title: Central and peripheral consequences of the chronic blockade of CB1 cannabinoid receptor with rimonabant or taranabant.
abstract: The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid 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) cannabinoid 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.
authors.affiliation: Laboratori de Neurofarmacologia, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.forename: Aurelijus
authors.initials: A
authors.lastname: Burokas
authors.forename: Miquel
authors.initials: M
authors.lastname: Martín
authors.forename: Fernando
authors.initials: F
authors.lastname: Berrendero
authors.forename: Blanca
authors.initials: B
authors.lastname: Rubí
authors.forename: Christoph
authors.initials: C
authors.lastname: Kiesselbach
authors.forename: Andrea
authors.initials: A
authors.lastname: Heyne
authors.forename: Juan Domingo
authors.initials: JD
authors.lastname: Gispert
authors.forename: Olga
authors.initials: O
authors.lastname: Millán
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D048588:Benzoxazines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003511:Cyclohexanols / Q000493:pharmacokinetics; D004033:Diet Fads / Q000009:adverse effects; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007391:International Cooperation; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy / Q000209:etiology; D010880:Piperidines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D015898:Tomography Scanners, X-Ray Computed; D014316:Tritium / Q000493:pharmacokinetics; D051598:Whole Body Imaging
chemical_list: D000577:Amides; D048588:Benzoxazines; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D013460:Sulfur Isotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide