期刊
NEUROPHARMACOLOGY
卷 89, 期 -, 页码 298-307出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2014.10.008
关键词
Kappa opioid receptor; Cannabinoid receptor type 1; Rimonabant; Mouse forebrain; Elevated plus maze; Light-dark box
资金
- National Development Agency (NFU), Budapest, Hungary [CK-78566, TAMOP-4.2.2A-11/1KONV-2012-0024, OTKA 108518, TAMOP-4.2.2.A-11/1/KONV-2012-0052, TAMOP-4.2.4.A/2-11/1-2012-0001]
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.
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