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. Author manuscript; available in PMC: 2018 May 16.
Published in final edited form as: Exp Clin Psychopharmacol. 2016 Sep 19;24(6):477–484. doi: 10.1037/pha0000094

High-Fat Diet Meal Patterns During and After Continuous Nicotine Treatment in Male Rats

Ian A Mendez 1,*, Luis Carcoba 2, Paul J Wellman 3, Antonio Cepeda-Benito 4
PMCID: PMC5955698  NIHMSID: NIHMS810016  PMID: 27643914

Abstract

Smoking to control body weight is an obstacle to smoking cessation, particularly in western cultures where diets are often rich in calories derived from fat sources. The purpose of this study was to investigate the effects of continuous nicotine administration on meal patterns in rats fed a high-fat diet. Male rats were housed in cages designed to continuously monitor food intake and implanted with minipumps to deliver approximately 1.00 mg/kg/day of nicotine or saline. Meal patterns and body weights were assessed for 2 weeks of treatment and 1 week post-treatment. When compared to controls, rats with continuous nicotine treatment exhibited a decrease in the average meal duration (s) during the first week of treatment and a modest, yet sustained reduction in daily number of meals over the 14-day treatment period. Nicotine-induced decreases in body weight gain were observed throughout the 2 weeks of treatment. No differences in meal patterns or body weight gain were seen for 1 week following cessation of treatment. Results from this study suggest that while continuous nicotine treatment decreases daily food intake, meal durations, meal numbers, and weight gain, cessation of this treatment does not result in significant compensatory increases. Understanding the effects of nicotine on feeding patterns and weight gain may allow for improvements in treatment protocols aimed at addressing the factors that contribute to tobacco use.

Keywords: Nicotine, High-Fat Diet, Meal Pattern, Body Weight, Rat

Introduction

Understanding the mechanisms and conditions that control nicotine’s modulation of appetite, feeding patterns, and body weight could help develop or improve prevention and treatment strategies aimed to curb two major public-health threats, obesity and cigarette smoking. It has long been known that nicotine possesses inhibitory actions on food intake (Benowitz & Hatsukami, 1998; Blaha, Yang, Meguid, Chai, & Zadak, 1998; Nicklas, Tomoyasu, Muir, & Goldberg, 1999). This anorectic effect contributes to the belief that smoking can help control body weight (Chiolero, Faeh, Paccaud, & Cornuz, 2008; White, McKee, & O’Malley, 2007) and provides a powerful incentive for smoking in certain populations (Camp, Klesges, & Relyea, 1993; French, Perry, Leon, & Fulkerson, 1994). Cigarette smoking to control body weight has indeed become a common and extended practice in adults, particularly in those that are overweight, under 30 years age, and female (Kokkinos et al., 2007; White, 2012).

The expectation that smoking is an effective method for controlling body weight is supported by evidence showing that smokers weigh less than nonsmokers and that smoking termination leads to new weight gain (Cepeda-Benito & Ferrer, 2000; Kokkinos, et al., 2007). While these findings are extensive, the conditions under which smoking-induced weight-loss occurs remain unclear (Guan, Kramer, Bellinger, Wellman, & Kramer, 2004; Jo, Talmage, & Role, 2002). For example, some studies have shown that weight loss is observed in moderate but not heavy smokers, who tend to weigh more than moderate- and non-smokers (Chiolero, et al., 2008; Chiolero, Jacot-Sadowski, Faeh, Paccaud, & Cornuz, 2007). Other studies show the existence of subgroups where weight gain and smoking co-occur (Chiolero, et al., 2008; Peeters et al., 2003), suggesting that the effects of smoking and smoking cessation on body weight changes are complex and likely impacted by multiple factors.

To better understand the effects of smoking and smoking cessation on weight regulation and feeding behavior, investigators have developed and refined various animal models. Traditionally in these models, nicotine is administered either intermittently through acute injections or delivered continuously throughout the day via subcutaneously implanted osmotic minipumps. Both models are useful in that intermittent administration of nicotine provides an approximation for the nicotine dosing pattern of regular smokers, whereas continuous nicotine administration provides a better model for understanding the potential impact of nicotine delivered via nicotine transdermal patches in persons attempting to quit smoking (see Bellinger, Cepeda-Benito, & Wellman, 2003).

