Abstract
BackgroundNicotine exposure enhances Pavlovian conditioned approach (PCA), or the learned approach to reward-predictive cues. While females show elevated approach to conditioned stimuli compared to males, potentially indicating heightened addiction vulnerability, it is unknown how sex may interact with nicotine to influence approach behavior. Additionally, brain-derived neurotrophic factor (BDNF) levels can be altered significantly after repeated nicotine exposure, suggesting a potential mechanism contributing to nicotine-induced behavioral phenotypes. The present study investigated the role of sex on nicotine-induced changes to stimulus-response behavior and associated BDNF protein levels.MethodsMale and female rats were exposed to nicotine (0.4 mg/kg, subcutaneously) or saline 15 min prior to each PCA session. PCA training consisted of 29 sessions of 15 trials, in which a 30-s cue presentation ended concurrently with a sucrose reward (20% w/v in water, 100 μL), and a 120-s variable intertrial interval occurred between trials. Approach behavior to the cue and reward receptacle was recorded. Preference toward the reward receptacle indicated a goal-tracking phenotype, and preference toward the cue indicated a sign-tracking phenotype, demonstrating that the cue had gained incentive salience. Twenty-four hours after the last PCA session, brain tissue was collected and BDNF levels were measured in the basolateral amygdala, orbitofrontal cortex, and nucleus accumbens using Western blot analysis.ResultsNicotine exposure enhanced both sign- and goal-tracking conditioned approach, and females showed elevated sign-tracking compared to males. There were no sex-by-drug interactions on conditioned approach. Day-to-day variability in conditioned approach was similar between sexes. In contrast to prior studies, neither repeated exposure to nicotine nor sex significantly affected BDNF expression.ConclusionsDrug-naïve females exhibited heightened sign-tracking compared to males, and nicotine enhanced conditioned approach similarly in males and females. Further, non-significant changes to BDNF expression in brain regions highly associated with PCA indicate that BDNF is unlikely to drive nicotine-enhanced conditioned behavior.
Highlights
Nicotine exposure enhances Pavlovian conditioned approach (PCA), or the learned approach to reward-predictive cues
While this finding may be related to the observed sex differences in behavior, the larger data set suggests that brain-derived neurotrophic factor (BDNF) expression in these brain regions is not strongly associated with other aspects of conditioned approach or nicotine exposure in general
We examined BDNF levels in the nucleus accumbens (NAc), orbitofrontal cortex (OFC), and basolateral amygdala (BLA)—corticolimbic brain regions known to be involved in Pavlovian conditioning (e.g., [57, 58])
Summary
Nicotine exposure enhances Pavlovian conditioned approach (PCA), or the learned approach to reward-predictive cues. Brain-derived neurotrophic factor (BDNF) levels can be altered significantly after repeated nicotine exposure, suggesting a potential mechanism contributing to nicotineinduced behavioral phenotypes. The present study investigated the role of sex on nicotine-induced changes to stimulus-response behavior and associated BDNF protein levels. Pairing an environmental stimulus with a reward (unconditioned stimulus, US) can lead to the formation of a stimulus-reward association through Pavlovian mechanisms. This changes the previously neutral environmental stimulus to a conditioned stimulus (CS) that can induce conditioned responses (CRs), such as approach [1]. In animals that exhibit high levels of sign-tracking, the CS acquires conditioned reinforcing properties, in that the animals will perform instrumental responses to obtain the conditioned cue [6]. Sign-trackers and goal-trackers vary in terms of neurotransmitter release and neuronal activation associated with a preferred CR, suggesting that they are both acquired and heritable biological factors underlying the expression of these CRs [10,11,12,13,14]
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