Effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in mice M. Carmen Carrasco a , Paloma Vicens b , Jose Vidal a , Rosa Redolat a, * a Area de Psicobiologı ´a, Facultad de Psicologı ´a, Universitat de Vale `ncia, Blasco Iban ˜ez, 21, Valencia 46010, Spain b Departament de Psicologia, Facultat de Cie ´ncies de l’Educacio ´ i Psicologia, Universitat Rovira i Virgili, Carretera de Valls s/n, Tarragona 43007, Spain Accepted 23 November 2005 Available online 18 January 2006 Abstract There is evidence that the cholinergic nicotinic system is involved in the modulation of anxiety. Anxiolytic and anxiogenic effects of nicotine agonists have been reported in mice. Bupropion is an antidepressant drug which may alleviate some symptoms of nicotine withdrawal, although its effects on anxiety are not clear. It has been suggested that the interaction between bupropion and nicotinic mechanisms could be complex. The aim of the present study was to investigate acute effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in NMRI mice. Effects of nicotine, lobeline, and cytisine (0.35 and 0.175 mg/kg), administered alone or combined with bupropion (20 mg/kg) were tested in the plus-maze. Results indicated that nicotine (0.35 mg/kg) decreased number and percentage of entries and time spent in open arms, and increased percentage of protected stretched attend posture. Bupropion (20 mg/kg) plus lobeline (0.175 mg/kg) increased percentage of time spent in open arms, without altering total or closed arm entries. Our findings suggest that the highest dose of nicotine induces anxiogenic effects, which are counteracted when co-administered with bupropion. The combination of bupropion with a low dose of lobeline seems to have an anxiolytic profile in the conventional parameters of the plus-maze, although ethological measures do not support it clearly. D 2005 Elsevier Inc. All rights reserved. Keywords: Anxiety; Bupropion; Cytisine; Lobeline; Mice; Nicotine; Plus maze 1. Introduction Bupropion is an antidepressant drug which has been demonstrated to alleviate some symptoms of nicotine with- drawal (Hays and Ebbert, 2003; Hughes et al., 2004; Richmond and Zwar, 2003). It has been found that this drug alone or in combination with nicotine patches induces higher long-term abstinence rates than placebo (Jorenby et al., 1999; Jorenby, 2002). The mechanism of action by which bupropion produces its therapeutic effects has not been fully understood (Stahl et al., 2004). It has been proposed that its pharmacological properties are mediated by two different mechanisms. One central mechanism is the inhibition of the reuptake of dopamine and norepinephrine (Ascher et al., 1995; Cooper et al., 1980; Ferris et al., 1983). In rats, it has also been reported that bupropion can increase extracellular dopamine and norepinephrine concentrations in mesocorticolimbic areas without affecting serotonin concentrations (Li et al., 2002). Bupropion may also have neural effects mediated via a non- competitive nicotinic antagonist mechanism (Fryer and Lukas, 1999; Miller et al., 2002; Slemmer et al., 2000), although some studies do not support this clearly (Shoaib et al., 2003; Young and Glennon, 2002). There is much evidence to support the fact that bupropion produces complex behavioral actions in rodents. It induces dose-dependent hyperactivity (Carrasco et al., 2004; Cooper et al., 1980; Klimek et al., 1985; Redolat et al., 2005a,b), stereotyped sniffing (Muley et al., 1984; Zarrindast et al., 1996), climbing (Zarrindast et al., 1993), anorexia (Zarrindast and Hosseini-Nia, 1988), and changes on thermoregulation (Zarrindast and Abolfathi-Araghi, 1992; Hasegawa et al., 2005). During social encounters, bupropion increases aggres- sion in mice with low level of aggressiveness (Redolat et al., 2005a). In learning tasks, this drug inhibits reserpine-induced impairment in conditioned avoidance response (Nakagawa et 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.11.018 Abbreviations: HD, head dipping; NMRI, Naval Medical Research Institute; SAP, stretched attend posture; %p, percent protected. * Corresponding author. Tel.: +34 963864636; fax: +34 963864668. E-mail address: Rosa.Redolat@uv.es (R. Redolat). Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 455 – 462 www.elsevier.com/locate/pnpbp