Effects of nicotine on body weight and food consumption in rats

Recent human and animal studies have found that cigarette smoking or nicotine administration is accompanied by decreased consumption of sweet-tasting, high caloric foods. Cessation of smoking or nicotine is accompanied by increased consumption of these foods. Changes in consumption of these specific foods may partially account for the inverse relationship between smoking or nicotine and body weight. The present research was designed to determine whether consumption of nonsweet food is affected by nicotine and whether continuous access to only nonsweet foods attenuates the body weight changes associated with nicotine administration and cessation of nicotine administration. Alzet miniosmotic pumps were implanted SC to administer saline or three different concentrations of nicotine to male Sprague-Dawley albino rats for 2–3 weeks. Two studies on a total of 80 rats found an inverse dose-response relationship between nicotine administration and body weight without changes in bland food or water consumption. After cessation of nicotine administration, there were no differences in food consumption or body weight changes between groups. The effects of nicotine on body weight, both during and after drug administration, were attenuated in comparison to the results of studies that provided sweet-tasting foods.     

Effects of nicotine on body weight and food consumption in female rats

Women often report that they smoke cigarettes to avoid weight gains and that they relapse after abstaining from tobacco because of weight gains. Men also report these concerns but to a lesser extent. This gender difference may reflect sociological and cultural pressures about physical appearance, or it may reflect sex differences in the effects of nicotine. The present research was designed to examine the effects of nicotine administration and cessation of nicotine on body weight, food consumption, and water consumption. Alzet miniosmotic pumps were implanted SC to administer saline or three different concentrations of nicotine to female Sprague-Dawley rats for 17 days. This paradigm has been used in previous studies of nicotine and body weight in male rats. Animals were used as subjects to avoid cultural factors and cognitive concerns about body weight. Nicotine administration decreased normal body weight gains and cessation of nicotine was accompanied by significant increases in body weight compared to controls. In contrast to previous studies of male rats, the nicotine-related changes in body weight were accompanied by changes in bland food and water consumption. These findings indicate that females are more sensitive than males to the effects of nicotine on body weight and feeding during and after drug administration.     

Effects of nicotine on body weight in rats with access to “Junk” foods

The present experiment examined effects of nicotine on body weight of male and female rats when Oreo cookies, potato chips, laboratory chow, and water were available. Body weight and eating behavior were measured for 17-day periods before, during, and after nicotine or saline administration. There was an inverse relationship between nicotine and body weight. These effects were paralleled by changes in consumption of sweet foods. There were no effects of nicotine on salty or bland food consumption. Excessive gains in body weight after cessation of nicotine administration were greater for females than for males.     

The role of physical activity in nicotine's effects on body weight

The present study examined the effects of chronic nicotine administration and cessation of nicotine administration on body weight and 24-hour physical activity of rats. There was a significant, inverse, dose-effect relationship between nicotine administration and body weight. Cessation of nicotine was accompanied by increased rates of body weight gain compared to controls. The changes in body weight during nicotine administration could not be explained by changes in physical activity. However, decreases in physical activity after cessation of nicotine appeared to contribute to post-drug body weight increases. These findings have implications for weight control after cessation of cigarette smoking.     

Effects of initial body weight on anorexia and tolerance to fenfluramine in rats

The initial anorexia and development of tolerance to dl-fenfluramine was examined in rats with graded pretreatment body weight losses. Fenfluramine strongly attenuated food intake on the first test day in all weight groups and the magnitude of the initial anorexia did not differ between groups. The time course of anorectic tolerance was also similar in each of the groups. The results do not support a strict "set point" hypothesis according to which the tolerance to fenfluramine anorexia is an artifact of decreasing body weight and/or concurrently increasing relative food deprivation.     

Effects of chronic haloperidol treatment on ingestive behaviour and body weight regulation in the rat

This study was designed to investigate the effects of two doses of haloperidol on body weight, food spillage and food and water intake using rats as subjects. In the first experiment, 12 male Wistar albino rats were observed in individual cages for 30 days, six receiving a daily injection of haloperidol (1 mg/kg IP in 1 ml/kg isotonic saline), while the other six received a control injection of isotonic saline in the experimental phase. In the second experiment, 12 rats were observed for 9 days in individual cages, six receiving a daily injection of 10 mg/kg haloperidol in 4 ml/kg isotonic saline in the experimental phase. In both studies, haloperidol depressed food intake and food spillage. With the lower dose of haloperidol (1 mg/kg), body weight was not depressed until several days after a significant reduction of food intake had been recorded. With the higher dose (10 mg/kg), body weight was depressed during the first 24 h, but quickly returned to normal, although food intake remained depressed. It is suggested that haloperidol may have a limited facilitatory effect on body weight.     

