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3,4-N-Methlenedioxymethamphetamine-Induced Hypophagia Is Maintained in 5-HT1B Receptor Knockout Mice, but Suppressed by the 5-HT2C Receptor Antagonist RS102221

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3,4-N-Methlenedioxymethamphetamine-Induced Hypophagia Is Maintained in 5-HT1B Receptor Knockout Mice, but Suppressed by the 5-HT2C Receptor Antagonist RS102221 Neuropsychopharmacology (2005) 30, 1056–1063 & 2005 Nature Publishing Group All rights reserved 0893-133X/05 $30.00 www.neuropsychopharmacology.org 3,4-N-Methlenedioxymethamphetamine-Induced Hypophagia is Maintained in 5-HT1B Receptor Knockout Mice, but Suppressed by the 5-HT2C Receptor Antagonist RS102221 ´ 1 1 ´ 2 ¨ 1 ´ ,1 Gregory Conductier , Cyril Crosson , Rene Hen , Joel Bockaert and Valerie Compan* 1UPR CNRS 5203, Ge´nomique Fonctionnelle, Montpellier Cedex, France; 2Columbia University, Center for Neurobiology and Behavior, New York, NY, USA 3,4-Methylenedioxy-N-methamphetamine (MDMA or ‘ecstasy’) is a psychoactive substance, first described as an appetite suppressant in humans, inducing side effects and even death. MDMA increases serotonin (5-HT) levels, and 5-HT inhibits food intake, but the 5-HT receptors involved in MDMA-induced changes in feeding behavior are unknown. We examined whether a systemic MDMA injection would reduce the physiological drive to eat in starved mice and tested if the inactivation of 5-HT1B or 5-HT2C receptors could restore this response. Our results indicate that in starved mice, MDMA (10 mg/kg) provoked an initial hypophagia for 1 h (À77%) followed by a period of hyperphagia (studied between 1 and 3 h). This biphasic feeding behavior due to MDMA treatment was maintained in 5-HT receptor- 1B null mice or in animals treated with the 5-HT1B/1D receptor antagonist GR127935 (3 or 10 mg/kg). In contrast, MDMA-induced hypophagia (for the first 1 h period) was suppressed when combined with the 5-HT2C receptor antagonist RS102221 (2 mg/kg). However, RS102221 did not alter MDMA-induced hyperphagia (for the 1–3 h period) but did exert a stimulant effect, when administered alone, during that period. We have previously shown that MDMA or 5-HT1A/1B receptor agonist RU24969 fails to stimulate locomotor activity in 5-HT1B receptor-null mice. Our present data indicate that the 5-HT receptor antagonist RS102221 suppresses MDMA-induced hyperlocomotion. 2C These findings provide the first evidence that the inactivation of 5-HT receptors may reduce hypophagia and motor response to MDMA, 2C while a genetic deficit or pharmacological inactivation of 5-HT1B receptors was insufficient to alter the feeding response to MDMA. Neuropsychopharmacology (2005) 30, 1056–1063, advance online publication, 19 January 2005; doi:10.1038/sj.npp.1300662 Keywords: 3,4-N-methylenedioxymethamphetamine; 5-HT2C and 5-HT1B receptors; food intake; locomotion; GR127935; RS102221 INTRODUCTION the inactivation of 5-HT2C receptors alters fenfluramine- induced anorexia (Neill and Cooper, 1989; Vickers et al, It is well known that serotonin (5-HT) regulates feeding 1999, 2001; Heisler et al, 2002). 5-HT receptor-null mice, behavior, as shown by the potent anorectic properties of 5- 2C known for being obese (Tecott et al, 1995), display reduced HT releasers, such as fenfluramine. Pharmacological studies sensitivity to fenfluramine (Vickers et al, 1999, 2001). The combined with knockout strategies have clearly demon- possible roles of 5-HT receptors in d-fenfluramine-induced strated that among the 15 5-HT receptor subtypes, the 5- 1B anorexia are more complex. Acute treatment with GR127935, HT1B and 5-HT2C receptors are key elements regulating food a 5-HT1B receptor antagonist, or with cyanopindolol, a intake in mammals. The 5-HT1B, 5-HT2A, and 5-HT2C 5-HT1A/1B receptor antagonist, does not modify d-fenflur- receptor agonists produce hypophagia (Bendotti and Sama- amine-induced anorexia in starved rats (Vickers et al, 2001). nin, 1987; Kennett and Curzon, 1988; Schechter and In contrast, 5-HT receptor-null mice are less sensitive to Simansky, 1988; Macor et al, 1990; Aulakh et al, 1994; 1B d-fenfluramine than wild-type mice (Lucas et al, 1998). Halford and Blundell, 1996; Lee and Simansky, 1997; Lucas Among drugs that increase synaptic levels of 5-HT, et al, 1998; Vickers et al, 2001; Lee et al, 2004). Conversely, antidepressants are known clearly to modify food intake, whereas the action of some others such as 3,4-N-methyle- *Correspondence: Dr V Compan, UPR CNRS 5203, Ge´nomique nedioxymethamphetamine (MDMA or ‘ecstasy’) have not Fonctionnelle, 141 rue de la Cardonille, Montpellier Cedex 34094, been investigated. This is surprising since MDMA is a widely France, Tel: þ 33 4 67 14 29 95, Fax: þ 33 4 67 54 24 32, E-mail: [email protected] used recreational drug. MDMA is defined as a ‘substrate- Received 23 September 2004; revised 23 November 2004; accepted type 5-HT releaser’ (Rothman and Baumann, 2002) and