Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice

Abstract

Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.

Fig. 1.

Effects of bupropion on the acquisition of the nicotine-induced CPP. Nicotine (0.5 mg/kg s.c.) elicited significant place preference (shaded bar) that was blocked by administration of bupropion at different doses (0.1, 0.5, and 1 mg/kg) during the conditioning phase. Each bar represents the mean (n = 8–10/group) ± S.E.M. of preference score in seconds. *, p < 0.05 versus the vehicle control groups.

Fig. 2.

Effects of (2S,3S)-hydroxybupropion on the acquisition of the nicotine-induced CPP. Nicotine (0.5 mg/kg s.c.) elicited significant place preference (shaded bar) that was blocked by administration of (2S,3S)-hydroxybupropion at different doses (0.05, 0.1, or 0.5 mg/kg) during the conditioning phase. Each bar represents the mean (n = 8–10/group) ± S.E.M. of preference score in seconds. *, p < 0.05 versus the vehicle control groups.

Fig. 3.

Effects of (2R,3R)-hydroxybupropion on the acquisition of the nicotine-induced CPP. Nicotine (0.5 mg/kg s.c.) elicited significant place preference (shaded bar) that was not blockedby administration of (2R,3R)-hydroxybupropion at 1 mg/kg during the conditioning phase. Each bar represents the mean (n = 8–10/group) ± S.E.M. of preference score in seconds. *, p < 0.05 versus the vehicle control groups.

Fig. 4.

Effects of bupropion on affective and somatic signs of nicotine withdrawal in mice. Mice chronically infused with saline (0 mg/kg/day nicotine) or with nicotine (36 mg/kg/day) for 14 days had minipumps removed for 18 to 24 h and were tested on the elevated plus maze (time in seconds spent in open arms; top right), monitored for somatic signs (number of signs; top left), and assessed for hyperalgesia (hindpaw withdrawal latency, seconds; bottom) starting 30 min after receiving subcutaneous vehicle or bupropion (1, 10, or 15 mg/kg s.c.). Pretreatment with bupropion dose-dependently attenuated expression of both the somatic and affective nicotine withdrawal response in mice. Each point represents the mean ± S.E.M. of six to eight mice per group. *, p < 0.05 versus the saline group. #, p < 0.05 nicotine control groups.

Fig. 5.

Effects of (2S,3S)-hydroxybupropion on affective and somatic signs of nicotine withdrawal in mice. Mice chronically infused with saline (0 mg/kg/day nicotine) or with nicotine (36 mg/kg/day) for 14 days had minipumps removed for 18 to 24 h and were tested on the elevated plus maze (time in seconds spent in open arms; top right), monitored for somatic signs (number of signs; top left), and assessed for hyperalgesia (hindpaw withdrawal latency, seconds; bottom) starting 30 min after receiving subcutaneous vehicle or (2S,3S)-hydroxybupropion (2, 5, or 10 mg/kg s.c.). Pretreatment with (2S,3S)-hydroxybupropion dose-dependently attenuated expression of both the somatic and affective nicotine withdrawal response in mice. Each point represents the mean ± S.E.M. of six to eight mice per group. *, p < 0.05 versus the saline group. #, p < 0.05 versus nicotine control groups.

Fig. 6.

Effects of (2R,3R)-hydroxybupropion on affective and somatic signs of nicotine withdrawal in mice. Mice chronically infused with saline (0 mg/kg/day nicotine) or with nicotine (36 mg/kg/day) for 14 days had minipumps removed for 18 to 24 h and were tested on the elevated plus maze (time in seconds spent in open arms; top right), monitored for somatic signs (number of signs; top left), and assessed for hyperalgesia (hindpaw withdrawal latency, seconds; bottom) starting 30 min after receiving subcutaneous vehicle or (2R,3R)-hydroxybupropion (2, 5, or 10 mg/kg s.c.). Pretreatment with (2R,3R)-hydroxybupropion dose-dependently attenuated expression of both the somatic and affective nicotine withdrawal response in mice. Each point represents the mean ± S.E.M. of six to eight mice per group. *, p < 0.05 versus the saline group. #, p < 0.05 versus nicotine control groups.

Fig. 7.

Effects of bupropion and its hydroxymetabolites on nicotine drug discrimination in mice. A, effects of nicotine on percentage of nicotine lever responding (left-hand axis) and response rates (right-hand axis) after subcutaneous administration in mice trained to discriminate 0.8 mg/kg nicotine from vehicle. Points above vehicle (VEH) and nicotine (NIC) represent the results of control tests with vehicle and 0.8 mg/kg nicotine conducted before each dose-effect determination. Values represent the mean ± S.E.M. *, p < 0.05, significant decrease in response rates compared with mean rates of responding occurring during the VEH tests. B, effects of bupropion, (2R,3R)-hydroxybupropion (R-OH bupropion), and (2S,3S)-hydroxybupropion (S-OH bupropion) on percentage of nicotine lever in mice trained to discriminate 0.8 mg/kg nicotine from vehicle. Points above VEH and NIC represent the results of control tests with vehicle and 0.8 mg/kg nicotine conducted before each dose-effect determination. Values represent the mean ± S.E.M. C, effects of bupropion, R-OH bupropion, and S-OH bupropion on response rates in mice trained to discriminate 0.8 mg/kg nicotine from vehicle. Points above VEH and NIC represent the results of control tests with vehicle and 0.8 mg/kg nicotine conducted before each dose-effect determination. Values represent the mean ± S.E.M. *, p < 0.05, significant decrease in response rates compared with mean rates of responding occurring during the VEH tests.