The effect of chronic nicotine treatment on nicotine-induced seizures

Tolerance to nicotine occurs in mice after its chronic administration. This tolerance is accompanied by an up-regulation of nicotinic receptors as assessed by the binding of (³H)-nicotine and -(¹²⁵I)-bungarotoxin (BTX). Past studies (Marks et al. 1983, 1986) have shown that the increase in BTX binding sites is most evident in the hippocampus. Mice that have a greater concentration of BTX binding sites in the hippocampus are more sensitive to the convulsant effects of nicotine (Miner et al. 1984, 1985, 1986). In the study reported here, mice from the DBA/2Ibg strain, which are relatively resistant to nicotine-induced seizures and have a relatively low concentration of hippocampal BTX binding sites (Miner et al. 1984), were infused with nicotine for 10 days. At various time points after cessation of nicotine administration, sensitivity to the convulsant effects of nicotine was assessed. Mice were then sacrificed and BTX binding was determined in three regions: cortex, midbrain, and hippocampus. As expected, chronic treatment with nicotine resulted in a significant up-regulation of BTX binding sites in the hippocampus. Chronic nicotine treatment also produced significant tolerance to nicotine-induced seizures. Hippocampal BTX binding sites returned to control levels within 2 days after stopping nicotine infusion, whereas tolerance was not lost until 5 days. These results suggest that factors other than the number of hippocampal BTX binding sites affect nicotine-induced seizure sensitivity, at least following chronic nicotine treatment.     

Sex differences in nicotine's effects on consummatory behavior and body weight in rats

Nicotine administration and cessation have greater effects on body weight and eating behavior in female than in male rats. These generalizations are based on studies of body weight and eating behavior for 2–3 week periods before, during, and after nicotine administration. Therefore, the sex differences may reflect differences in sensitivity to nicotine or simply differences in the time course of nicotine's effects. The present research was designed to replicate these previous studies and to examine long-term effects of nicotine cessation on body weight. Nicotine or saline was administered SC to female and male Sprague-Dawley rats for 16 days. Body weight, food consumption, and water consumption were measured before, during, and after nicotine administration. In addition, body weight was measured for 4 months after cessation of nicotine. There was an inverse relationship between nicotine and body weight. Also, there was an inverse relationship between nicotine and general consummatory behavior for females but not for males. The body weight of females that had received nicotine were indistinguishable from controls up to 4 months after cessation of nicotine. The body weight of males that had received 12 mg nicotine per kg per day remained lower than controls.This work was supported by the USUHS Protocol No. C07223. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences     

Chronic and acute tolerance to the heart rate effects of nicotine

Tolerance to the effects of nicotine reflects physiological adaptation and may be related to the development and persistence of smoking behavior. However, little is known about tolerance to nicotine in humans,in part due to methodological difficulties. This study examined chronic and acute tolerance to nicotine's effect on heart rate(HR) using a measured-dose nasal spray nicotine procedure. Eight Light smokers (<20 cigarettes per day) and ten Heavy smokers ( 20 per day) participated in two sessions on separate days in which they received four administrations (1 every 20 min) of a high nicotine dose (15 g per kg body weight, equivalent to a typical cigarette) or a low nicotine dose (7.5 g/kg) while HR was monitored during the 5 min following each administration. Compared with Light smokers, Heavy smokers had significantly smaller HR responses to the high dose, indicating greater chronic tolerance, but there was no difference between groups in response to the low dose. Acute tolerance to HR response across the four 5-min periods was not observed with either dose. However, subsequent examination of HR response in the first 2 min following each dose administration did suggest acute tolerance, particularly for the low dose, as this more acute HR response declined from the first to the last administration. These results demonstrate chronic and, to a lesser extent, acute tolerance to HR effects of nicotine and suggest that both may be dose dependent.     

Behavioral effects of pergolide mesylate on food intake and body weight

In a crossover design experiment, pergolide mesylate significantly suppressed food intake and body weight in spayed female rats. Inhibition of food intake by a constant dose of pergolide progressively diminished with repeated administrations. Pergolide continued to suppress body weight with no indications of tolerance. When pergolide was discontinued, body weight increased sufficiently to compensate for the loss and failure to gain during drug treatment. A second experiment investigated the observation that animals injected first with vehicle showed greater anorexia when subsequently injected with pergolide than did animals injected first with pergolide. In addition, tolerance was further assessed by administering on two occasions a higher dose of pergolide. Following chronic pergolide treatment, this dose was insufficient to reinstate anorexia; however, after a period of abstinence, this dose produced anorexia comparable to that observed at the beginning of pergolide treatment. Due to pergolide mesylate's action as a postsynaptic dopamine agonist, a dopaminergic neural system is implicated in pergolide induced anorexia.     

