Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats |
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Authors: | Ramón Sotomayor-Zárate Katia Gysling Usoa E Busto Bruce K Cassels Lutske Tampier María Elena Quintanilla |
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Institution: | 1. Departamento de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Breta?a 1111, Playa Ancha, Valparaíso, Chile 2. Millennium Science Nucleus in Stress and Addiction (NEDA) and Center for Addiction Studies (CEDA-UC), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile 3. Centre for Addiction and Mental Health and Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada 4. Millennium Institute for Cell Dynamics and Biotechnology and Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile 5. Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile 6. Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70.000, Santiago 7, Chile. Av. Independencia 1027, Santiago, Chile
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Abstract: | Rationale Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied. Objectives This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB). Results Repeated dosing (0.5 or 1.0 mg/kg/day?i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8–10 days induced tolerance to their effects on ethanol consumption. Conclusions This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use. |
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