is an 24 November 2004 amphetamine-like stimulant. MDMA (10 mg/kg) increases Online publication: 29 November 2004 at http://www.acnp.org/citations/ the levels of 5-HT, but can also increase dopamine (DA) NPP112904040435/default.pdf levels, especially at higher doses (Colado et al, 2004). Suppression of disorders after MDMA/RS102221 treatment G Conductier et al 1057 The primary goals of this study were to investigate food was reintroduced into the trough 10 min after an acute whether MDMA (10 mg/kg) could counteract starvation- i.p. injection of one of the treatments described above. Food induced eating and whether the 5-HT1B and 5-HT2C was briefly removed (o20 s) and weighed at 1 and 3 h receptors were involved in this effect. following the initial reintroduction. First, we tested the effects of MDMA (10 mg/kg) in mice of both genotypes. To make sure that our results did not depend on different MATERIALS AND METHODS experimentalists or laboratory conditions, other groups of Animals mice of both genotypes were also treated with the 5-HT1A/1B receptor agonist RU24969 (5 mg/kg), as used by Lucas and All experiments were performed on male adult wild-type co-workers (1998). In parallel, we assessed for the first time and 5-HT1B receptor-null mice on a 129/Sv genetic back- the effects of the selective 5-HT1B receptors agonist ground (see Phillips et al, 1999 for a description of the exact CGS12066A (0.5, 1 or 2 mg/kg) in wild-type and null mice. genetic background of the mice), aged 4–6 months. The Second, wild-type mice received a 3, 5, or 10 mg/kg dose of 5-HT1B receptor-null mice were generated as described the 5-HT1B/1D receptor antagonist GR127935 coadminis- previously (Saudou et al, 1994). Both the wild-type and null tered with or without MDMA (10 mg/kg). Third, a series of mice were all obtained from heterozygous breeding at the experiments were conducted following the injection of a 1 transgenic animal facility of the UPR CNRS 5203 in or 2 mg/kg dose of the selective 5-HT2C receptor antagonist Montpellier (France). The genotype of each mouse was RS102221 that was combined or not to MDMA (10 mg/kg) identified using the PCR technique. For the 5-HT2C receptor in wild-type mice. experimental paradigms, wild-type mice on a 129/Sv (Iffa In each experiment, animals received an i.p. injection of Credo, France) were used at 4–6 months old. Mice were sterile 0.9% NaCl. Food intake and body weight were housed five per cage with food and water available ad measured daily using a Sartorius CP32S balance (1 mg libitum and maintained in a temperature-controlled envir- precision), which automatically provides the mean body onment on a 12-h light/dark cycle with light onset at 06:00. weight of 10 values for each animal in movement. The experiments were carried out in accordance with the Guide for Care and Use of Laboratory Animals established Pharmacological Treatments by the National Institutes of Health of the United States of America. MDMA HCl (10 mg/kg, Sigma), 5-HT1A/1B agonist 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole Procedures (RU24969; generously supplied by Roussel-Uclaf, Romain- ville, France), 5-HT1B agonist 7-trifluoromethyl-4(4-methyl- In summary, three different sets of experiments were 1-piperazinyl)-pyrrolo[1,2-a]quinoxaline maleate (CGS12066A; performed using the feeding paradigm described in detail 0.5, 1 and 2 mg/kg, Sigma), 5-HT1B/1D receptor antagonist below and previously used by Lucas and co-workers (1998). 20-methyl-40-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl- First, the wild-type and 5-HT1B receptor-null mice were 4-carboxylic acid [4-methoxy-3-(4-methyl-piperazine-1-yl)- treated with a single intraperitoneal (i.p.) injection of saline, phenyl]amide (GR127935; 3 and 10 mg/kg, generously MDMA, or 5-HT1B receptor agonist. Second, another group provided by Glaxo Welcome, Taplow, UK), the selective of wild-type mice was similarly injected with NaCl, MDMA, 5-HT2C receptor antagonist 8-[5-(2,4-dimethoxy-5-(4-tri- or 5-HT1B receptor antagonist GR127935 either alone or in fluoromethylphenylsulfonamido)phenyl-5-oxopentyl)]-1,3,8- combination with MDMA. Third, NaCl, MDMA, or 5-HT2C triazaspiro[4.5]decane-2,4-dione hydrochloride (RS102221, receptor antagonist RS102221 alone or combined with 1 and 2 mg/kg, Tocris) were freshly dissolved in sterile 0.9% MDMA was administered in the same manner to a naı¨ve NaCl before their i.p. injection, on the day of testing. group of wild-type mice. Finally, four additional groups of wild-type mice were treated with NaCl, MDMA, or Activity RS102221 either alone or coadministered with MDMA and tested in open field chambers (Activity section), as Open-field test. Naı¨ve male mice were tested for 3 h described previously (Compan et al, 2003, 2004). In each following NaCl, MDMA (10 mg/kg), RS102221 (2 mg/kg experimental paradigm, animals were treated with an dose), or MDMA combined with RS102221.
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