It is well established that nicotine exposure decreases food intake in rats, but how nicotine impacts specific meal structures may depend on whether nicotine is administered intermittently via injections (Guan, et al., 2004) or continuously via minipumps (Blaha, et al., 1998; Miyata, Meguid, Varma, Fetissov, & Kim, 2001). For example, whereas nicotine, regardless of delivery method, initially decreases meal size when reported as grams consumed (Bellinger, et al., 2003; Miyata, et al., 2001), only rats that receive nicotine via intermittent injections show significant compensatory increases in their number of daily meals (Guan, et al., 2004). Additionally, cessation of intermittently or continuously administered nicotine appears to normalize meal sizes, occasionally following a transient hyperphagia phase that is often insufficient to fully correct nicotine’s suppression of body weight in rats (Bellinger, et al., 2003; Grunberg, 2007; Levin, Morgan, Galvez, & Ellison, 1987; Miyata, et al., 2001; Wager-Srdar, Levine, Morley, Hoidal, & Niewoehner, 1984).

Most studies of nicotine’s effects on food intake and body weight in rats have examined feeding exclusively on standard, low-calorie chow diets (e.g. Bellinger et al., 2005; Guan, et al., 2004; Miyata, Meguid, Fetissov, Torelli, & Kim, 1999). In an attempt to improve on the animal model of nicotine’s effects on the feeding behavior and weight regulation of humans, Wellman et al. (2005) examined feeding behavior in rats maintained on a high-fat, calorie-dense diet, which is more comparable to the diet commonly consumed by humans, and smokers in particular (Dallongeville, Marecaux, Fruchart, & Amouyel, 1998; Wellman, et al., 2005). Wellman et al. found that intermittent nicotine exposure induced a greater suppression of caloric intake and weight gain in rats on a high-fat diet, when compared to rats on a standard, low-fat chow diet. As expected, nicotine administered to rats consuming a low-fat, standard rodent chow diet produced an initial decrease in meal size (Kcal) and a gradual compensatory increase in meal number. In contrast, nicotine administered to rats consuming a high-fat diet decreased both meal size and meal number, with the latter returning to control levels by day 4 of a 14-day nicotine-treatment period. Regardless of diet, cessation of nicotine injections resulted in transient increases in 24-hour food intake.

The present study primarily aimed to expand on the findings of Wellman et al. (2005), by investigating the effects of continuous nicotine administration on the reciprocity of meal patterns (i.e. meal size, meal number), in animals maintained on a high-fat diet. Furthermore, while previous investigators examining the effects of continuous nicotine administration on feeding have limited nicotine treatment to 1 week (Blaha, et al., 1998; Miyata, et al., 2001), we extended the nicotine treatment phase to 2 weeks. An investigation of how extended, continuous nicotine administration in rats may impact consumption of a high-fat diet and weight gain also provides a closer approximation than previous research, to the potential effects of the nicotine transdermal patch on feeding and weight gain patterns in humans.

Materials and methods

Subjects

Subjects were 12 adult male Sprague-Dawley rats weighing 250–300 g upon arrival (Charles River Laboratories, Wilmington, NC, USA). Rats were housed individually in a climate-controlled vivarium (23° C), had food and water available ad lib (see Section 2.5 for additional details) and were maintained on a 12-hour light/dark schedule (lights off at 1200 h). A red light bulb (15 W) allowed dim illumination within the colony room during dark phase handling. Animal testing was conducted according to the “Principles of Laboratory Animal Care” (National Academy of Sciences, USA) and met all NIH and institutional animal care and use guidelines.

Drugs

The nicotine solution was prepared by mixing nicotine hydrogen tartrate (Sigma Chemical Company, St. Luis, MO) at a concentration of 6.84 mg/ml (as the salt) into a 0.9% saline solution. The pH of the nicotine solution was adjusted to 7.0 using sodium hydroxide. The nicotine solution was inserted into 14-day, 2 ml minipumps (Alzet, Cupertino, CA, USA), to allow continuous nicotine infusions at 5 μl/hr. The average weight of the nicotine-treated rats over the 14-day nicotine-delivery period ranged from 257 to 287 (M = 265, SD = 13) g. Thus, the free base nicotine dosage throughout the 14-day treatment period ranged from 1.04 to 0.93 (M = 0.98, SD = 0.04) mg/kg/day.

