Evaluation of Sex Differences in the Elasticity of Demand for Nicotine and Food in Rats

Abstract

Introduction

Animal studies can inform policy regarding nicotine levels in tobacco products and e-cigarette solutions. Increasing the price of nicotine-containing products decreases their use, but it is unknown how the relationship between price and consumption is affected by both sex and nicotine dose.

Methods

A behavioral economics procedure was used to determine the demand elasticity for nicotine in male and female rats. Demand elasticity describes the relationship between price and consumption. A high level of elasticity indicates that consumption is relatively sensitive to increases in price. The rats self-administered a low dose (0.01 mg/kg/inf) or a standard dose (0.03 mg/kg/inf) of nicotine for 9 days under a fixed-ratio (FR) 1 schedule. Then the price (FR schedule) of nicotine was increased, and a demand analysis was conducted. A similar study was conducted with palatable food pellets.

Results

There were no sex differences in nicotine or food intake under the FR1 schedule. However, demand for 0.03 mg/kg/inf of nicotine was more elastic in females than males. Demand for 0.01 mg/kg/inf of nicotine and food was more elastic in males than females.

Conclusions

These findings indicate that there are no differences in nicotine and food intake between males and females when the price is low. When the price of nicotine or food is increased, males maintain their old level of intake longer than females when they have access to a standard dose of nicotine, and females maintain their intake longer when they have access to a low dose of nicotine or food.

Implications

This behavioral economics analysis indicates that there is no sex difference in nicotine intake when the price of nicotine is low. Increasing the price of nicotine decreases nicotine intake in a dose- and sex-specific manner. Males maintain their old level of intake longer when they have access to a standard dose of nicotine and females when they have access to a low dose. This has implications for tobacco regulatory policy. In a regulatory environment where only low nicotine-containing products are allowed, increasing the price of nicotine products may lead to a greater decrease in nicotine use in males than females.

Introduction

Tobacco is highly addictive and it has been established that nicotine is the main psychoactive component in tobacco smoke.¹ Tobacco smoke also contains compounds that enhance the reinforcing properties of nicotine and have reinforcing effects independent of nicotine.² Animal studies have shown that nicotine causes dependence and studies with tobacco users show that lowering the nicotine content in cigarettes leads to withdrawal.^3–5 Smoking cessation causes anxiety, dysphoria, cognitive impairments, and somatic withdrawal symptoms.⁶ The relapse rate is very high when people try to quit smoking. Without smoking cessation treatment, only 3–5% of smokers can maintain abstinence for 6–12 months.^7,8

Tobacco control policies reduce the likelihood of smoking initiation and encourage smoking cessation. One of the most successful methods to decrease smoking has been to increase the price of cigarettes.⁹ Increasing the price of cigarettes decreases demand for cigarettes.^10,11 It has also been suggested that decreasing the nicotine content in cigarettes will decrease smoking.¹² Indeed, it has now been shown that reducing the nicotine content in cigarettes leads to a decrease in the use of cigarettes.^13,14 Therefore, both an increase in the price of cigarettes and a reduction in the nicotine content decrease demand for cigarettes. The U.S. Food and Drug Administration has been authorized to reduce nicotine levels in tobacco, and therefore, research into the relationship between nicotine dose, price, and intake is essential.¹⁵

Price can refer to monetary cost or nonmonetary value.¹⁶ In animal studies, price often refers to the amount of effort that is required to obtain a reinforcer (i.e., FR schedule).¹⁷ The vast majority of nicotine self-administration studies have been conducted with male rats and the price (FR schedule) of nicotine is usually low.^18–20 Recently developed behavioral economics procedures provide insight into changes in drug intake in response to a change in the price of drugs.²¹ Traditional FR studies with rodents have provided insight into how environmental factors or treatments affect nicotine intake when the price of nicotine is low. However, in the real-world, nicotine products are expensive, and prices continue to be increased to curb its use. Demand analysis provides insight into the elasticity of demand, which is the change in drug intake relative to the change in price.¹⁷ Goods or drugs with high elasticity of demand are more sensitive to price increases than goods with a low elasticity of demand. Demand analysis also provides insight into the price (Pmax) at which the response output is maximal (Omax).¹⁶ In animal studies, in which rewards are earned by operant responding, Pmax is the FR schedule at which the animals have their highest total number of lever presses (Omax). When the price is increased beyond Pmax, the total response output decreases.