Adrenalectomy reverses chronic injection-induced tolerance to nicotine

A recent study from our laboratory has demonstrated that C57BL/6 male mice that are chronically injected with nicotine develop a profound tolerance to nicotine that is not associated with changes in brain nicotinic receptors. We have proposed that alterations in the secretion of corticosterone (CCS) may regulate tolerance development in chronically injected animals. In the present study we have directly tested this hypothesis. Female DBA/2 mice were injected three times each day for 12 days with saline or 2 mg/kg nicotine. Blood samples were collected at various time points during the course of treatment and plasma CCS levels were determined. The animals were divided into two groups following the last injection on day 12. The first group of animals was tested for nicotine-induced release of corticosterone on day 13 of the experiment and then sacrificed. The brains of these animals were subsequently used to measure nicotinic receptor binding. The second group of animals was adrenalectomized (ADX) or sham-operated on day 13 of the experiment and tested for nicotine sensitivity on day 14 of the experiment. Plasma CCS levels were significantly elevated in animals that were chronically injected with nicotine (versus saline controls) by the fourth day of the experiment. Chronic nicotine-injected animals were tolerant to nicotine-induced CCS release. Animals that were chronically injected with nicotine and sham-operated were tolerant to acute nicotine challenge; however, tolerance to nicotine was not detected in ADX animals. These data support the hypothesis that the capacity to release CCS may underscore the expression of tolerance to nicotine in chronically injected animals.     

The importance of sweet taste and caloric content in the effects of nicotine on specific food consumption

There is an inverse relationship between nicotine and body weight that has been partially explained by changes in consumption of sweet-tasting high calorie foods. The present research was designed to determine the relative importance of sweet taste and caloric content in the effects of nicotine on specific food consumption and body weight. Alzet miniosmotic pumps were implanted SC to administer saline or two different concentrations of nicotine to 63 male Sprague-Dawley rats for 17 days. Three experiments were performed in which animals had access to two foods, a nonsweet low calorie food and a target food (sweet low calorie, sweet high calorie, or nonsweet high calorie). Body weight, food consumption, and water consumption were measured daily before, during, and after drug administration. In all three experiments, there was an inverse relationship between nicotine and body weight. Both sweet taste and caloric content were involved in the effects of nicotine on specific food consumption and body weight, but sweet taste was particularly important. In fact, the effects of nicotine on body weight were attenuated when sweet-tasting low calorie foods were available. These findings have implications for controlling body weight gains after cessation of cigarette smoking.     

Use of phenylpropanolamine to reduce nicotine cessation induced weight gain in rats

The present study was conducted to determine if phenylpropanolamine (PPA) administered during the first week of nicotine termination could reduce or eliminate the body weight rebound which accompanies nicotine cessation. Sprague-Dawley rats were administered nicotine for 2 weeks after which they received either PPA or saline for 1 week. Control animals received saline during both drug periods. Body weight, food consumption, and water consumption were measured daily before drug, during nicotine and PPA administration, and for 14 days after PPA administration. In contrast to animals receiving saline upon termination of nicotine, animals receiving PPA did not gain weight at an accelerated rate. Termination of PPA did not result in a body weight rebound. To the extent that these results generalize to humans, they suggest that PPA could be used to reduce or eliminate postcessation weight gain in smokers who stop smoking.     

Schedule induced self injections of nicotine with recovered body weight

In a recent series of experiments we have shown that high rates of self injection of nicotine were acquired when rats are at 80% body weight on an FT-1 min food delivery schedule. This rate was significantly higher than that of rats at reduced or normal body weightwithout food delivery schedules or that of rats injecting saline under three parallel control conditions. In the present experiment naive rats were trained to acquire nicotine self injection at 80% body weight with an FT-1 min food delivery schedule. These rats maintained their self injection rates after they were allowed to regain free feeding body weight. The data indicate that once nicotine intake behavior is established it can be maintained with changing nutritional factors.     

Acute tolerance to the locomotor stimulant effects of nicotine in the rat

Studies of peripheral nicotinic receptors have revealed that, after an initial agonist action, the receptors remain inhibited either through continued depolarization blockade due to continued presence of the agonist or through a brief inactivation of the receptor following its activation. If a similar phenomenon occurs at central nervous system nicotinic receptors, then behavioral responses to nicotine should exhibit an acute tolerance (tachyphylaxis). Groups of rats were given either saline or 0.2 mg/kg nicotine injections at 20-min intervals in photocell activity cages. A progressive decline in the locomotor responsiveness to nicotine was observed. The time course of this acute tolerance was observed in other rats given initial 0.2 mg/kg nicotine injections followed at differing time intervals by second 0.2 mg/kg nicotine test injections. The secondary antagonism to nicotine's locomotor stimulant effects was maximal at 45–60 min and recovered by 90–120 min. The locomotor response to 0.2 mg/kg nicotine test injections was observed in other rats following exposure to 1.8 mg/kg nicotine, and the behavioral response was attenuated for more than 5 h.     

