Chronic fluoxetine ameliorates adolescent chronic nicotine exposure-induced long-term adult deficits in trace conditioning

Abstract

Development of the brain, including the prefrontal cortex and hippocampus, continues through adolescence. Chronic nicotine exposure during adolescence may contribute to long-term deficits in forebrain-dependent learning. It is unclear if these deficits emerge immediately after exposure and if they can be ameliorated. In this study, C57BL/6J mice were treated with chronic nicotine (6.3 or 12.6 mg/kg/day) over 12 days beginning at adolescence, postnatal day (PND) 38, or adulthood, PND 56-63 ± 3. We investigated the effects of short-term (24 h) abstinence on trace fear conditioning and found that adult treatment resulted in deficits (6.3 and 12.6 mg/kg/day), but adolescent chronic nicotine treatment had no effect. In contrast, adolescent treatment with chronic nicotine (12.6 mg/kg/day) elicited a long-term (30 days) learning deficit, but adult chronic nicotine treatment did not. Using the elevated plus maze (EPM) we found no long-term changes in anxiety-related behavior after chronic nicotine exposure at either time-point. We investigated if chronic fluoxetine (FLX) could ameliorate adolescent chronic nicotine-associated long-term deficits in trace conditioning. We found that chronic FLX (160 mg/L) in drinking water ameliorated the long-term deficit in trace fear conditioning associated with nicotine exposure during adolescence. Additionally, in the same animals, we examined changes in total BDNF protein in the dorsal hippocampus (DH), ventral hippocampus (VH), and prefrontal cortex (PFC). Chronic FLX increased DH BDNF. Our data indicate nicotine administration during adolescence leads to late onset, long-lasting deficits in hippocampus-dependent learning that chronic FLX treatment ameliorate.

Keywords: Addiction; Adolescence; Cognition; Fluoxetine; Learning; Nicotine.

Figure 1

Experimental design schematics for (A) short-term abstinence from chronic nicotine, (B) long-term abstinence from chronic nicotine, and (C) FLX treatment during long-term abstinence from adolescent chronic nicotine exposure.

Figure 2

Effects of short-term (24 hr) abstinence from chronic nicotine administration during adolescence and adulthood on trace fear conditioning. Adult mice treated with 12.6 and 6.3 mg/kg/day chronic nicotine froze significantly less to the CS during testing compared to saline controls. Error bars indicate SEM, (*) indicates a significant between subjects t-test, p < 0.05.

Figure 3

Effects of long-term (30 days) abstinence from chronic nicotine administration during adolescence and adulthood on trace fear conditioning. Mice treated with 12.6 mg/kg chronic nicotine during adolescence froze significantly less during testing than Saline treated controls. Error bars indicate SEM, (*) indicates a significant between subjects t-test, p < 0.05.

Figure 4

Age-Dependent effects of long-term abstinence from chronic nicotine on EPM. No effect of prior chronic nicotine exposure was observed for 12.6 or 6.3 mg/kg/day on EPM percent open arm time. Error bars indicate SEM.

Figure 5

Effect of chronic fluoxetine on adolescent chronic nicotine exposure-induced long-term trace fear conditioning deficits. Mice treated with nicotine froze significantly less to the CS during testing compared to saline controls. In contrast, mice treated with FLX and nicotine froze at levels not significantly different than Water/Saline controls. Error bars indicate SEM, (*) indicates a significant Games-Howell post-hoc test compared to Water/Saline group, p < 0.05.

Figure 6

Effect of chronic fluoxetine on total BDNF protein. Chronic FLX increased BDNF protein within the DH (A), but no change was seen in the VH (B) or PFC (C). Error bars indicate SEM, (*) indicates a significant Dunnet’s post-hoc test comparison to Saline/Water control group, p ≤ 0.05.