The rat nicotine self-administration model was developed to study the neurobiological mechanisms underlying tobacco use.¹⁸ Rats readily learn to self-administer nicotine, and plasma nicotine and cotinine levels in rats are similar to those in smokers.²² Nicotine self-administration in rodents leads to a plasma nicotine level of 20–50 ng/mL, and plasma nicotine levels in smokers are in the same range.^22–24 Nicotine self-administration models have played a critical role in elucidating the neuronal and molecular mechanisms that mediate smoking in humans.^25,26 A recent study investigated how a reduction in the dose of nicotine affects nicotine self-administration in male and female rats.²⁷ Decreasing the dose of nicotine decreased nicotine intake, but there was no difference in the elasticity of demand for nicotine between males and females. A study with male rats showed that the self-administration of nicotine is more sensitive to nicotine dose reductions than to nicotine price increases (FR schedule).²⁸ Therefore, the goal of the present study was to further investigate the relationship between the price of nicotine and nicotine intake by increasing the effort required to obtain an infusion with a low (0.01 mg/kg/inf) or standard (0.03 mg/kg/inf) dose of nicotine. Demand analysis is considered a more sensitive procedure to measure the reinforcing properties of drugs than the traditional progressive ratio (PR) procedure. In contrast to the PR procedure, demand curve analysis provides insight into the behavior of the animals at multiple price points, whereas the PR procedure only provides insight into one price point, namely, the breakpoint.²¹ Also, in contrast to the PR procedure, demand curve analysis adjusts for difference in intake when the response requirements are very low and therefore baseline differences in drug intake do not affect the elasticity of demand.²¹

There is extensive evidence for sex differences in nicotine self-administration in rodents and tobacco use in humans (for comprehensive reviews, see refs. ^29–31). Female tobacco users have more difficulty maintaining long-term abstinence, and non-nicotine factors play a greater role in tobacco use in females.^31,32 Female rats tend to have higher levels of nicotine intake than males.³⁰ In the present studies, male and female rats self-administered 0.01 or 0.03 mg/kg/inf of nicotine for 9 days and then the price of nicotine was raised by increasing the FR schedule. A demand curve analysis was conducted to determine the elasticity of demand (α), intensity of demand (Q₀), Pmax, and Omax. An additional study was done to assess sex differences in the demand for chocolate-flavored food pellets. There is evidence that females like chocolate more than males and also crave chocolate more.³³ Previous studies have also suggested that it is more difficult for females than males to quit smoking.³⁴ It was therefore hypothesized that the demand for nicotine and food is more elastic in males than females. This would indicate that females maintain their old level of nicotine and food intake longer than males when the price is increased.

The studies described here can affect tobacco policy. Previous studies have mainly explored sex differences in nicotine intake when the price of nicotine is low. These new studies describe the relationship between nicotine intake and price at different nicotine dose levels in males and females. These studies suggest that increasing the price of nicotine decreases nicotine intake and demand in a dose- and sex-dependent manner. Males are more resistant to price increases at a regular dose and females are more resistant to price increases at a low dose.

Methods

Animals

Male and female Wistar rats (males 200–225 g, females 175–200 g, 7–8 weeks of age, Charles River, Raleigh, NC) were socially housed (2 per cage) in a climate-controlled vivarium on a reversed 12 h light-dark cycle (lights on at 07:00 pm). Food and water were available ad libitum before the onset of the studies, and during the studies, food intake was slightly restricted. The experimental protocols were approved by the University of Florida Institutional Animal Care and Use Committee.

