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

NEUROPHARMACOLOGY

卷:89

Article

Zador, Ferenc¹  Lenart, Nikolett¹  Csibrany, Balazs¹  Santha, Miklos¹  Molnar, Mate²  Tuka, Bernadett³  Samavati, Reza¹  Klivenyi, Peter²  Vecsei, Laszlo^2,3  Marton, Annamaria¹  Vizier, Csaba¹  Nagy, Gyorgy M.⁴  Borsodi, Anna¹  Benyhe, Sandor¹  Paldy, Eszter¹ 

[1] Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, H-6726 Szeged, Hungary

[2] Univ Szeged, Dept Neurol, H-6725 Szeged, Hungary

[3] Univ Szeged, MTA SZTE Neurosci Res Grp, H-6725 Szeged, Hungary

[4] Semmelweis Univ, Dept Human Morphol & Dev, H-1094 Budapest, Hungary

关键词: Kappa opioid receptor;    Cannabinoid receptor type 1;    Rimonabant;    Mouse forebrain;    Elevated plus maze;    Light-dark box;   

DOI  :  10.1016/j.neuropharm.2014.10.008

来源: Elsevier

【 摘 要 】

What is known: 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. Objectives: 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 [H-3]U69593 binding in the micromolar range in competition binding experiments and specifically reduced KOR basal activity at lower micromolar concentrations in [S-35]GTP gamma S binding assays. Rimonabant significantly inhibited dynorphin (1-11)-induced [S-35]GTP gamma S binding in micromolar range in CHO-rKOR cells, CB1 knockout (CBI KO.) 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 CBI KO. 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. Conclusion: Rimonabant reduced KOR ligand binding, receptor mediated G-protein activity and protein expression level, which overall leads to altered anxiety-like behavior. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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