The effects of chronic treatment with d-amphetamine on food intake,body weight,locomotor activity and subcellular distribution of the drug in rat brain

Female Wistar rats were treated chronically with d-amphetamine sulphate in drinking water. The concentrations of amphetamine were 0.01%, 0.02%, 0.03%, 0.04% and 0.05% in the 1st, 2nd, 3rd, 4th, and 5th week of treatment. The consumed doses of amphetamine increased from 16 mg/kg on the first day up to 90 mg/kg on the 36th day of treatment. The effects of chronic treatment with amphetamine on food intake, body weight and locomotor activity of rats were determined. The rats developed tolerance to the overall toxicity and to the anorexigenic effect of maphetamine. No tolerance to the effects of the drug on body weight and locomotor activity was observed. The concentration of H³-d-amphetamine in brains of chronically treated rats is significantly higher than in controls. No difference in the pattern of distribution of radioactivity among the subcellular fractions of rat brain was observed between control and chronically treated groups. The relationship between developmen tof tolerance and the concentration of amphetamine in the brain is discussed.     

Modification of the behavioral effects of phencyclidine by repeated drug exposure and body weight changes

In the first experiment, the effects of phencyclidine (PCP) on intake of sweetened condensed milk by rats were compared before and during a period of repeated daily injections of PCP or saline. A shift to the right in the PCP dose-effect function was found in rats receiving daily PCP injections indicating tolerance development to the effects of PCP on milk intake. The dose-effect function of PCP was shifted to the right in animals receiving daily saline as well. However, when body weight changes were controlled for in this groups of animals, the effects of PCP were the same as they had been initially, implicating body weight as a determinant of the behavioral effects of PCP. In the second experiment, a direct comparison of the behavioral effects of PCP in high- and low-weight animals revealed diminished effects of PCP in high-weight animals. When these animals were treated with ³H-PCP, brain total radioactivity as well as ³H-PCP in the high-weight animals were significantly lower than those in the low-weight animals.     

Improvement of performance on an attention task with chronic nicotine treatment in rats

Male, Holtzman rats were trained extensively on an attention task which required them to respond with a single lever-press to a very short, variably presented stimulus for food reinforcement, but which also required them to inhibit inappropriate responses. After performance had stabilized, two groups were treated with either nicotine base (100 g/kg, s.c., t.i.d.) or saline for 4 weeks. The groups were crossed-over so that the first received saline and the second nicotine for an additional 4 weeks. A 3-week saline recovery period followed. Rats were tested on the attention task daily through all periods. Analysis of the data indicated that independent of the treatment-order, rats performed more efficiently under nicotine treatment than under saline conditions. The improvement in performance was most notable in the reduction of inappropriate responding during chronic nicotine treatment. The significance of the behavioral changes in relation to proposed nicotine-induced neurophysiological changes and the two-arousal hypothesis are discussed.This work was supported by a Grant from the Council for Tobacco Research, U.S.A.Portions of the data in this paper were presented at the Meeting of the American Society for Pharmacology and Experimental Therapeutics, Burlington, Vt., August, 1971.     

Associative and behavioral tolerance to the analgesic effects of nicotine in rats: tail-flick and paw-lick assays

Rationale Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine.Objective We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine.Methods and results Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test.Conclusions The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.     

The effects of long-term nicotine treatment on locomotion,exploration and memory in young and old rats

To assess the effects of long-term treatment with nicotine on several behavioral measures (locomotor activity, exploratory efficiency, habituation, short-term and long-term memory) of young (5 months) and old (22 months) rats in a hexagonal tunnel maze, nicotine was added to the drinking water (0, 20 or 50 mg/l) for up to 131 experimental days. With the exception of effects on exploratory efficiency, young and old rats did not differ in their response to the drug. Nicotine decreased body weight throughout the experiment. Nicotine treatment reduced water intake during the first 30 min of the daily 4.5 h access to drinking water. Nicotine increased locomotor activity throughout the experiment. When nicotine treatment was discontinued during a 7-day withdrawal period, locomotor activity immediately dropped to control values. Intertrial habituation was not affected by nicotine. Long-term nicotine treatment had an attenuating effect on exploratory efficiency in young rats; however, the drug did not influence performance in tasks measuring spatial memory. Finally, age increased weight, decreased locomotor activity and impaired exploratory efficiency and short-term memory. Age, however, did not affect the performance of the long-term memory task.