Experimental Design

In the first experiment, the rats (males n = 14, females n = 13) were trained to respond for food pellets under a fixed-ratio 1, time-out 10s (FR1-TO10s) schedule. After completing the food training, the rats self-administered 0.03 mg/kg/inf of nicotine for 2 h per day for 9 days. During the first self-administration session, the maximum number of infusions was set to 20 to prevent the rats from self-administering extremely high doses of nicotine. After the 9-day self-administration period, the response requirements were gradually increased (FR1-960, 2-h sessions). Two cohorts of rats were used and the data sets were combined for the demand analysis. For the second experiment, a new group of animals was used. This experiment was conducted the same way as the first experiment, but the rats (males n = 14, females n = 14) self-administered 0.01 mg/kg/inf of nicotine. In the third experiment, new groups of rats (males n = 10, females n = 10) were trained to respond for food pellets under an FR1-TO10s schedule. Total food intake of the rats was determined when they had ad lib access to lab chow in the home cage and also when they had access to food (2 h/day) in the operant chamber. After this, the response requirements were gradually increased (FR1-960, all sessions 2 h).

Catheter Implantation and Operant Responding for Nicotine

For experiments 1 and 2, the rats were anesthetized and prepared with a catheter in the right jugular vein. The surgery was conducted as described before,^35–37 with the exception that a different type of catheter was used (model 3Fr, Instech Laboratories, Plymouth Meeting, PA; see Supplementary Material for details). The rats were singly housed after the implantation of the catheters. Food training and nicotine self-administration sessions were conducted as described previously.^36–38 First, the rats were trained to respond for food pellets (45 mg, F0021, Bio-Serv, Frenchtown, NJ). For the duration of the food training and nicotine self-administration sessions, the male rats were fed about 20 g of lab chow per day and the females 15 g (75–80% of baseline ad libitum calories).^39,40 The rats were fed immediately after the operant sessions. A mild level of food restriction and feeding after the operant sessions facilitates nicotine self-administration in rats.⁴¹ The rats were trained to respond on the right lever (RL, active lever) to receive food pellets. Responding on the left lever (LL, inactive lever) was recorded but did not have scheduled consequences. Instrumental training started under an FR1-TO1s reinforcement schedule and after several sessions, the time-out period was increased to 10 s (FR1-TO10s). The rats then self-administered nicotine at the 0.03 mg/kg/infusion dose for 9 days. During the first day, the maximum number of nicotine infusions was set to 20. Responding on the RL resulted in the delivery of a nicotine infusion (0.1 mL infused over a 5.6-s period). The initiation of the delivery of an infusion was paired with a cue light, which remained illuminated throughout the 10-s time-out period. After the rats had been on the FR1 schedule for 9 days, the response requirements were gradually increased according to the following schedule: 2, 3, 6, 9, 15, 30, 60, 120, 240, 480, and 960. In the first experiment, the rats self-administered 0.03 mg/kg/inf of nicotine, and in the second experiment, the rats self-administered 0.01 mg/kg/of nicotine. The self-administration sessions were conducted 5 days per week and ended when none of the rats in a group received nicotine.

Operant Responding for Food

In experiment 3, sex differences in the elasticity of demand for chocolate-flavored food pellets were investigated using an open economy model (Hursh, 1993). In an open economy model, the rats receive a percentage of their daily food in the home cage and the remainder in the operant chamber. The test sessions were conducted one time per day, 6 days per week. The rats were trained to respond for food pellets under an FR1-TO10s schedule (20-min sessions). The rats were fed in the home cage immediately after the operant sessions. During the initial food training sessions, the rats were socially housed and upon completion of the food training sessions, the rats were housed individually. We then measured ad lib food intake in the home cage for 3 days. During the remainder of the study, the rats received 65% of their daily ad lib food intake in the home cage and responded for food pellets (F0299, 45 mg chocolate flavored pellets, Bio-Serv, Flemington, NJ) in the operant chamber for 2 h per day. The rats were tested for 3 days under an FR1-TO10s schedule. Under the FR1 schedule, total food intake in the male and female rats was 90–105% of daily ad lib food intake. A demand curve was obtained by gradually increasing the price of food (FR value). Two sessions at each of the following FR schedules were conducted: 2, 3, 6, 9, 15, 30, 60, 120, 240, 480, and 960. Operant sessions were conducted 6 days per week, and during off days, the rats received an amount of food that was equivalent to their intake on the prior test day (home cage food + pellets earned in the operant chamber). The rats received 70% of daily ad lib food in their home cages when their total food intake decreased to 65% of daily ad lib food intake for 3 consecutive days. That only occurred when rats did not earn any food in the operant chamber.

