Neurochemistry International 58 (2011) 78–84 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/neuint Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex Hans Rollema a,*, Gary G. Wilson b, Theodore C. Lee c, Joost H.A. Folgering d,1, Gunnar Flik d,1 a Neuroscience, Pfizer Global Research and Development, Groton, CT, USA b Worldwide Safety Strategy, Pfizer Inc, New York, NY, USA c Medical Affairs, Pfizer Inc, New York, NY, USA d Brains On-Line BV, Groningen, The Netherlands ARTICLE INFO ABSTRACT Article history: Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid Received 27 October 2010 varenicline might occasionally be prescribed to patients who are simultaneously treated with Accepted 28 October 2010 antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and Available online 5 November 2010 not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a Keywords: pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interac- Varenicline tions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, Antidepressants while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To Monoamine release Microdialysis investigate this we examined whether varenicline administration modulates the effects of the selective Serotonin syndrome serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release. ß 2010 Elsevier Ltd. All rights reserved. 1. Introduction population. The World Health Organization predicts that by 2030 more than 8 million deaths per year will be caused by smoking- Nicotine dependence and depression are illnesses that have related illnesses, while depression is one of the leading causes of serious health consequences and affect a large proportion of the disability affecting more than 120 million people worldwide (U¨ stu¨ n et al., 2004; World Health Organization, 2008). There is substantial epidemiologic evidence that smokers are more likely to Abbreviations: aCSF, artificial cerebrospinal fluid; DA, dopamine; MAO-I, mono- have mood or personality disorders, depressive symptoms, or amine oxidase inhibitor; mPFC, medial prefrontal cortex; MRM, multiple-reaction- clinical depression and that the smoking prevalence is approxi- monitoring; nAChR, nicotinic acetylcholine receptor; NE, norepinephrine; SSRI, mately 50% among psychiatric outpatients with depression selective serotonin reuptake inhibitor; SNRI, selective norepinephrine and serotonin reuptake inhibitor; 5-HT, serotonin; s.c., subcutaneous; MS/MS, tandem (Kalman et al., 2005; Paperwalla et al., 2004; Ziedonis et al., mass spectrometry; TCAs, tricyclic antidepressants. 2008). Data from the first wave of the US National Epidemiologic * Corresponding author at: Department of Neuroscience, Pfizer Global Research Survey on Alcohol and Related Conditions indicate that, among and Development, Eastern Point Road, MS 8220-4457, Groton, CT 06340, USA. nicotine-dependent individuals, 21.1% had a mood disorder (Grant Tel.: +1 860 441 6374; fax: +1 860 715 5382. et al., 2004). The US National Comorbidity Study demonstrated E-mail address: hans.rollema@pfizer.com (H. Rollema). 1 Address: Brains On-Line BV, L.J. Zielstraweg 1, 9713 GX Groningen, The that smoking prevalence in those with a psychiatric diagnosis Netherlands. (41.0%) is about two times the rate seen in those without a 0197-0186/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2010.10.015 H. Rollema et al. / Neurochemistry International 58 (2011) 78–84 79 psychiatric diagnosis (22.5%) (Lasser et al., 2000). An association and to have maximal effect on dopamine release in nucleus between smoking and occurrence of depressive symptoms has also accumbens (Coe et al., 2005; Rollema et al., 2007). Monoamine been reported in other population-based studies of adults in the release was measured in the medial prefrontal cortex (mPFC), a United States (Breslau et al., 1998; Kinnunen et al., 2006), Finland brain area that plays an important role in serotonin syndrome (Korhonen et al., 2007), Norway (Klungsøyr et al., 2006), and The (Gillman, 2006) as well as in the effects of antidepressants (Artigas Netherlands (Cuijpers et al., 2007). and Adell, 2007). In addition, we compiled in vitro data of Treating nicotine dependence and depression are effective varenicline to examine whether its binding affinities or inhibitory ways to improve health, and a substantial number of smokers are potencies for relevant receptors, enzymes, or transporters would thus likely to receive antidepressant and smoking cessation be sufficient to inhibit or potentiate the pharmacologic effects of medication simultaneously. Given the possibility of pharmacoki- antidepressants at therapeutic doses. netic or pharmacodynamic drug–drug interactions, it is important to investigate whether and to what extent treatments for smoking 2. Materials and methods cessation could interact with co-administered antidepressants. 2.1. Materials Varenicline was recently introduced as a novel efficacious Varenicline tartrate and sertraline HCl were synthesized at Pfizer (Groton, CT, smoking cessation aid that acts as an a4b2 nicotinic acetylcholine USA); clorgyline HCl and all other chemicals were purchased from Sigma (St. Louis, receptor (nAChR) partial agonist (Coe et al., 2005; Rollema et al., MO, USA) unless indicated otherwise. 2007). Since varenicline is virtually not metabolized, has low plasma protein binding, is excreted unchanged renally, and does 2.2. In vivo microdialysis not inhibit or induce the activity of the major cytochrome P450 Male Wistar rats (280–350 g; Harlan, Horst, The Netherlands) were individually enzymes (Burstein et al., 2007; Faessel et al., 2010; Obach et al., housed in plastic cages (30 cm  30 cm  40 cm) under a 12:12 h light/dark cycle 2006), pharmacokinetic interactions between varenicline and (starting at 7:00 a.m.) and had access to food and water ad libitum. Experiments antidepressant drugs are highly unlikely. It was for instance were conducted in accordance with the declarations of Helsinki and were approved shown that concomitant administration of varenicline with the by the Institutional Animal Care and Use Committee of the University of Groningen, The Netherlands. Rats were anesthetized using isoflurane (2%, 800 ml/min O2). dopamine (DA) and norepinephrine (NE) reuptake inhibitor, Bupivacain/epinephrine was used for local anesthesia and fynadine (0.1%, 1 ml/kg) bupropion, in a randomized, placebo-controlled study in smokers for pre/peri operative analgesia. The animals were placed in a stereotaxic frame did not result in clinically relevant effect on bupropion’s (Kopf Instruments, Tujunga, CA, USA), and I-shaped probes (Hospal membrane, pharmacokinetics (Faessel et al., 2010). 4 mm exposed surface; Brainlink, Groningen, The Netherlands) were inserted into the mPFC. Coordinates for the tips of the probes were posterior (AP) +3.4 mm to However, both varenicline and antidepressant agents affect bregma, lateral +0.8 mm to midline, and ventral À5.0 mm to dura; the toothbar was monoaminergic neurotransmission and it is conceivable that a set at À3.3 mm (Paxinos and Watson, 1982). Experiments were performed 24–48 h pharmacodynamic interaction could cause either a reduction or an after probe implantation. On the day of the experiment, the probes were connected increase in the antidepressant-induced release of the monoamine with flexible PEEK tubing to a microperfusion pump (Syringe pump UV 8301501, neurotransmitters DA, NE, and serotonin (5-HT). Pharmacody- TSE, Karlsruhe, Germany) and perfused with artificial cerebrospinal fluid (aCSF) containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl2, and 1.2 mM MgCl2, at a flow namic interactions with the nAChR partial agonist varenicline rate of 1.5 ml/min. Microdialysis samples were collected for 15-min periods into could occur at nAChRs, since most antidepressant monoamine mini-vials containing 7.5 ml of 0.02 M formic acid,