Accentuating effects of nicotine on ethanol response in mice with high genetic predisposition to ethanol-induced locomotor stimulation

Abstract

Background: Co-morbid use of nicotine-containing tobacco products and alcohol is prevalent in alcohol dependent individuals. Common genetic factors could influence initial sensitivity to the independent or interactive effects of these drugs and play a role in their co-abuse.

Methods: Locomotor sensitivity to nicotine and ethanol, alone and in combination, was assessed in mice bred for high (FAST) and low (SLOW) sensitivity to the locomotor stimulant effects of ethanol and in an inbred strain of mouse (DBA/2J) that has been shown to have extreme sensitivity to ethanol-induced stimulation in comparison to other strains.

Results: The effects of nicotine and ethanol, alone and in combination, were dependent on genotype. In FAST and DBA/2J mice that show high sensitivity to ethanol-induced stimulation, nicotine accentuated the locomotor stimulant response to ethanol. This effect was not found in SLOW mice that are not stimulated by ethanol alone.

Conclusions: These data indicate that genes underlying differential sensitivity to the stimulant effects of ethanol alone also influence sensitivity to nicotine in combination with ethanol. Sensitivity to the stimulant effects of nicotine alone does not appear to predict the response to the drug combination, as FAST mice are sensitive to nicotine-induced stimulation, whereas SLOW and DBA/2J mice are not. The combination of nicotine and ethanol may have genotype-dependent effects that could impact co-abuse liability.

Figure 1

Nicotine accentuated the locomotor stimulant response to ethanol (EtOH) in FAST mice. Shown are means ± SEM for the first (A), middle (B) and last (C) 10-min periods of a 30-min test. Distance traveled for each animal was calculated by subtracting the day 2 baseline from the day 3 drug score. Data are combined for the two sexes and replicates because these factors did not significantly influence the results; thus, group size is 21–24 mice per dose group. *: p<0.05; ***: p<0.001; for the comparison of saline with ethanol 1 g/kg for each dose of nicotine. $$$: p<0.001 for the comparison of the indicated group with the ethanol 1 g/kg/nicotine 0 mg/kg group. ###: p<0.001 for the main effect of ethanol.

Figure 2

Ethanol (EtOH) and nicotine had locomotor depressant effects in SLOW mice. Shown are means ± SEM for the first (A), middle (B) and last (C) 10-min periods of a 30-min test. Distance traveled for each animal was calculated by subtracting the day 2 baseline from the day 3 drug score. Data are combined for the two sexes and replicates because these factors did not significantly influence the results; thus, group size is 20–24 mice per dose group. There were no significant interaction effects, therefore specific mean comparisons were not appropriate. ###: p<0.001 for the main effect of ethanol. +++: p<0.001, for the main effect of nicotine.

Figure 3

Nicotine did not significantly alter blood ethanol levels in FAST or SLOW mice. Blood samples were obtained at the end of the 30-min activity test on day 3 from all mice that had received ethanol. Data are mean ± SEM blood ethanol concentration. ###: p<0.001 for the main effect of line.

Figure 4

Nicotine accentuated the locomotor stimulant response to ethanol (EtOH) in DBA/2J (D2) mice. Shown are means ± SEM for the first (A), middle (B) and last (C) 10-min periods of a 30-min test. Distance traveled for each animal was calculated by subtracting the day 2 baseline from the day 3 drug score. Group size was 21–23 mice per dose group. ***: p<0.001; for the comparison of saline with ethanol 1 g/kg for each dose of nicotine. $$: p<0.01 for the comparison of the indicated group with the ethanol 1 g/kg/nicotine 0 mg/kg group. ###: p<0.001 for the main effect of ethanol.

Figure 5

Nicotine did not alter blood ethanol levels in DBA/2J mice. Blood samples were obtained at the end of the 30-min activity test on day 3 from all mice that had received ethanol. Data are mean ± SEM blood ethanol concentration. N: mg/kg of nicotine; E: g/kg of ethanol.

Figure 6

Ethanol increased blood cotinine levels in nicotine-treated DBA/2J mice. Blood samples were obtained at the end of the 30-min activity test on day 3 from all mice that had received nicotine. Data are mean ± SEM blood cotinine concentration. N: mg/kg of nicotine; E: g/kg of ethanol. *: p<0.05; for the comparison of saline and ethanol groups treated with the same dose of nicotine.