Demand Curve Analysis

The demand curve analysis was conducted according to a model proposed by Hursh and Silberberg.²¹ This model has been used previously to determine the relationship between the price of nicotine and nicotine consumption in rats.^27,42,43 The data were fit using the following exponential demand equation: log Q = log Q₀ + k(e^-α^QoC–1), where Q is the amount of nicotine or food consumed and C is the cost of each reinforcer (FR value). Q₀ or demand intensity is the estimated consumption at zero price and k is a scaling constant that describes the range of consumption in log-units. The demand curves were generated by adding the data of each rat into a template (Institutes for Behavior Resources, Baltimore, MD) for GraphPad Prism. Demand elasticity (α) and model fit (R²) were obtained from the aggregated analysis of the demand curves. The elasticity describes the relative rate of decline in consumption (log nicotine or food consumption) with an increasing price (FR schedule). When the price of a reinforcer increases but the consumption remains stable, demand is relatively inelastic (small α). When a small increase in the price leads to a large decrease in consumption, the demand is considered elastic (large α). As in previous studies and recommended by Hursh, zero values in consumption were not altered.⁴⁴ Omax and Pmax were also determined.⁴⁵ Omax is the maximum response output (RL responding) and Pmax is the price at which the response output is maximum. Pmax and Omax were determined by entering the individually fit Q₀ and α values and the best-fit group k values into an Excel template.^46,47 The k value describes the range of consumption in each group and was the same for groups of animals that were compared but varied across different comparisons (Table 1).⁴⁸ The best-fit k values that were used to generate the demand curves were also used to estimate Pmax and Omax. The data were fitted to the Hursh and Silberberg equation (see above) using nonlinear regression. The percentage of variance that is accounted for by the Hursh and Silberberg equation is described by the R² value.

Table 1.

Sex Differences in the Behavioral Economics of Nicotine Intake

			α		Q0		Pmax		Omax
Reinforcer	Day	K	Male	Female	Male	Female	Male	Female	Male	Female
Nic-0.03	1	1.6	0.000363 ± 0.000101	0.001118 ± 0.000331*	22 ± 1	28 ± 3	143 ± 37	42 ± 16*	852 ± 217	312 ± 123*
Nic-0.03	2	1.8	0.000332 ± 0.000076	0.001033 ± 0.000332*	24 ± 1	31 ± 4	118 ± 30	38 ± 16*	765 ± 179	301 ± 122*
Nic-0.01	1	2.7	0.000405 ± 0.000112	0.000442 ± 0.000125	33 ± 5	87 ± 52	48 ± 18	42 ± 12	474 ± 143	546 ± 211
Nic-0.01	2	2.7	0.000423 ± 0.000111	0.000510 ± 0.000132	36 ± 5	50 ± 11	33 ± 8	37 ± 13	355 ± 75	532 ± 225
FOOD	1	3.5	0.000024 ± 0.000005	0.000014 ± 0.000002	181 ± 17	179 ± 5	52 ± 11	70 ± 10	3100 ± 640	4277 ± 666
FOOD	2	3.5	0.000021 ± 0.000004	0.000016 ± 0.000003	177 ± 11	164 ± 4	50 ± 9	71 ± 12	2958 ± 519	3982 ± 695

*Significant difference from male rats (p < .05).

Statistics

Operant responding for nicotine during days 2–9 (RL and LL presses and nicotine intake) was analyzed with a two-way ANOVA with time as within-subject factor and sex as between-subject factor. The extra sum-of-squares (ESS) F-test was used to determine if there were differences in the demand curves between the male and female rats.⁴⁹ The function assessed whether the best fit α value differed between the males and females. The null hypothesis was that the data sets could be described by one function and that the α values for the different groups were the same. In a secondary one-way ANOVA analysis, the individually fit α values were compared between males and females. This secondary analysis using individually fit α values is considered more conservative than the ESS F-test.⁵⁰ Responding on the RL after increasing the price of nicotine was analyzed with a two-way ANOVA with FR schedule as within-subject factor and sex as between-subject factor. During the first day of nicotine self-administration, the number of nicotine infusions was restricted, and therefore, this time point was not included in the data analysis. To compare the demand for nicotine and food, a normalized demand-curve analysis was conducted.⁵¹ The number of nicotine infusions and food pellets that the animals received was normalized by converting nicotine and food intake to a normalized unit. The normalized unit is the nicotine or food intake expressed as consumption at the lowest FR schedule. The price was normalized by converting it to the number of responses at a specific FR schedule that is required to obtain 1 percent of maximal consumption (Q₀). Demand analyses were conducted for both Day 1 and Day 2. Day 1 refers to the first day that the rats were on a specific FR schedule and Day 2 refers to the second day that the rats were on the FR schedule. The FR schedule was increased after 2 days. The data were analyzed with SPSS Statistics 25 and GraphPad Prism 7 for Windows.

