Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

Abstract

Objective and rationale: Alcohol and nicotine are commonly co-abused; one possible explanation for co-abuse is that each drug ameliorates the aversive effects of the other. Both drugs have dose-dependent effects on learning and memory. Thus, this study examined the interactive effects of acute ethanol and acute, chronic, or withdrawal from chronic nicotine on fear conditioning in C57BL/6J mice.

Materials and methods: Conditioning consisted of auditory conditioned stimulus-foot-shock unconditioned stimulus pairings. For acute studies, saline or ethanol, then saline or nicotine was administered before training, and saline or nicotine was also administered before testing. For chronic and withdrawal studies, saline or nicotine was administered chronically, and ethanol or saline was administered before training.

Results: Acute nicotine (0.09 mg/kg) reversed ethanol-induced deficits (1.0 and 1.5 g/kg) in contextual and cued fear conditioning, whereas a low dose of ethanol (0.25 g/kg) reversed nicotine (6.3 mg kg(-1) day(-1)) withdrawal-induced deficits in contextual conditioning. Tolerance developed for the effects of nicotine on ethanol-induced deficits in conditioning and cross-tolerance between chronic nicotine and acute ethanol was seen for the enhancing effects of ethanol on conditioning.

Conclusions: The complex and sometimes polar actions of ethanol and nicotine on behavior may contribute to co-abuse of these drugs. Specifically, smoking may initially reduce the aversive effects of ethanol, but tolerance develops for this effect. In addition, low doses of alcohol may lessen nicotine withdrawal symptoms.

Fig. 1

Acute nicotine reversed ethanol-induced impairments in contextual and cued conditioning (mean±SEM; asterisk indicates significant difference from controls, p<0.05; number sign indicates significant difference between nicotine and saline treatment within each ethanol condition, p<0.05)

Fig. 2

Acute ethanol impaired contextual and cued conditioning, but chronic nicotine did not reverse these deficits and actually contributed to deficits in contextual fear conditioning with the 0.5 g/kg dose of ethanol (mean±SEM; asterisk indicates significant difference from controls, p<0.05)

Fig. 3

Both acute ethanol and withdrawal from chronic nicotine independently impaired conditioning (mean±SEM; asterisk indicates significant difference from controls, p<0.05; number sign indicates significant difference between nicotine and saline treatment within each ethanol condition, p<0.05)

Fig. 4

Acute nicotine and a low dose of ethanol enhanced contextual conditioning in a nonadditive manner. The low dose of ethanol also enhanced cued conditioning (mean±SEM; asterisk indicates significant difference from controls, p<0.05)

Fig. 5

Acute ethanol enhanced contextual and cued conditioning, but chronic nicotine blocked enhancement of conditioning by ethanol, suggesting cross-tolerance (mean±SEM; asterisk indicates significant difference from controls and cross indicates significant differences between groups collapsed by ethanol treatment, p<0.05)

Fig. 6

Withdrawal from chronic nicotine impaired contextual conditioning, whereas a low dose of ethanol enhanced contextual and cued conditioning and reversed nicotine withdrawal-associated deficits in contextual fear conditioning (mean±SEM; asterisk indicates significant difference from controls, p<0.05)

Fig. 7

Testing cued conditioning first did not alter the effects of either ethanol or nicotine on conditioning (mean±SEM; asterisk indicates significant difference from controls, p<0.05)

Fig. 8

Average blood alcohol concentration (mg/dl) 15 min after ethanol injection and 5 min after nicotine injection. Higher doses of ethanol produced significantly greater blood alcohol concentrations, but there was no effect of nicotine treatment on blood alcohol concentration (mean±SEM; bar indicates no difference in BAC)