Benwell, Balfour, and Birrell (1995) reported that free-base nicotine doses of 0.25, 1.00, and 4.00 mg/kg/day delivered via 2 ml minipumps in rats produce stable plasma nicotine levels of about 9, 24, and 87 ng/ml, respectively, and that the relationship between nicotine dose and plasma nicotine concentration was strong (r = 0.92). Given that a 21 mg nicotine patch produces steady-state plasma nicotine concentrations between 12 and 23 ng/ml (Hukkanen, Jacob, & Benowitz, 2005), our average dose of 0.98 mg/kg/day may have produced plasma nicotine levels similar to the peak levels associated with a 21 mg nicotine transdermal patch.

Diet

The high-fat diet consisted of two parts ground chow and one part melted vegetable shortening (Hill Country Farms, San Antonio, TX) and was prepared fresh every third day. The high-fat diet was thoroughly mixed while hot, allowed to cool, and then remixed and stored at room temperature. The nutritional content of the high-fat diet was about 35.9% fat (by weight) and 16.3% protein, with a calculated energy content of 5.28 Kcal/g.

Apparatus

We used Wellman’s (2004) modified BioDAQ system with a stainless steel cover and a commercially available aluminum food cup (Lab Products, 50 mm high × 70 mm wide). Each of the 12 automated feeding cups was interfaced with a serial bus controller that reported meal pattern data to a computer. A proprietary software program (Research Diets, Inc.; New Brunswick, NJ) was used to record meal patterns. For our experiment, meals began as soon as activity was detected in the food hopper and were deemed terminated when there were no additional movements of the food hopper for 240 s (Castonguay, Kaiser, & Stern, 1986). The minimum meal amount was set at 0.05 g. Statistical analyses were conducted on the total meal number, average meal size (reported as duration, s), and total food intake (g) per 23-hr feeding cycle.

Procedures

The rats were acclimated to the colony room and maintained on standard rodent chow for 7 days before introducing the high-fat diet and the behavioral testing procedures. On the eighth day, the rats were exposed to the high-fat diet for 3 days. On the eleventh day, and for the remainder of the experiment, each rat was transferred to a BioDAQ feeding cage and offered 23 h per day access to a metal food cup filled with high-fat diet. Following 17 days of baseline measures, rats were surgically implanted with 2 ml osmotic minipumps filled with either nicotine or saline. Minipump filling and solution delivery were verified at the beginning and end of the experiment by weighing the minipumps.

At 1100 h of each test day, the software system was terminated and data for that day stored for subsequent analysis. The final volume of each drinking tube was recorded to the nearest ml. Each rat was weighed to the nearest gram and transferred to a separate clean holding cage with access to water, but not food. Each food cup was weighed to the nearest 0.1 g, refilled, reweighed, and returned to the test cage. Food spillage was collected on a sheet of paper placed beneath each cage and recorded to the nearest 0.1 g. The BioDAQ system was set to measure meal duration to the nearest 1 s, and the automated measure of total food intake was validated with a manual weighing of the food. Additionally, each gauge was calibrated and submitted to a “zero-meal” check (a verification that movement of the food cup did not alter the baseline weight reported for that cup). At the start of the dark phase (1200 h), each rat was returned to the feeding cage, and its feeding was monitored until the next morning at 1100 h.

Data Analyses

The overall design of the experiment included a between-group factor of Treatment (nicotine or saline) and a within-group factor of Day. To assess meal patterns prior to nicotine treatment, feeding behavior was analyzed across all 17 baseline days. For the nicotine treatment period, the 14 days following minipump implantation were analyzed. For the post-nicotine treatment period, the 7 days following minipump removal were analyzed. For each period, repeated measures analysis of variance (ANOVA) were computed using SPSS (IBM, St. Luis, MO) to compare dark phase, light phase, and 23-hr group differences for each of our three feeding measures: total food intake (g), meal number, and meal duration (s); as well as water intake (ml) and percent weight gain. To assess between treatment group differences on each day, statistically significant effects of treatment group were followed with independent samples t-tests. Difference probabilities less than 0.05 were considered to be statistically significant.