Results

Demand for 0.03 mg/kg/inf of Nicotine

At the beginning of the study, female rats weighed less than male rats and the females also gained less weight over the course of the study than the males (Time: F_2,50 = 505.387, p < .0001; Sex: F_1,25 = 371.913, p < .0001; Time x Sex: F_2,50 = 124.169, p < .0001; Supplementary Table S1). During the first day of nicotine self-administration, all the rats reached the maximum number of nicotine infusions (data not included in figures). During the following 8 days of nicotine self-administration, there was no effect of Time or Sex on the number of nicotine infusion, nicotine intake (mg/kg), RL responding, or LL responding (Figure 1, A and B).

Figure 1.

Nicotine self-administration in male and female rats. Before increasing the price of nicotine, the rats had access to nicotine for 9 days. In the first experiment, the rats had access to a standard dose of nicotine (0.03 mg/kg/inf; A, B) for 2 h per day and in the second experiment the animals had access to a relatively low dose of nicotine (0.01 mg/kg/inf; C, D) for 2 h per day. During the first day, the maximum number of infusions was set to 20, and this time point was not included in the data analysis or the figure. There was no difference in the self-administration of nicotine between the male and the female rats. Group sizes: nicotine 0.03 mg/kg/inf (males n = 14, females n = 13), nicotine 0.01 mg/kg/inf (males n = 14, females n = 14). Data are expressed as means ± SEM.

Demand for nicotine at the 0.03 mg/kg/inf dose was more elastic in females than males. The ESS F-test indicated that two curves better describe the change in nicotine intake after increasing the price than one aggregated curve (Day 1, F_1,15 = 48, p < .0001; Day 2, F_1,15 = 101, p < .0001; Figure 2, A and B). A secondary ANOVA analysis using the α values derived from the individual-subject demand curve fits confirmed that the α values of the females were larger (more elastic) than the α values of the males (Day 1, Sex: F_1,25 = 5.068, p < .05; Table 1). At Day 2, the α values of the females were also larger than those of the males (Day 2, Sex: F_1,25 = 4.552, p < .05; Table 1).

Figure 2.

Demand curves for nicotine and food in male and female rats. The rats were kept at each FR schedule for 2 days, and the data for Day 1 and Day 2 are presented separately. The rats had access to 0.03 mg/kg/inf of nicotine (A, B), 0.01 mg/kg/inf of nicotine (C, D), or chocolate flavored food pellets (E, F). Demand for 0.03 mg/kg/inf of nicotine was more elastic (larger α) in the females than the males. Demand for 0.01 mg/kg/inf of nicotine and the food pellets was more elastic in the males than the females. Group sizes: nicotine 0.03 mg/kg/inf (males n = 14, females n = 13), nicotine 0.01 mg/kg/inf (males n = 14, females n = 14), and food pellets (males n = 10, females n = 10). Data are expressed as means.

An analysis was conducted to determine if there were differences in the Q₀, Pmax, and Omax between the male and female rats (Table 1). Separate analyses were conducted for Day 1 and Day 2. Pmax was lower in the females at Day 1 (F_1,25 = 6.089, p < .05) and Day 2 (F_1,25 = 5.219, p < .05) and Omax was also lower in the females at Day 1 (F_1,25 = 4.421, p < .05) and Day 2 (F_1,25 = 4.446, p < .05). There was no difference between the Q₀ of the males and the females on Day 1 or Day 2. The exponential model fitted the data well. The mean R² based on the group values ranged from 0.96 to 1.

