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
| Autor: | Nikolett Lénárt, Reza Samavati, Eszter Páldy, Ferenc Zádor, György M. Nagy, Péter Klivényi, Annamária Marton, László Vécsei, Sándor Benyhe, Anna Borsodi, Balázs Csibrány, Csaba Vizler, Miklós Sántha, Bernadett Tuka, Mate Molnar |
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| Rok vydání: | 2014 |
| Předmět: |
Agonist
medicine.medical_specialty medicine.drug_class medicine.medical_treatment Narcotic Antagonists Dynorphin CHO Cells Pharmacology Anxiety κ-opioid receptor Receptor Cannabinoid CB2 Cellular and Molecular Neuroscience Mice Cricetulus Prosencephalon Rimonabant Piperidines Receptor Cannabinoid CB1 Internal medicine Cannabinoid receptor type 1 medicine Inverse agonist Animals Maze Learning Cannabinoid Receptor Antagonists Swimming Mice Knockout Chemistry Adaptation Ocular Receptors Opioid kappa Analgesics Opioid Mice Inbred C57BL Disease Models Animal Endocrinology Pyrazoles Cannabinoid Norbinaltorphimine medicine.drug Protein Binding |
| Zdroj: | Neuropharmacology. 89 |
| ISSN: | 1873-7064 |
| Popis: | 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 [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. Conclusion Rimonabant reduced KOR ligand binding, receptor mediated G-protein activity and protein expression level, which overall leads to altered anxiety-like behavior. |
| Databáze: | OpenAIRE |
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