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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. 2015 Feb; 89:298-307.N

Abstract

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.

Authors+Show Affiliations

Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt. 62, H-6726 Szeged,Hungary. zador.ferenc@gmail.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25446673

Citation

Zádor, Ferenc, et al. "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, vol. 89, 2015, pp. 298-307.
Zádor F, Lénárt N, Csibrány B, et al. 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. 2015;89:298-307.
Zádor, F., Lénárt, N., Csibrány, B., Sántha, M., Molnár, M., Tuka, B., Samavati, R., Klivényi, P., Vécsei, L., Marton, A., Vizler, C., Nagy, G. M., Borsodi, A., Benyhe, S., & Páldy, E. (2015). 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, 89, 298-307.
Zádor F, et al. 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. 2015;89:298-307. PubMed PMID: 25446673.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Zádor,Ferenc, AU - Lénárt,Nikolett, AU - Csibrány,Balázs, AU - Sántha,Miklós, AU - Molnár,Máté, AU - Tuka,Bernadett, AU - Samavati,Reza, AU - Klivényi,Péter, AU - Vécsei,László, AU - Marton,Annamária, AU - Vizler,Csaba, AU - Nagy,György M, AU - Borsodi,Anna, AU - Benyhe,Sándor, AU - Páldy,Eszter, PY - 2014/06/30/received PY - 2014/09/19/revised PY - 2014/10/04/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/7/16/medline SP - 298 EP - 307 JF - Neuropharmacology JO - Neuropharmacology VL - 89 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/25446673/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(14)00372-4 DB - PRIME DP - Unbound Medicine ER -