Demand for 0.01 mg/kg/inf of Nicotine

At the beginning of the study, the body weights of the females were lower than those of the males and the females gained less weight over the course of the study than the males (Time: F_2,52 = 167.694, p < .0001; Sex: F_1,26 = 108.56, p < .0001; Time x Sex: F_2,52 = 27.735, p < .0001; Supplementary Table S1). Before increasing the response requirements, the rats had access to nicotine under a FR1 schedule. During the first day of nicotine self-administration, all the male rats reached the maximum number of nicotine infusions and 12 of the 14 female rats reached the maximum number of infusions (data not included in figures). During the first few days, nicotine intake decreased but then stabilized (Time: F_7,182 = 5.92, p < .0001; Figure 1C). Responding on the RL also decreased and then stabilized (Time: F_7,182 = 5.24, p < .0001; Figure 1D). Responding on the LL did not change over time but responding on the LL was higher in the females than the males (F_1,26 = 7.73, p < .05).

Changes in nicotine intake after increasing the price were better described by two curves than one aggregated curve (Day 1, F_1,18 = 23, p < .0001; Day 2: F_1,16 = 10, p < .01, Figure 2, C and D). At the 0.01 mg/kg/inf dose, the demand for nicotine was more elastic in the males than the females. A secondary ANOVA analysis using the α values derived from the individual-subject demand curve fits did not support that the α values of the males differed from those of the females (Table 1). There was no effect of Sex on Q₀, Pmax, or Omax (Table 1). The exponential model fitted the data well as the mean R² based on the group values ranged from 0.92 to 1.

Demand for Food Pellets

Food intake (home cage plus operant chamber) and body weights were recorded during the study. Total food intake in the males and females was stable when the price of food was low, but food intake started to decrease after FR15 (Time: F_23,414 = 80.53, p < .0001; Supplementary Figure S2A). Total food intake was higher in the males than the females (F_1,18 = 33.29, p < .0001). The body weights of the male and female rats initially increased and then stabilized (Time: F_23,414 = 154.1, p < .0001; Supplementary Figure S2B). Furthermore, the females had lower body weights than the males (Sex: F_1,18 = 169.8, p < .0001). A close look at the figures also shows that the males gained more weight during the study than the females (Time x Sex: F_23,414 = 41.35, p < .0001).

There were no differences in operant responding for food between males and females during the last 3 days of food training (FR1-TO10s, 20-min sessions; Table 2). Changes in operant responding for food after increasing the price were better described by two curves than one aggregated curve (Day 1, F_1,17 = 10, p < .01; Day 2, F_1,17 = 27, p < .0001; Figure 2, E and F). The figures show that the demand for the chocolate-flavored food pellets is more elastic (larger α) in the males than the females. A secondary ANOVA analysis using the α values derived from the individual-subject demand curve fits did not indicate that the α values of the males differed from those of the females (Table 1). The were no sex differences in RL responding for food pellets. There was no significant effect of sex on Q₀, Pmax, or Omax (Table 1). The exponential model fit the data extremely well. The mean R² based on the group values was 0.97 on Day 1 and 0.98 on Day 2.

Table 2.

Baseline Operant Responding for Food Pellets in Male and Female Rats

	Food pellets (n)		Right lever (RL) responses		Left lever (LL) responses
Day	Male	Female	Male	Female	Male	Female
1	76.6 ± 4.4	78.1 ± 4.6	79.0 ± 4.4	79.2 ± 4.8	5.7 ± 1.7	5.1 ± 1.0
2	85.1 ± 3.6	74.1 ± 5.4	88.9 ± 3.6	81.1 ± 9.8	3.3 ± 1.4	1.5 ± 0.6
3	84.4 ± 3.6	73.9 ± 4.5	90.7 ± 3.2	82.3 ± 10.6	1.9 ± 1.0	1.4 ± 0.6

Demand for Food and Nicotine

An additional analysis was conducted to determine if the dose of nicotine (0.03 versus 0.01 mg/kg) affects nicotine intake and the number of infusions. Nicotine intake (mg/kg) was higher when the rats had access to 0.03 versus 0.01 mg/kg/inf of nicotine and this effect was observed in the males (Dose: F_1,26 = 42.21, p < .0001; Supplementary Figure S3A) and females (Time: F_7,175 = 3.982, p < .001, Dose: F_1,25 = 10.36, p < .01; Supplementary Figure S3B). Furthermore, the number of nicotine infusions was lower in the males (Time: F_7,182 = 2.63, p < .05; Dose: F_1,26 = 8.711, p < .01, Supplementary Figure S3C) and females (Time: F_7,175 = 4.246, p < .001; Dose: F_1,25 = 21.19, p < .0001, Time x Dose: F_7,175 = 2.363, p < .05; Supplementary Figure S3D) with the 0.03 mg/kg/inf dose compared with the 0.01 mg/kg/inf dose.

