and reduce deprivation-induced eating in mice (8). 5-HT- Ir, immunoreactivity; MDMA, 3,4-N-methylenedioxymethamphetamine; NAc, nucleus induced hypophagia is mediated by both 5-HT1B and 5-HT2C accumbens; QR-PCR, quantitative real-time PCR; si5-HT4R, siRNA-mediated 5-HT4R receptors (5-HT1BR and 5-HT2CR) (9–11). In particular, knockdown; siCART, tissue-specific knockdown of CART with siRNA. ʈ 5-HT2CR in the hypothalamus contributes to fenfluramine- To whom correspondence should be addressed. E-mail: [email protected]. and MDMA-induced anorexia-like behavior (5, 8, 12). More- © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0701471104 PNAS ͉ October 9, 2007 ͉ vol. 104 ͉ no. 41 ͉ 16335–16340 Downloaded by guest on September 25, 2021 Fig. 1. Influence of the 5-HT4R on food intake and CART mRNA expression into the NAc. (A and C) The data are means Ϯ SEM of total food intake in fed and food-deprived WT mice treated with an intraaccumbal infusion of 1 ␮l/min NaCl (n ϭ 11–12), BIMU8 (n ϭ 6–11 per each dose), RS39604 (n ϭ 5–11 per each dose), si5-HT4R control (siCt, 0.05 ␮g/␮l, n ϭ 5–6), or si5-HT4R (0.05 ␮g/␮l, n ϭ 5–7). Food intake was measured between 1 and 3 h after treatments. (B–D) Number of CART mRNA copies in the NAc of identical mice over 3 h. (E) si5-HT4R-mediated decreases in the levels of 5-HT4R mRNA over 3 and 6 h, which is restored for 24 h. 125 (F) Autoradiographs of 5-HT4R-binding sites labeled with [ I]SB207710 in transverse midbrain sections (a) at the level of the NAc (b) from mice treated with siCt (c) and si5-HT4R(d) over 6 h, into the NAc. (e) Nonspecific binding (see Experimental Procedures). Arrows point to decreases in 5-HT4R binding sites (d) and the injection site in a midbrain section labeled with hematoxylin (f), which labeled the nuclei and illustrates that siRNA did not induce any tissue damage. A significant treatment effect is noted (§, P Ͻ 0.05; §§, P Ͻ 0.01 compared with NaCl. *, P Ͻ 0.05; **, P Ͻ 0.01 compared with siCt). (Scale bar: 1 mm.) 8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H- as RS39604, injecting si5-HT4R into the NAc increased food benzimidazol-1-carboxamide hydrochloride (BIMU8), a intake in fed (ϩ89% vs. si5-HT4R control, ϩ92% vs. NaCl, Fig. 5-HT4R agonist. Two different doses of BIMU8 reduced food 1A) and not in food-deprived mice (Fig. 1C) compared with intake in both fed (42–46%, Fig. 1A) and food-deprived mice controls. In all groups, there were no changes in CART mRNA (27–33%, Fig. 1C). As expected, no significant effect of BIMU8 levels observed in the NAc (Fig. 1 B and D) and the hypothal- Ϫ4 (4 ϫ 10 ␮g/␮l) was observed in food-deprived 5-HT4RKO amus (data not shown). [total food intake in g: wild type (WT), 0.58 Ϯ 0.05; KO, 0.60 Ϯ 0.06 (mean Ϯ SEM)]. BIMU8-induced hypophagia is then Intracellular Signaling Events Involved in 5-HT4R-Induced CART mRNA mediated specifically by the activation of 5-HT4R. Expression. We hypothesized that the observed 5-HT4R-mediated The animals used in the experiments presented in Fig. 1 A and up-regulation of CART mRNA expression in the NAc may involve C were killed3haftertheinjections and the levels of CART the Gs/cAMP/PKA pathway for two reasons. First, stimulating mRNA determined in the NAc.
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