Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Abstract

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning.

Figure 1

The effects of bupropion on contextual and cued fear conditioning in C57BL/6 mice when administered at training and testing. High doses of bupropion (20 and 40 mg/kg) impaired contextual and cued fear conditioning, suggesting that bupropion may dose-dependently disrupt the acquisition and/or expression of fear conditioning. Error bars indicate SEM. (*) indicates p < 0.05 compared to all other groups for contextual fear conditioning data, and (#) indicates p < 0.05 compared to all other groups for cued fear conditioning data.

Figure 2

The effects of bupropion on fear conditioning in C57BL/6 mice when administered on training day alone. A high dose of bupropion (40 mg/kg) administered on training day to chronic nicotine-treated mice produced deficits in contextual fear conditioning but not cued fear conditioning. These results suggest that bupropion dose-dependently disrupts the acquisition of contextual fear conditioning. Error bars indicate SEM, and (*) indicates p < 0.05 compared to all other groups for contextual fear conditioning data.

Figure 3

The effects of bupropion on fear conditioning in C57BL/6 mice when administered on testing day alone. Higher doses of bupropion (20 and 40 mg/kg) produced deficits in contextual and cued fear conditioning when administered on testing day. These results suggest that bupropion dose-dependently disrupts the expression of fear conditioning. Error bars indicate SEM. (*) indicates p < 0.05 compared to all other groups for contextual fear conditioning data, and (#) indicates p < 0.05 compared to all other groups for cued fear conditioning data.

Figure 4

The effects of bupropion on fear conditioning during withdrawal from chronic nicotine (WCN) or withdrawal from chronic saline (WCS) in C57BL/6 mice. The administration of bupropion on both training and testing days dose-dependently reversed nicotine withdrawal-related deficits in contextual fear conditioning (Figure 4a). In contrast, no differences in cued fear conditioning were observed between groups (Figure 4b). Error bars indicate SEM, and (*) indicates p < 0.05 compared to all other chronic saline-treated groups.

Figure 5

The effects of bupropion on fear conditioning during withdrawal from chronic nicotine (WCN) or withdrawal from chronic saline (WCS) when administered on training day alone or testing day alone. Bupropion administered on testing day alone reversed nicotine withdrawal-related deficits in contextual fear conditioning. In contrast, bupropion administered on training day alone had no effect. No differences in cued fear conditioning were observed between groups. Error bars indicate SEM, and (*) indicates p < 0.05 compared to all other chronic saline-treated groups.