Normalized nicotine and food intake data (Day 2, 0.03 mg/kg/inf versus food pellets) are presented in Figure 3. Because of the strong similarities in the demand analysis for Day 1 and Day 2, only the data from Day 2 are presented. In the males, changes in operant responding for nicotine and food after increasing the response requirements were better described by two curves than one aggregated curve (F_1,15 = 202, p < .0001; Figure 3A). In the females, changes in operant responding for nicotine and food after increasing the price were also better described by two curves than one aggregated curve (F_1,15 = 367, p < .0001; Figure 3B). A more conservative ANOVA analysis with the individual α-values also indicated that the demand for nicotine is more elastic (larger α) than the demand for food in both the males (F_1,22 = 9.663, p < .01; α nicotine 0.000049 ± 0.000011, α food 0.000007 ± 0.000001) and females (F_1,21 = 6.818, p < .05; α nicotine 0.001117 ± 0.000332, α food 0.000044 ± 0.000008).

Figure 3.

Normalized demand curves for nicotine and food in male and female rats. Normalized consumption of 0.03 mg/kg/inf of nicotine and food pellets are plotted as a function of the normalized price (FR schedule) in males (A) and females (B). The figures indicate that the demand for nicotine is more elastic than the demand for food in both males and females. Group sizes: nicotine 0.03 mg/kg/inf (males n = 14, females n = 13) and food pellets (males n = 10, females n = 10).

Discussion

The goal of the present study was to compare the elasticity of demand for nicotine and palatable food pellets between male and female rats. The demand for 0.03 mg/kg/inf of nicotine was more elastic in the females than in the males. This indicates that males maintained their old level of intake longer when the price of a standard dose of nicotine was increased. At the lower dose, 0.01 mg/kg/inf, the demand for nicotine was more elastic in males than females. Furthermore, the demand for chocolate-flavored food pellets was more elastic in the males than the females. This indicates that the females maintained their old level of intake longer when the price of a low dose of nicotine or food pellets was increased. The high goodness of fit (R² values: 0.92–1) indicated that the exponential demand equation fitted the data well in the nicotine and food studies.

In the present study, we compared the self-administration of 0.01 and 0.03 mg/kg/inf of nicotine under an FR1 schedule between male and female rats. There was no difference in the amount of nicotine self-administered between the male and female rats. This is in line with several previous studies that have shown no difference in the self-administration of nicotine between male and female rats under standard FR schedules.^27,52–54 However, it should be noted that studies have also reported higher levels of nicotine intake in females than males.³⁰ In the present study, the animals were trained to respond for food pellets before operant responding for nicotine and therefore started out with a relatively high level of nicotine intake. A previous study reported that the acquisition of nicotine intake is faster in female than male rats.⁵⁴ Therefore, it cannot be ruled out that differences in the acquisition of nicotine intake between the males and females might have been observed without prior food training.

To the best of our knowledge, this is the first study to compare the elasticity of demand for nicotine between males and females by increasing the price of nicotine through increasing the FR size. In a previous study, Grebenstein et al. compared the elasticity of demand for nicotine between males and females by decreasing the dose of nicotine (0.03–0.00025 mg/kg/inf).²⁷ In that study, there was no difference in the elasticity of demand for nicotine between the male and the female rats. There are several possible explanations for the difference between our findings and those previously reported. First of all, nicotine intake is differently affected by dose reduction, and price increases.²⁸ There were also some technical differences between the present study and the study by Grebenstein. For example, there were differences in acquisition phase (food training versus 23-h nicotine access), duration of test sessions (2 versus 23 h), starting dose (0.03 versus 0.06 mg/kg), and number of days on each schedule per dose (2 versus 5 days). Some of these methodological differences might explain why Grebenstein et al. did not observe sex differences in the elasticity of demand for nicotine. Donny and colleagues compared the breakpoints for nicotine between males and females under a PR schedule.⁵⁴ There were minimal differences in the breakpoints between males and females. The breakpoint was the same for the males and females at the 0.03 mg/kg/inf dose and slightly higher for the females at the 0.02, 0.06, and 0.09 mg/kg/inf dose, but there were no significant differences between the males and females at any specific dose. Sex differences in the elasticity of demand for cigarettes have also been investigated.