Consistent with previous research (Wellman, et al., 2005), regardless of nicotine or saline treatment, the rats consumed almost all of their food during the dark phase of the 23-hr, dark-light cycle. Given that the results for the dark phase and the 23-hr cycles were comparable, and no statistically significant effects were found during the light phase, we report only the results for the 23-hr cycle.

Results

Daily Meal Patterns Prior to Nicotine Treatment

A repeated measures ANOVA did not yield significant main or interaction effects for Treatment group or Day on food intake, meal number, or meal duration across the 17-day baseline period, Fs < 1.34, ps > 0.16. That is, our analyses of baseline feeding behavior suggest that rats prospectively assigned to the nicotine and saline treatment groups had acclimated to the BioDAQ system at similar rates and achieved stable and similar meal patterns prior to nicotine treatment.

Daily Meal Patterns During Nicotine Treatment

Continuous treatment with nicotine suppressed total food intake in rats, particularly during the initial phase of nicotine exposure (Figure 1A). Significant main effects of Treatment, F(1,10) = 7.71, p < 0.05, and Day, F(13,130) = 13.22, p < 0.001, were observed for total 23-hr food intake. Additionally, the interaction between Treatment and Day was statistically significant, F(13,130) = 3.07, p < 0.01. Post-hoc analysis revealed that 23-hr food intake was suppressed in nicotine-treated rats relative to saline controls, on days 2, 3, 4, 5, and 12 of treatment, ps < 0.05. Importantly, the effects of nicotine treatment observed during week 1 were also seen when statistically analyzed as a percentage of body weight. The daily food-intake difference between the two groups across days 2 to 5 was 4.5 g, which translates to nicotine-treated rats consuming about 18.2 (or 36.5%) less Kcal per day than saline-treated rats.

Figure 1.

Figure 1

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Effects of nicotine treatment on 23-hr high-fat diet meal patterns. (A) Across all treatment days, animals treated with nicotine showed decreases in total food intake, when compared to saline controls, primarily during the first week of treatment. (B) Animals treated with nicotine engaged in fewer daily meals than saline controls, persistently across all treatment days. (C) A significant interaction between treatment day and group suggests that nicotine-treated rats had significantly shorter meals than saline controls, but only during week 1 of nicotine treatment. Baseline (BL) indicates average score across all pre-treatment days. Plus sign (+) indicates main effect of group, pound sign (#) indicates interaction of group and day, and asterisk (*) shows group effect on given day, with p < 0.05.

Analyses of specific meal patterns suggest that the observed decrease in food intake early during nicotine treatment was driven by decreases in both meal numbers (Figure 1B) and meal duration (Figure 1C). Significant main effects on total 23-hr meal number were observed for Treatment, F(1,10) = 6.80, p < 0.05, and Day, F(13,130) = 2.78, p < 0.01. Although no significant interactions were observed, post-hoc treatment comparisons for daily meal numbers revealed that whereas nicotine-treated rats engaged in fewer total meals across 13 of the 14 treatment days, these differences reached statistical significance only on day 6, p < 0.05.

No significant main effect of Treatment was observed for meal duration; however there was a main effect for Day, F(13,130) = 2.65, p < 0.01, and a Treatment by Day interaction, F(13,130) = 3.43, p = 0.001. Post-hoc analyses of daily meal duration revealed significantly shorter average meal duration in nicotine- versus saline-treated rats only on treatment day 4, p < 0.05.

Daily Meal Patterns After Nicotine Treatment

Analysis of meal patterns after nicotine treatment revealed no compensatory increases in feeding behavior in nicotine-treated rats, relative to saline-treated rats (see Figure 2). That is, no statistically significant main or interaction effects were found, Fs < 2.14, ps > 0.06.

Figure 2.

Figure 2

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Effects of nicotine withdrawal on 23-hr high-fat diet meal patterns. No significant differences in food intake, meal number, or meal duration were seen between treatment groups, during the post-treatment period.

Water Intake

No statistically significant main or interaction effects were observed on 23-hr water intake during either the treatment or post-treatment periods, Fs < 1.33, ps > 0.21.

