Repeated nicotine exposure during adolescence alters reward-related learning in male and female rats

Abstract

Rationale: Repeated nicotine exposure causes neuroadaptations in limbic cortico-striatal circuits involved in learning and motivation. Such alterations are relevant to addiction because they are suggested to mediate the ability of smoking-associated stimuli to control behavior and to enhance nicotine-seeking and -taking behaviors. Female smokers report higher cue reactivity relative to their male counter parts, yet little is known about putative gender-specific effects of adolescent nicotine exposure on reward-related learning. Prior repeated nicotine exposure in adult male rats enhances Pavlovian approach behavior and conditioned reinforcement.

Objective: Given that smoking is typically initiated during adolescence, here we assessed the extent to which adolescent nicotine exposure impacts Pavlovian approach and conditioned reinforcement in male and female rats.

Methods: Rats were injected with nicotine on postnatal days 31-45 prior to training on Pavlovian approach behavior starting on day 51. They were trained to associate a conditioned stimulus (CS), illumination of a magazine light, and tone, with an unconditioned stimulus (US), the delivery of water, for 10-daily sessions, and then were tested on the acquisition of responding with conditioned reinforcement.

Results: Adolescent nicotine exposure selectively increased approach to the magazine during the CS in males but decreased approach to the magazine during the CS in female rats. Vehicle-exposed female rats, however, showed greater magazine approach during the CS than did male control rats. Prior nicotine exposure also enhanced conditioned reinforcement in both male and female rats.

Conclusions: Repeated exposure to nicotine during adolescence had opposite effects on Pavlovian approach behavior in male and female rats but enhanced acquisition of a new response with conditioned reinforcement. Novel information on how nicotine exposure influences reward-related learning during adolescence may increase our understanding of neurobiological mechanisms involved in the initiation of smoking behavior.

Keywords: Conditioned reinforcement; Nicotine; Pavlovian approach; Reward learning; Sex differences.

Fig. 1

Effects of repeated nicotine exposure (0.35 mg/kg sc; 15 days) during adolescence (PD 35–50) on nicotine-induced locomotor activity following an acute nicotine (0.35 mg/kg sc) injection on exposure day 15. Statistics: ANOVA for repeated measures with follow-up t-tests for each timepoint comparison; n=8, all groups. There was a significant effect of nicotine exposure (p•0.001). * significant difference compared to habituation, # significant difference compared to the first thirty minutes after injection.

Fig. 2

Effects of prior repeated nicotine exposure (0.35 mg/kg sc; 15 days) during adolescence (PD 36–50) on magazine entries during A) CS, B) US and C) non-CS+US periods.: ANOVA for repeated measures; n=10, all groups. There were significant effects of training day (p•0.001) but no significant effect of nicotine exposure.

Fig. 3

Effects of repeated daily nicotine exposure (0.35 mg/kg sc; 15 days) during adolescence (PD 36–50) on responding with conditioned reinforcement. Prior repeated nicotine exposure increased responding on the active (i.e., CR) lever but had no effect on responding on the inactive (NCR) lever. Statistics: ANOVA for repeated measures; n=10, all groups. In this experiment, there was a significant effect of lever (p•0.001) and a lever X nicotine exposure interaction (p•0.05). * p•0.05