,1 ,1 *Laboratori de Neurofarmacologia, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain  Medimod pharmacology services GmbH, Reutlingen, Germany àInstitut d’Alta Tecnologia PRBB Fundacio ´ Privada (IAT), PRBB, Barcelona, Spain Obesity continues to grow as a worldwide health problem and represents a major concern in the health care system in developed and developing countries (Hagmann 2008). Multiple physiological systems are involved in the control of food intake and metabolism and participate in the pathophysiological mechanisms leading to obesity. In this sense, several studies have recently identified the crucial role played by the endocannabinoid system in the control of energy balance. The endocannabinoid system constitutes a ‘silent’ mechanism that is activated in a transitory way to maintain the homeostatic equilibrium (Di Marzo and Matias 2005; Di Marzo 2008). This system includes the cannabi- noid receptors (CB 1 , CB 2 and G-protein-coupled receptor 55), the endogenous lipid ligands (endocannabinoids), and the enzymatic machinery for their synthesis and inactivation. Obesity seems to be associated with a pathological over- activation of the endocannabinoid system revealed by an up-regulation of CB 1 receptor and/or an enhancement of endocannabinoid levels (Di Marzo and Matias 2005; Di Marzo 2009). Animal and clinical studies have revealed that the overactivity of the endocannabinoid system is a key component in the pathophysiological mechanisms leading to obesity and metabolic unbalance (Cota et al. 2003; Ravinet et al. 2004; Despres et al. 2005; Van Gaal et al. 2005; Vickers and Kennett 2005; Ward and Dykstra 2005; Pagotto et al. 2006; Pi-Sunyer et al. 2006; Scheen et al. 2006; Schafer et al. 2008). Therefore, the blockade of CB 1 receptor was considered a potential pharmacological tool Received September 11, 2009; revised manuscript received December 9, 2009; accepted December 12, 2009. Address correspondence and reprint requests to Rafael Maldonado, Departament de Ciencies Experimentals i de la Salut, Universitat Pom- peu Fabra, PRBB, C/Dr. Aiguader 88, 08003, Barcelona, Spain. E-mail: rafael.maldonado@upf.edu 1 These authors contributed equally to this work. Abbreviations used: CB 1 , cannabinoid receptor 1; CB 2 , cannabinoid receptor 2; CD, cafeteria diet; CT, computed tomography; GTPcS, guanosine 5¢-[c-thio] triphosphate; HU, Hounsfield; SC, standard chow. Abstract The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of can- nabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB 1 cannabinoid antagonist rimonabant or the CB 1 inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB 1 blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB 1 receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB 1 cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB 1 receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB 1 canna- binoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists. Keywords: autoradiography, CB 1 cannabinoid receptor, obesity, rimonabant, taranabant, withdrawal. J. Neurochem. (2010) 112, 1338–1351. JOURNAL OF NEUROCHEMISTRY | 2010 | 112 | 1338–1351 doi: 10.1111/j.1471-4159.2009.06549.x 1338 Journal Compilation Ó 2010 International Society for Neurochemistry, J. Neurochem. (2010) 112, 1338–1351 Ó 2010 The Authors