Body Weight Gain

Nicotine-treated rats gained less weight than saline-treated rats during the 14-day treatment period (Figure 3A). Analysis of daily percent body weight change from baseline (last day of baseline period) during the 14-day treatment period revealed significant main effects for Treatment, F(1,10) = 57.67, p < 0.001, and Day, F(13,130) = 107.30, p < 0.001, and a significant Treatment by Day interaction, F(13,130) = 6.19, p < 0.001. Post-hoc analysis revealed that nicotine-treated rats had lower weight gains relative to saline-treated rats beginning on treatment day 2 and continuing throughout treatment day 14, ps < 0.05. The interaction revealed that saline- but not nicotine-treated rats consistently gained weight throughout the 14-day treatment period. Weight gain in nicotine-treated rats was particularly suppressed from treatment days 1 to 4 and days 11 to 14 (see Figure 3A).

Figure 3.

Figure 3

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Effects of nicotine treatment and withdrawal on body weight gain. (A) Nicotine-treated rats had significantly reduced weight gain beginning on day two and continuing throughout treatment, relative to saline controls. These reductions were particularly evident during week 2 of treatment. (B) While nicotine-treated animals show slightly more weight gain during the post-treatment period than saline controls, these differences are not significant. Baseline (BL) indicates day prior to start of nicotine treatment (3A) or day prior to start of the post-nicotine period (3B). Plus sign (+) indicates main effect of group, pound sign (#) indicates interaction of group and day, with p < 0.05. Asterisk (*) shows group effect on given day with p < 0.05, while arrow (^) shows given day effect with p < 0.001.

Analyses of daily percent body weight gain post-treatment (relative to last day of treatment period) revealed no significant Treatment or Treatment by Day effects, Fs < 2.64, ps > 0.14; however, a main effect for Day was observed, F(6,60) = 39.76, p < 0.001, revealing that all animals gained weight during the post-treatment period (Figure 3B).

Discussion

Investigators studying the effects of smoking and smoking cessation on weight regulation and feeding behavior have developed animal models of nicotine administration in which nicotine is delivered either intermittently (through acute injections) or continuously throughout the day (via subcutaneously implanted osmotic minipumps). It has been proposed that intermittent administration of nicotine provides an approximation for the nicotine dosing pattern of regular smokers, whereas continuous nicotine administration provides a better model for understanding nicotine delivered via transdermal nicotine patches (see Bellinger, et al., 2003). Similarly, investigators have proposed that maintaining rats on a high-fat diet, rather than regular chow, provides a better model for the effects of human nicotine-use on food consumption and weight gain (see Wellman et al., 2005). Notwithstanding the fact that the nicotine patch and subcutaneous minipumps utilize two different nicotine delivery methods, we believe the current study is the first to examine the effects of continuous nicotine administration on feeding patterns and weight changes on rats maintained on a high-fat diet, and while using a nicotine dose that is comparable to the dosage delivered by nicotine patches in humans. Our investigation also extends previous research demonstrating that nicotine delivered intermittently via subcutaneous injections differentially changes feeding and weight gain patterns in rats maintained on either a high-fat or regular chow diet (Wellman, et al., 2005).

Overall, we found that continuous administration of nicotine (0.98 mg/kg/day for 14 days) subcutaneously infused in male rats solely sustained on a high-fat diet decreased total food intake and body weight gain. Our findings are consistent with other findings showing that nicotine produces anorectic effects (Caggiula, Epstein, & Stiller, 1989; Grunberg, Bowen, Maycock, & Nespor, 1985; McNair & Bryson, 1983). Nicotine induced decreases in daily high-fat diet food intake and weight gain were also reported by Wellman et al. (2005). In Wellman’s study, nicotine was intermittently injected (1.4 mg/kg/day, free base) across 14 days in high-fat diet fed rats and produced a marked decrease in food intake, particularly during the first 7 days of treatment. In our study, we found that continuous nicotine infusions also suppressed 23-hr food intake, particularly during the first week of treatment.

