Microstructural meal pattern analysis reveals a paradoxical acute increase in food intake after nicotine despite its long-term anorexigenic effects

Abstract

Rationale: Nicotine consumption in both human and animal studies has been strongly associated with changes in feeding-related behaviors and metabolism. The current dogma is that nicotine is an anorexic agent that decreases food intake and increases metabolism, leading to decreased body weight gain. However, there are conflicting reports about the acute effects of nicotine on hunger in humans. No study has reported nicotine-induced decreases in food intake within minutes of consumption, suggesting that our understanding of the pharmacological effects of nicotine on appetite and feeding may be incorrect.

Objectives: The aim of this study was to elucidate effects of acute nicotine intake on feeding and drinking behavior.

Methods: Adult male Wistar rats were trained to intravenously self-administer nicotine. Microstructural and macrostructural behavioral analyses were employed to look at changes in food and water intake at different timescales.

Results: At the macrostructural level (hours to days), nicotine decreased body weight gain, decreased feeding, and was associated with increases in feeding and body weight gain during abstinence. At the microstructural level (seconds to minutes), nicotine increased feeding and drinking behavior during the first 5 min after nicotine self-administration. This effect was also observed in animals that passively received nicotine, but the effect was not observed in animals that self-administered saline or passively received saline.

Conclusions: These results challenge the notion that the initial pharmacological effect of nicotine is anorexigenic and paradoxically suggest that an acute increase in food intake minutes after exposure to nicotine may contribute to the long-term anorexigenic effects of nicotine.

Keywords: Addiction; Drinking; Feeding; Food; Metabolism; Self-administration.

Fig. 1

Changes in body weight in nicotine vs. saline rats. A Average change in body weight in nicotine (red) and saline (blue) rats over the course of the nicotine self-administration paradigm. Unshaded area represents continuous long access. Gray shaded area represents intermittent long access (4 days ON, 3 days OFF). The data are expressed as a percent change in body weight relative to baseline. Time × treatment interaction, p < 0.0001 (two-way repeated-measures ANOVA). B Average change in body weight in nicotine (red) and saline (blue) rats within each cycle of the nicotine self-administration paradigm. The data are expressed as a percent change in body weight relative to D01 OFF1. Time × treatment interaction, p = 0.0023 (two-way repeated-measures ANOVA). Nicotine (N = 8), saline (N = 3). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 (Sidak multiple-comparison post hoc test)

Fig. 2

Average food and water intake in nicotine vs. saline rats. A Average daily food intake in nicotine (red) vs. saline (blue) rats during the nicotine ON and OFF phases. The data are expressed as calories consumed normalized to body weight in a 24-h period. Time × treatment interaction, p = 0.0019 (two-way ANOVA). B Average daily water intake in nicotine (red) vs. saline (blue) rats during the nicotine ON and OFF phases. The data are expressed as milliliters of water consumed normalized to body weight in a 24-h period. Time × treatment interaction, p = 0.2225 (two-way ANOVA). Nicotine (N = 8), saline (N = 9). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 (Tukey’s multiple-comparison post hoc test)

Fig. 3

Peristimulus time histograms of drug, food, and water self-administration events that surrounded a single self-administration within a 1000-s time window. A Average normalized probability of nicotine (dark red) and saline (light red) intake events that surrounded a single nicotine or saline self-administration event, represented by time t = 0. B Average normalized probability of food intake events that surrounded a single nicotine (dark orange) or saline (light orange) self-administration event. C Average normalized probability of water intake events that surrounded a single nicotine (dark blue) or saline (light blue) self-administration event. Asterisk denotes p < 0.05 with Mann–Whitney test. D Number of inactive lever presses recorded during the first hour of the self-administration session for animals self-administering nicotine or saline. p = 0.1510 (Student’s t-test). E The number of inactive lever presses recorded during the total self-administration session for animals self-administering nicotine or saline. p = 0.4293. N = 8 nicotine, 9 saline

Fig. 4

Peristimulus time histograms of food and water intake events that surrounded single food or water intake events within a 1000-s time window. A Average normalized probability of food intake events that surrounded a single food intake event in rats that self-administered nicotine (dark orange) or saline (light orange). B Average normalized probability of water intake events that surrounded a single food intake event in rats that self-administered nicotine (dark blue) or saline (light blue). C Average number of water intake events that surrounded a single water intake event in rats that self-administered nicotine (dark blue) or saline (light blue). Asterisk denotes p < 0.05 with Mann–Whitney post hoc test. D Average duration of feeding bout in rats that self-administered nicotine (dark orange) or saline (light orange). p = 0.1232 (Student’s t-test). E Average duration of drinking bout in rats that self-administered nicotine (dark blue) or saline (light blue). p = 0.2193 (Student’s t-test). Nicotine (n = 8), saline (n = 3)

Fig. 5

Peristimulus time histograms of nicotine, food, and water intake events that surrounded passive administration events within a 1000-s time window. A Average normalized probability of 1 saline infusion (pink), 1 nicotine infusion (red), and 3 nicotine infusions (maroon). B Average normalized probability of food intake events in rats following three nicotine infusions (dark orange), one nicotine infusion (orange), or one saline infusion (light orange). C Average normalized probability of water intake events in rats following three nicotine infusions (dark blue), one nicotine infusion (blue), or 1 saline infusion (light blue). **p < 0.01, ****p < 0.0001, Kruskal–Wallis and Dunn’s multiple comparisons post hoc. N = 7 per group. D Number of inactive lever presses recorded during the first hour of the self-administration session for animals receiving 1 saline infusion, 1 nicotine infusion, or 3 nicotine infusions. p = 0.9709 (one-way repeated measures ANOVA). E Number of inactive lever presses recorded during the total self-administration session for animals receiving 1 saline infusion, 1 nicotine infusion, or 3 nicotine infusions. p = 0.3703 (one-way repeated measures ANOVA). N = 5 per group

Fig. 6

Peristimulus time histograms of food and water intake events that surrounded single food or water intake events within a 1000-s time window. A Average normalized probability of food intake events compared with a single food intake event in rats that were given three nicotine infusions (dark orange), one nicotine infusion (orange), or one saline infusion (light orange). B Average normalized probability of water intake events compared with a single food intake event in rats that were given three nicotine infusions (dark blue), one nicotine infusion (blue), or one saline infusion (light blue). C Average normalized probability of water intake events compared with a single water intake event in rats that were given three nicotine infusions (dark blue), one nicotine infusion (blue), or one saline infusion (light blue). ****p < 0.0001, Kruskal–Wallis with Dunn’s multiple comparisons post hoc. D Average duration of feeding bout in rats that self-administered nicotine (dark orange) or saline (light orange). p = 0.5838 (one-way ANOVA). E Average duration of drinking bout in rats that self-administered nicotine (dark blue) or saline (light blue). p = 0.7154 (one-way ANOVA). N = 5 per group