title: Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa opioid receptors in a cannabinoid receptor independent manner.
abstract: BACKGROUND
  There is an increasing number of studies demonstrating the direct effect of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant on the opioid system. The kappa opioid receptors (KORs) are well known to mediate depression- and anxiety-like behavior. Clinical studies on chronic rimonabant administration have revealed that rimonabant leads to a very similar pathophysiology, suggesting a potential impact of rimonabant on KORs.
  
  
  OBJECTIVE
  Our objectives were to examine the putative effects of rimonabant on KOR ligand binding, G-protein activity, protein expression and how all these contribute to the development of depression- and anxiety-like behavior.
  
  
  RESULTS
  In Chinese hamster ovary (CHO) cell membranes transfected with rat KOR (CHO-rKOR) rimonabant inhibited KOR agonist [3H]U69593 binding in the micromolar range in competition binding experiments and specifically reduced KOR basal activity at lower micromolar concentrations in [35S]GTPγS binding assays. Rimonabant significantly inhibited dynorphin (1-11)-induced [35S]GTPγS binding in micromolar range in CHO-rKOR cells, CB1 knockout (CB1 K.O.) and CB1/CB2 double knockout mouse forebrain membranes. A single dose of i.p. 0.1 mg/kg rimonabant significantly reduced dynorphin (1-11)-induced KOR G-protein activity and KOR protein expression levels 24 h following the administration in both wild type and CB1 K.O. mice forebrain. Furthermore, in elevated plus maze mice showed an anxiolytic-like effect upon rimonabant injection that could be reversed by 1 mg/kg KOR antagonist norbinaltorphimine. The anxiolytic-like effects were further confirmed with the light–dark box test.
  
  
  CONCLUSIONS
  Rimonabant reduced KOR ligand binding, receptor mediated G-protein activity and protein expression level, which overall leads to altered anxiety-like behavior.
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt. 62, H-6726 Szeged,Hungary. zador.ferenc@gmail.com
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zádor
authors.forename: Nikolett
authors.initials: N
authors.lastname: Lénárt
authors.forename: Balázs
authors.initials: B
authors.lastname: Csibrány
authors.forename: Miklós
authors.initials: M
authors.lastname: Sántha
authors.forename: Máté
authors.initials: M
authors.lastname: Molnár
authors.forename: Bernadett
authors.initials: B
authors.lastname: Tuka
authors.forename: Reza
authors.initials: R
authors.lastname: Samavati
authors.forename: Péter
authors.initials: P
authors.lastname: Klivényi
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
authors.forename: Annamária
authors.initials: A
authors.lastname: Marton
authors.forename: Csaba
authors.initials: C
authors.lastname: Vizler
authors.forename: György M
authors.initials: GM
authors.lastname: Nagy
authors.forename: Anna
authors.initials: A
authors.lastname: Borsodi
authors.forename: Sándor
authors.initials: S
authors.lastname: Benyhe
authors.forename: Eszter
authors.initials: E
authors.lastname: Páldy
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D016466:CHO Cells; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D003412:Cricetulus; D004195:Disease Models, Animal; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D000077285:Rimonabant; D013550:Swimming / Q000523:psychology
chemical_list: D000701:Analgesics, Opioid; D063387:Cannabinoid Receptor Antagonists; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D017473:Receptors, Opioid, kappa; D000077285:Rimonabant