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. Author manuscript; available in PMC: 2018 Jul 5.
Published in final edited form as: Behav Brain Res. 2017 Mar 30;327:155–161. doi: 10.1016/j.bbr.2017.03.037

Female Sprague-Dawley rats display greater appetitive and consummatory responses to alcohol

Steven J Nieto 1, Therese A Kosten 1
PMCID: PMC6033544  NIHMSID: NIHMS866558  PMID: 28365196

Abstract

The narrowing of the gender gap in alcohol drinking patterns is a concern because women are more susceptible to adverse health consequences of alcohol use. Animal models of alcohol-seeking and –consuming are useful to delineate sex differences to test for effective sex-specific pharmacological treatments. We investigated potential sex differences in appetitive and consummatory responses to alcohol. Appetitive behaviors included numbers of head entries into the dipper access area and active lever presses. Consummatory behaviors included number of reinforcers delivered and consumed. Male and female Sprague-Dawley rats were placed on an overnight alcohol (10%) drinking schedule and trained to lever press for alcohol (10% solution). Separate groups of male and female animals had access to water overnight and were trained to lever press for sucrose (3% solution). Tests were conducted under a progressive ratio schedule of reinforcement. Alcohol-responding females demonstrated higher alcohol intake overnight and showed greater appetitive and consummatory responses compared to males. Similar sex differences were seen in the sucrose group. Effect sizes indicated greater sex differences in consummatory measures in the alcohol vs. sucrose groups. Conversely, greater sex differences in appetitive behaviors were observed in the sucrose vs. alcohol groups. Overall, the magnitude of the sex differences was stronger for appetitive behaviors compared to consummatory behaviors. Findings of quantitative sex differences in appetitive and consummatory behaviors for alcohol and for the natural reinforcer, sucrose, suggest this procedure is useful to assess efficacy of sex-specific treatments aimed at reducing appetitive and consummatory responses to alcohol.

Keywords: operant self-administration, females, progressive ratio, alcohol, sex differences

1. Introduction

Alcohol use disorder (AUD) affects approximately 17 million adults in the United States [1] and contributes to more than $250 billion in societal costs annually [2]. AUD is more prevalent in men than women [1], however, epidemiological reports indicate that the gender disparity in alcohol consumption is beginning to narrow [3]. For example, compared to older cohorts, younger cohorts of women report a higher percentage of frequent binge drinking while these percentages have decreased in younger cohorts of men [3]. These findings are concerning given that women are more susceptible to negative health consequences associated with alcohol use [4–7].

There have been many studies that have documented sex differences in drug self-administration (reviewed in [8–15]), but alcohol studies are lacking in this area. Preclinical studies of AUD have consistently found sex differences in alcohol consumption. For example, female rodents consume more alcohol [16–21] and will escalate their drinking over time compared to males [22]. These sex differences in alcohol consumption in rodents have been identified primarily using continuous- or limited-access two bottle choice methods. However, females are rarely used in operant oral self-administration procedures. To date, studies of sex differences in alcohol self-administration have mostly used rodents that were genetically bred to prefer alcohol [8, 23]. Since rodents do not readily self-administer unadulterated alcohol solution, inbred alcohol-preferring rat strains have been a useful alternative to study AUD mechanisms compared to procedures that require animals to respond for a sweetened alcohol solution (reviewed in [24]). However, the use of a genetically homogeneous strain can mask individual differences that are often seen in a genetically heterogeneous population, like humans.

Animal models of alcohol drinking, craving, and relapse are an essential part of the process of developing potential treatments for AUD. In general, different procedures are used to test targets at specific phases of the addiction process [25]. For example, maintenance of operant alcohol self-administration may reflect the binge-intoxication phase of drinking because the focus of this assessment is on consumption. Procedures that employ reinstating operant behavior after its extinction may reflect the preoccupation-anticipation phase because it is generally tested in the absence of alcohol reinforcement and thus, it reflects appetitive behaviors [25]. However, it is possible to obtain both appetitive and consummatory behaviors during maintenance of operant self-administration [26].

