The ability of reboxetine, a selective inhibitor of the norepinephrine transporter and noncompetitive antagonist at neuronal nicotinic receptors, to alter nicotine self-administration in rats was compared with that of mecamylamine, a classical noncompetitive antagonist at nicotinic receptors. The ability of reboxetine to alter sucrose-maintained responding was also examined to assess the specificity of the effect on nicotine self-administration. Rats were trained on a fixed ratio 5 schedule to selfadminister nicotine (0.02 mg/kg/infusion i.v.) or to respond for sucrose pellets. Upon reaching a stable baseline, rats were pretreated 15 min before the session with vehicle, reboxetine (racemic), (ϩ)-(S,S)-reboxetine (0.3-30 mg/kg s.c.) or mecamylamine (0.5-4 mg/kg s.c). To assess the effect of repeated administration, reboxetine (5.6 mg/kg) was injected once daily for 14 consecutive sessions before either nicotine self-administration or sucrose-maintained responding. Specificity was further assessed by examining the ability of repeated administration of reboxetine (5.6 mg/kg) to alter nicotine-induced hyperactivity (0.8 mg/kg). Reboxetine, (ϩ)-(S,S)-reboxetine, and mecamylamine dose dependently decreased nicotine self-administration by ϳ60%, whereas reboxetine and (ϩ)-(S,S)-reboxetine decreased sucrose-maintained responding to a lesser extent (ϳ20%). Repeated administration of reboxetine (5.6 mg/kg) decreased nicotine self-administration and sucrose-maintained responding across the 14 sessions, suggesting that tolerance did not develop to these effects of reboxetine. Additionally, reboxetine did not alter baseline locomotor activity, indicating that the decrease in operant responding for nicotine and sucrose was not the result of a nonspecific decrease in activity. The reboxetine-induced decrease in nicotine self-administration and sucrose-maintained responding may be the result of inhibition of norepinephrine transporters and/or neuronal nicotinic receptor function.Clinical and epidemiological evidence has linked smoking and depression. The incidence of major depression is higher among smokers than nonsmokers (Glassman, 1993;Kendler et al., 1993;Breslau et al., 1998). The likelihood of successful smoking cessation decreases in those individuals with a history of major depression or depressive symptoms at the initiation of smoking cessation (Hall et al., 1991;Glassman, 1993). Furthermore, depressive symptoms associated with nicotine withdrawal are more severe in depressed patients compared with patients without histories or symptoms of depression (Glassman, 1993). The onset of smoking cessation may initiate an acute depressive episode in certain individuals (Stage et al., 1996;Covey et al., 1997). Furthermore, nicotine has been reported to have antidepressant properties in depressed individuals (Glassman, 1993;Salin-Pascual and Drucker-Colin, 1998) and in animal models of depression (Tizabi et al., 1999). Such evidence has led to the self-medication hypothesis of nicotine dependence, such that individuals ma...

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