Interestingly, while meal patterns for a high fat-diet were attenuated following both intermittent (Wellman, et al., 2005) and continuous nicotine exposure, the specific effects of these distinct treatment regimens on meal patterns were quite distinct. In our study the significant reduction of food intake observed appeared to be driven, in part, by small yet consistent decreases in the number of meals an animal engaged in during treatment days. Specifically, rats receiving nicotine continuously via minipumps consistently engaged in fewer daily meals in all but one of the 14 days of treatment (although post-hoc analyses revealed a statistically significant difference only on day 6). Conversely, reductions in food intake following intermittent nicotine exposure in the Wellman study appeared to be driven, in part, by a large, yet transient decrease in meal numbers during week 1 of treatment. That is, whereas rats injected with a small nicotine dose appeared to rapidly develop behavioral tolerance to nicotine’s immediate and marked attenuating effect on high-fat meal number (as seen in Wellman et al.), rats that received nicotine continuously via minipumps appeared to experience a subtle decrease in daily meals that remained moderately depressed throughout the 14-day nicotine treatment period. Together, these observations suggest that intermittent, but not continuous nicotine administration is conducive to the development of behavioral tolerance to nicotine’s anorectic effects on meal number (for a more complete analysis on the parameters that control contextual and associative tolerance to nicotine’s effects in rats, see Cepeda-Benito et al., 2006; Cepeda-Benito, Reynoso, & Erath, 2000).

Another distinction regarding meal patterns was that whereas Wellman et al. (2005) reported nicotine induced decreases in average meal size (reported as kCals consumed) consistently throughout most days of the 14-day intermittent nicotine treatment period, nicotine induced decreases in meal size (reported as meal duration) in our study were less persistent, and evident only in the first week of nicotine infusion. Taken together, these findings suggest that intermittent and continuous nicotine deliveries differentially foster tolerance development to the anorectic effects of nicotine on specific feeding patterns. That is, while intermittent injections might promote the development of behavioral tolerance to nicotine’s anorectic effects on high-fat-meal number, continuous nicotine administration promotes the development of tolerance to nicotine’s anorectic effects on meal size (Caggiula et al., 1991).

Overall, post-treatment meal pattern differences between nicotine- and saline-treated rats in our study were minimal and nonsignificant. The absence of hyperphagia on a high-fat diet following nicotine cessation does not align with the results of previous studies, which have found post-nicotine treatment increases in regular-chow feeding (Levin, et al., 1987; Miyata, et al., 2001; Wellman, et al., 2005). Therefore, if previously reported compensatory increases in food intake after nicotine cessation underlie the expression of tolerance to nicotine’s hypophagic effects (see Caggiula, et al., 1989), it could be that rats maintained on a high-fat diet are more adept at regulating or inhibiting compensatory-based tolerance responses, particularly following continuous nicotine treatment. Understanding the adaptive changes in high-fat diet meal patterns following nicotine exposure will be important for the development of tobacco cessation treatment strategies for individuals concerned about body weight, as different meal patterns have been suggested to reflect distinct psychological processes driving feeding behavior (see Bellisle, 1989; Mendez, Maidment, & Murphy, 2016 for further discussion).

Regarding nicotine’s effects on weight, our results also replicated the findings reported by others (McNair & Bryson, 1983; Rupprecht, Smith, Donny, & Sved, 2016; Wellman, et al., 2005). We found that nicotine consistently suppressed body weight throughout the duration of the 14-day nicotine treatment. Surprisingly, however, no compensatory increases in weight gain were observed in nicotine-treated rats, relative to saline-treated rats, following cessation of nicotine treatment. Interestingly, while the absence of feeding behavior differences was synchronous with the absence of weight-gain differences between the two treatment groups during the post-treatment period, the suppression of weight gain during the treatment phase cannot be entirely accounted for by differences in caloric intake between the two groups. That is, we found that differences in daily, total food intake (in grams) were predominantly observed during the first week of nicotine treatment, while weight gain in nicotine-treated rats was particularly stunted during the second week of treatment. This pattern of results was partially congruent with the findings of a recent study with male rats demonstrating that self-administered nicotine decreased body weight independently of food intake (Rupprecht, et al., 2016). Rupprecht et al. attributed their finding largely to the utilization of a 1-hr self-administration procedure that resulted in a relatively small, nicotine dosage (0.2 to 0.8 mg/kg/day). They also suggest that the dissociation between energy intake and weight gain was observed because nicotine-induced hypophagia might be expressed only when plasma nicotine levels remain elevated longer than that which is achievable by a 1-hr self-administration session. Conversely, our results suggest that the dissociation between energy intake and weight gain can indeed be observed with extended nicotine exposure.

