Nicotine Enhances Goal-Tracking in Ethanol and Food Pavlovian Conditioned Approach Paradigms

Abstract

Rationale: Nicotine promotes alcohol intake through pharmacological and behavioral interactions. As an example of the latter, nicotine can facilitate approach toward food- and alcohol-associated stimuli ("sign-tracking") in lever-Pavlovian conditioned approach (PavCA) paradigms. However, we recently reported that nicotine can also enhance approach toward locations of reward delivery ("goal-tracking") triggered by ethanol-predictive stimuli when the location of ethanol delivery is non-static (i.e., a retractable sipper bottle).

Objective: To determine whether the non-static nature of the reward location could have biased the development of goal-tracking in our previous study (Loney et al., 2019); we assessed the effect of nicotine in a lever-PavCA paradigm wherein the location of ethanol delivery was static (i.e., a stationary liquid receptacle). Then, to determine whether nicotine's enhancement of goal-tracking is unique to ethanol-predictive stimuli, we assessed the effect of systemic nicotine on approach triggered by food-predictive stimuli in a lever-PavCA paradigm.

Methods: Long-Evans rats were used in two PavCA experiments wherein a lever predicted the receipt of ethanol (15% vol/vol; experiment 1) or food (experiment 2) into a stationary receptacle. Prior to testing, rats were administered nicotine (0.4 mg/kg subcutaneously) or saline systemically.

Results: In both experiments, nicotine increased measures of goal-tracking, but not sign-tracking.

Conclusion: Nicotine can facilitate approach to reward locations without facilitating approach to reward-predictive stimuli. As such, conceptualization of the mechanisms by which nicotine affects behavior must be expanded to explain an enhancement of goal-tracking by nicotine.

Keywords: alcohol; conditioned approach; cue-reactivity; goal-tracking; nicotine.

FIGURE 1

Diagram of the experimental design for experiments 1 and 2. In experiment 1, the 10-s extension of an illuminated lever (CS) predicted the delivery of 0.2 mL ethanol (15% vol/vol; US) into a receptacle. There were 12 CS–US trials, and each trial was separated by an intertrial interval (ITI) of either 120, 240, or 360 s. Rats received an injection of either nicotine (0.4 mL/kg s.c.) or saline 15 min prior to each session. In experiment 2, the 8-s extension of an illuminated lever (CS) predicted the receipt of a single banana-flavored food pellet (US) into a receptacle. There were 25 CS–US trials, and each trial was separated by an ITI on a 90-s (60–150 s) variable time schedule. As in experiment 1, rats in experiment 2 also received an injection of either nicotine (0.4 mL/kg s.c.) or saline 15 min prior to each session.

FIGURE 2

Prior to starting PavCA testing in experiment 1, ethanol-exposed rats increased home-cage ethanol intake and preference. Intakes (grams of ethanol consumed per kilogram of body weight over each 24-h session) and preferences (ratio of grams of ethanol consumed to total grams of fluid consumed over each 24-h session) observed across Ethanol Sessions were significantly greater than those on Ethanol Session 1. Post hoc analyses indicated that ethanol intake was higher on sessions 2–8 and 10–12 than the first ethanol session (p’s < 0.0045) and that ethanol preference was significantly higher on sessions 5, 7, 8, and 10–12 relative to the first ethanol session (p’s < 0.0045). Data reflect the subjects included in the second ANOVA of experiment 1; thus, one rat of the original 20 ethanol-exposed subjects is excluded.

FIGURE 3

In experiment 1, nicotine increased goal location entries during both the entire ITI and the 10-s pre-CS period immediately prior to lever presentations. In order to determine whether nicotine had a non-specific effect on behavior directed toward the goal location, we assessed the effect of nicotine on receptacle entries during both the entire ITI (A) and during the 10-s pre-CS period (B). Because nicotine increased receptacle entries during both the ITI and the pre-CS period in experiment 1, we express the number of receptacle entries in our evaluation of goal-tracking (Figure 4A) as an elevation score, as opposed to raw values. The elevation score was calculated by subtracting the number of receptacle entries made during the 10-s pre-CS from the number of receptacle entries made during the 10-s lever presentation. Asterisk (^∗) indicates significant Treatment × Session interactions.

FIGURE 4

In experiment 1, nicotine enhanced measures of goal-tracking elicited by an ethanol-predictive stimulus relative to saline treatment. During the extension of a lever that predicted the non-contingent receipt of ethanol (15% vol/vol), nicotine (A) increased the number of receptacle entries as calculated by the elevation score, (B) increased the probability of making a receptacle entry, and (C) decreased the latency to the first receptacle entry. Conversely, nicotine did not affect (D) the number of lever presses, (E) the probability of contacting the lever, or (F) the latency to the first lever contact. Asterisk (^∗) indicates significant Treatment × Session interactions, whereas daggers (^†) indicate significant differences on the indicated test sessions. Data reflect the subjects included in the second ANOVA of experiment 1; thus, rats that did not have an affinity for ethanol are excluded and are collapsed across Ethanol Exposure.

FIGURE 5

In experiment 2, nicotine had no effect on the number of goal location entries during the ITI. As in experiment 1, we sought to determine whether nicotine had any non-specific effect on behavior directed toward the goal location by evaluating the effect of nicotine on receptacle entries during the ITI. In this experiment, nicotine did not have any effect on the number of receptacle entries during the ITI. Therefore, we did not compute an elevation score for experiment 2 and report the raw values for the number of goal-tracking responses in Figure 6A.

FIGURE 6

In experiment 2, nicotine enhanced measures of goal-tracking elicited by a food-predictive stimulus relative to saline treatment. During the extension of a lever that predicted the non-contingent receipt of a solid food reward, nicotine (A) increased the number of receptacle entries, (B) increased the probability of making a receptacle entry, and (C) decreased the latency to the first receptacle entry. Conversely, nicotine (D) did not affect the number of lever presses, (E) tended to reduce the probability of contacting the lever, and (F) did not affect the latency to the first lever contact. The effect of nicotine did not differ by Sex for any measure. Asterisk (^∗) indicates significant Treatment × Session interactions, whereas daggers (^†) indicate significant differences on the indicated test sessions.