One study reported that the demand for cigarettes is more elastic in young males than in young females.⁵⁵ Thus, young males are more sensitive to the effects of a price increase on smoking than females. This is in line with another study that showed that the demand for cigarettes is more elastic in males than females.⁵⁶ The present finding contributes to these studies by demonstrating that the elasticity of demand for nicotine is dose-dependent. When the rats had access to a standard dose of nicotine, the demand for nicotine was more elastic in the females. In contrast, when the rats had access to a low dose of nicotine, the demand for nicotine was more elastic in the males. This observation suggests that a standard dose of nicotine is more reinforcing in males and a low dose of nicotine is more reinforcing in females. The present finding has implications for tobacco regulatory policy. The FDA has the authority to regulate the nicotine content in cigarettes,⁵⁷ and federal and state taxes curb tobacco use by increasing the price. The present findings suggest that increasing the price of nicotine-containing products will have a greater impact on male than female nicotine users in a regulatory environment where only low nicotine-containing products are allowed.

In the present study, the elasticity of demand for nicotine was compared with two statistical methods. First, it was determined if the demand curves differed from each other with the ESS F-test. Secondly, it was determined if there was a difference between the individually fit α values of the males and the females. The ESS F-test analyses indicated that elasticity of demand for 0.03 and 0.01 mg/kg/inf of nicotine and food differed between the males and the females. In contrast, when one-way ANOVAs were conducted with the individually fit α values, only the elasticity of demand for 0.03 mg/kg/inf differed between the males and the females. The ANOVA analysis using individually fit α values is more conservative than determining whether the demand curve is better described by multiple curves than one curve with the ESS F-test.⁵⁰ Overall, this study suggests that when using a widely used behavioral economics approach and statistical analysis (ESS F-test), there are differences in the elasticity of demand for nicotine and food between males and females.^58–61 However, when using a more conservative statistical approach, there is only a difference in the elasticity of demand between males and females at the 0.03 mg/kg/inf dose.

In the present study, we also compared the elasticity of demand between nicotine and palatable food pellets. The demand for nicotine was much more elastic than the demand for food pellets. This observation is in line with numerous previous studies that showed that the demand for drugs of abuse is more elastic than the demand for food.^43,62,63 Furthermore, the demand for nicotine is more elastic than the demand for a sucrose solution.⁴³ This suggests that in rodents food and sugar are more reinforcing than drugs of abuse. It is not known yet if the demand for nicotine in rats is less elastic after the development of dependence. However, long access to cocaine, which leads to the escalation of cocaine intake and dependence, decreases the elasticity of demand for cocaine.^64,65 Therefore, this would suggest that the elasticity of demand for nicotine is decreased after the development of nicotine dependence. Tobacco smoke contains compounds that have reinforcing properties and affect the reinforcing effects of nicotine. Therefore, additional animal studies with tobacco extract⁶⁶ or studies with smokers are needed to confirm these findings.

In conclusion, the present studies indicate that there is no difference in nicotine self-administration between males and females when the price of nicotine is low (standard FR schedule). Increasing the price of nicotine affects nicotine intake in males and females differently. At the 0.03 mg/kg/inf dose, nicotine intake in the females was more elastic than nicotine intake in the males. At the 0.01 mg/kg/inf dose, nicotine intake in the males was more elastic than nicotine intake in the females. The demand for palatable food pellets was also more elastic in the males than the females. This animal study suggests that there are sex differences in the elasticity of demand for nicotine and food. Our finding suggests that in a low-nicotine regulatory environment, female smokers might be more resistant to the effects of price increases on smoking than males.

Funding

This work was supported by a NIDA/NIH and FDA Center for Tobacco Products (CTP) grant (DA042530 to A.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.

Declaration of Interests

None declared.