Nicotine may produce acute aversive or ill effects in many species, including rats (Fowler & Kenny, 2014); and these effects may be potentiated by distinctive environmental cues, through classical conditioning (Caggiula, et al., 1989; Epstein, Caggiula, & Stiller, 1989). Thus, one potential confound in our study is that illness and classically conditioned aversive responses may have suppressed food intake in the nicotine-treatment group. In one study with humans, however, non-smokers receiving continuous infusions of nicotine from 15 mg transdermal patch reported only transient feeling of nausea, which subsided within the first hour of exposure (although, non-smokers exposed to a high dose, 30 mg nicotine transdermal patch reported experiencing severe illness within the first 8 hours of nicotine exposure and were consequently removed from the study, Srivastava, Russell, Feyerabend, Masterson, & Rhodes, 1991). Additionally, if acute illness from nicotine exposure was severe enough to induce suppression of food intake across nicotine treatment days, it is likely that we would have also observed significant decreases in water intake across this period (which we did not find). Regarding the role of environmental cues, we propose that our nicotine-treated rats did not learn a nicotine-induced conditioned food-aversion response, as rats were extensively habituated to the high-fat diet (20 days) and the experimental context and procedures (17 days), before the introduction of nicotine (Best, 1975; Bouton, 1993).

Another important limitation of our investigation is that we did not study female rats, even though smoking effects on appetite and weight suppression are a greater obstacle to smoking cessation in women than men (Reynoso, Susabda, & Cepeda-Benito, 2005). This shortcoming hinders the generalization and limits the comparability of our findings to the existent, but scant research on the effect transdermal nicotine patches on eating and weight gain (see Allen, Kleppinger, Lando, & Oncken, 2013; Hughes & Hatsukami, 1997). Finally, while transdermal patches and subcutaneous minipumps both deliver nicotine continuously, they do deliver it differently (i.e. transdermally versus subcutaneously). Although we believe that the minipump design offers an improved and reasonably adequate animal model for the study of the effects of nicotine transdermal patches in humans, we recognize that we do not provide evidence of the relative equivalence of these two delivery methods. Therefore, we can only deduce, not prove, that our average nicotine dose of 0.98 mg/kg/day via minipump delivery produces sustained blood plasma levels in male rats that are similar or slightly higher than those produced by a 21 mg nicotine transdermal patch in humans (Benowitz, Hukkanen, & Jacob, 2009; Benwell, et al., 1995).

The ability of nicotine to suppress appetite and the belief that cessation of smoking will lead to weight gain is a major motivator for initiation, maintenance, and relapse of cigarette smoking. The nicotine transdermal patch is a nicotine-delivery system that gradually releases small amounts of nicotine to reduce smoking cravings and help the smoker stay abstinent (Cepeda-Benito, Reynoso, & Erath, 2004). In the present study, continuously delivered nicotine to male rats via osmotic minipump decreased food intake, meal patterns, and weight gain during treatment, without any subsequent, compensatory increases in feeding behavior or weight gain. Therefore, notwithstanding the limitations noted above, we speculate that nicotine transdermal patch therapy could be a particularly effective treatment approach for smokers concerned with weight gain following smoking cessation. The current study may represent a valid animal model of transdermal nicotine replacement therapy; however, future efforts should continue to improve and refine the methodology to make the rat model more comparable and relevant to humans (for example, by using female rats, increasing the range of daily nicotine dosages, or following intermittent nicotine exposure with continuous exposure). More refined research will be necessary to elucidate if, and under which conditions, transdermal nicotine replacement therapy becomes an advantageous approach for smokers seeking abstinence.

Public Significance.

Using male rats maintained on a high-fat diet, this study found that weight gain was attenuated throughout 2 weeks of continuous nicotine administration, despite the fact that decreases in daily number of meals, average duration of each meal, and overall daily food intake were only observed during the first week of treatment. These findings support the need to investigate the extent to which transdermal patch therapy may impact smoking cessation outcomes via reductions in energy intake and weight gain.

Acknowledgments

The NIH (through T32MH065728 and R01DA013188) provided funding for conducting these experiments. NIH had no other role in these experiments.

We thank Gregory Mendez and Shane Clifford for their support in conducting these experiments.

Footnotes

All authors contributed in a significant way to the manuscript and have read and approved the final manuscript.

All authors have reviewed the manuscript, approve it for publication, and report no conflicts of interest.

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