Social learning promotes nicotine self-administration by facilitating the extinction of conditioned aversion in isogenic strains of rats

Abstract

Both social environment and genetic factors are critical for smoking initiation and nicotine addiction. We reported that rats developed conditioned flavor (i.e., taste and odor) aversion to intravenously self-administered (IVSA) nicotine, and that social learning promoted nicotine IVSA with flavor cues. We thus tested the hypothesis that socially acquired nicotine IVSA is a heritable trait by using female rats of six inbred strains and six F1 hybrids. Each strain was tested for 10 daily IVSA sessions. We found that the intake of nicotine (15 and 30 μg/kg/inf) varied among these strains by 33.7-56.6-fold. The heritability of nicotine intake was estimated to be 0.54-0.65. Further, there was a strong correlation in nicotine intake (R² = 0.85, p < 0.0001) between the two nicotine doses. Another cohort of rats was given three daily IVSA sessions followed by five sessions that tested conditioned flavor aversion. Nicotine intake was highly correlated with the extinction of the conditioned aversion (R² = 0.58, p < 0.005). These data showed that nicotine intake in the socially acquired nicotine self-administration model is controlled by genetic factors and that the role of social learning is likely in facilitating the extinction of conditioned aversive response to nicotine.

Figure 1

Female adolescent rats from 12 isogenic strains were tested by using the socially acquired nicotine (15 μg/kg/inf) IVSA procedure. See Methods for a detailed description of the procedure. A logarithmic scale is used for the Y-axis.

Figure 2

Female adolescent rats from 12 isogenic strains were tested by using the socially acquired nicotine (30 μg/kg/inf) IVSA procedure. See Methods for a detailed description of the procedure. The Y-axis used a logarithmic scale.

Figure 3

Average nicotine intake during the last three IVSA sessions. The number of nicotine infusions was highly correlated when two different doses were tested (a). The gray area represents the 95% confidence interval of the linear model. When compared to the 30 μg/kg/inf dose, the number of infusions almost doubled across the strains when 15 μg/kg/inf was used. As a result, the amount of nicotine obtained was very similar between the two doses (b). Three-way repeated measures ANOVA found there was a significant effect of strain on nicotine intake (F_11,160 = 9.0, p < 0.001) but dose (F_1,166 = 0.13, p > 0.05) and session (F_2,320 = 0.17, p > 0.05) had no effect.

Figure 4

Strain difference. Strain differences in the average number of nicotine infusions obtained during the last three IVSA sessions were analyzed by post-hoc Tukey HSD tests. Each color block represented the p-value when the two strains listed on the x and y-axis were compared.

Figure 5

Nicotine CFA and extinction of CFA. Twelve isogenic strains of adolescent rats self-ministered nicotine (30 μg/kg/inf, i.v.) with an appetitive flavor cue for three daily sessions without demonstrator rats (sessions 1–3). This was followed by five daily extinction sessions (sessions 4–8) where nicotine was not provided. Control rats received i.v. saline.

Figure 6

Correlation between nicotine intake and indices for CFA and extinction of CFA. The CFA index (a) was calculated using data obtained from the first extinction session (i.e. session four, Fig. 5). The extinction index (b) was calculated using data obtained from session eight. The correlation between the number of nicotine infusions at 30 μg/kg/inf with both indices were calculated. The gray area represents the 95% confidence interval of the linear model.