Agonist and antagonist effects of cytisine in vivo Elena V. Radchenko, Olga A. Dravolina * , Anton Y. Bespalov 1 Department of Psychopharmacology, Valdman Institute of Pharmacology, Pavlov State Medical University, Russia article info Article history: Received 26 November 2014 Received in revised form 22 February 2015 Accepted 14 March 2015 Available online 31 March 2015 Keywords: Nicotine Cytisine Smoking Addiction Dependence Rat abstract Varenicline, the most successful smoking cessation aid, is a selective partial agonists at a4b2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self- administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1e3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05e0.4 mg/kg), but not cytisine (0.3e3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15e0.6 mg/kg), but not cytisine (0.3e3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15e0.6 mg/kg), but not cytisine (0.3e3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction Stimulation of neuronal nicotinic receptors is currently the most effective treatment strategy for tobacco smoking cessation. Vare- nicline, the most successful drug in this class, is a fairly selective partial agonist of a4b2* nicotinic receptors. Varenicline is clearly effective in the clinic, resulting in significantly higher quit rates and higher continuous abstinence rates vs placebo (Nides et al., 2006; Oncken et al., 2006). Being a partial agonist, varenicline is expected to antagonize effects of nicotine where the patient smokes while alleviating a withdrawal state while the patient abstains from smoking (Rollema et al., 2007b). Preclinical data seem to support these expectations. On one hand, varenicline fully substituted for nicotine in drug discrimination studies (LeSage et al., 2009; Rollema et al., 2007a), lowered brain stimulation reward thresholds (Spiller et al., 2009), and enhanced locomotor activity (Zaniewska et al., 2008). On the other hand, varenicline blocked nicotine-induced dopamine release, reduced nicotine self-administration in rats and supported lower self-administration break point than nicotine (Rollema et al., 2007a). For several decades preceding the introduction of varenicline into clinical practice, there was another nicotinic receptor ligand, cytisine, in clinical use in Eastern and Central European countries as a smoking cessation agent (Etter et al., 2008). Like varenicline, cytisine is a partial agonist acting on a4b2* nicotinic receptors. It was argued though that cytisine has a limited bloodebrain barrier penetration and this limits its efficacy (Rollema et al., 2010). Nevertheless, recent clinical analysis suggested that cytisine does facilitate smoking cessation and may be an affordable alternative to other more expensive treatment options (Hajek et al., 2013; West et al., 2011; Walker et al., 2014). Although effect sizes in cytisine trials may be similar to those observed in varenicline trials, a * Corresponding author. Department of Psychopharmacology, Valdman Institute of Pharmacology, Pavlov State Medical University, 6-8 Lev Tolstoy Street, St. Petersburg 197022, Russia. Tel./fax: þ7 812 338 6714. E-mail address: olga.dravolina@gmail.com (O.A. Dravolina). 1 Current address: Neuroscience Research, AbbVie Deutschland GmbH & Co KG, P.O. Box 21 08 05, 67008 Ludwigshafen, Germany. Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm http://dx.doi.org/10.1016/j.neuropharm.2015.03.019 0028-3908/© 2015 Elsevier Ltd. All rights reserved. Neuropharmacology 95 (2015) 206e214