Operant self-administration procedures vary widely, including the schedules of reinforcement used. The fixed ratio (FR) schedule provides an initial qualitative assessment of reinforcer efficacy and drug intake [27, 28], whereas, the progressive ratio (PR) schedule of reinforcement provides a quantitative assessment of reinforcer efficacy [27]. Under a PR schedule, the response requirement gradually increases, often after each reinforcer delivery, and, in contrast to the FR schedule, it provides a measure (break point or final ratio completed) of an animal’s motivation to obtain the reinforcer [27]. Because there is a paucity of operant alcohol self-administration studies that have examined sex differences under a PR schedule, the main goal of the present study was to compare male and female outbred rats in their motivation to seek and consume alcohol. Since alcohol is a unique drug of abuse in that it contains calories, it can interact with food intake to influence subsequent alcohol intake [29]. Thus, the second goal of our study was to evaluate the specificity of sex differences in operant responses to alcohol by including sucrose-responding comparison groups of rats of both sexes.

2. Methods

2.1 Animals

Adult male (400–500g) and female (200–250 g) Sprague-Dawley rats (Charles River, Wilmington, MA) were used in this study. Rats were single-housed in amber polysulfone cages and kept in a temperature- and humidity-controlled vivarium maintained on a 12:12 light/dark cycle (lights on at 7:00 AM). Animals were given ad libitum access to food and water except during fluid restriction. The Institutional Animal Care and Use Committee at the University of Houston approved the experimental procedures in accordance with guidelines set forth in the "Guide for the Care and Use of Laboratory Animals 8th Edition” [30]. Separate groups of male (n=11) and female (n=7) rats were trained to lever-press to obtain alcohol solution. Another cohort of male (n=6) and female (n=8) rats were trained to lever-press to obtain sucrose solution as described below.

2.2 Solution and drug preparations

Alcohol (ethyl alcohol, 190 Proof, USP grade, Koptec, King of Prussia, PA) or sucrose (Calbiochem, La Jolla, CA) was mixed with tap water to reach concentrations of 10% alcohol (v/v) and 3% sucrose (w/v) solutions.

2.3 Alcohol drinking in the dark schedule

Animals in the alcohol group were subjected to a drinking in the dark (DID) schedule beginning two weeks before self-administration training. Rats were given access to only 10% alcohol (v/v) from 5pm to 9am with water available for 1 hr during the mornings. This schedule alternated four days on with three days off throughout the course of the study. There was no fluid restriction during the three off days. Self-administration training and test sessions began 3–6 hrs after the end of the DID period. Alcohol intake and body weights were measured weekly throughout the entire course of the study. Alcohol intake was converted to g/kg to provide dose of alcohol consumed.

2.4 Self-administration apparatus

Behavioral training and testing were conducted in operant chambers, placed within sound-attenuating cubicles equipped with fans (Coulbourn Instruments, Whitehall, PA). The chambers were equipped with a house light on one side of the cage, two retractable levers on the opposite wall that were situated on either side of a dipper access area into which a dipper arm delivered 0.1 ml of a solution, and triple cue lights above each lever.

2.5 Self-administration training

Rats were first trained to drink from the dipper for one week. Levers were retracted during this first week and each session began with two dipper presentations. After these two dipper "primes" and for the rest of these 30 min training sessions, any head entry into the dipper access area triggered a dipper presentation. Dipper presentation times gradually decreased from 15 sec to 3 sec, the duration used for the rest of the study. Lever press training began the following week. These 30 min sessions started with the house light illuminated and protrusion of the levers into the chamber. Two dipper primes were given and then the dipper was only activated after the active lever was pressed. Inactive lever presses had no programmed consequences.

Operant training continued until the rat achieved at least 25 active lever presses and responding was consistent (<20% variability of active lever presses over 2 days). After the animal reached stable responding on the fixed ratio 1 schedule (FR1), the response requirement to receive a dipper presentation was increased to two presses on the active lever (i.e., FR2). Once an animal showed stable responding under the FR2 schedule, test sessions were initiated.

2.6 Self-administration testing

Test sessions were conducted under a 3 hr progressive ratio (PR) schedule as described previously [31, 32]. With this schedule, animals must respond for deliveries of a reinforcer at higher levels for each subsequent delivery in the following steps: 1, 1, 2, 2, 3, 3, 4, 4, 5, 5, 7, 7, 9, 9, 11, 11, 13, 13, 15, 15, 18, 18, 21, 21, 24, 24, etc.

2.7 Appetitive and consummatory behaviors

Appetitive and consummatory behaviors were measured during the 3 hr PR test. The first appetitive response was total number of head entries into the dipper access area whether the dipper containing alcohol or sucrose was present or not (dipper approaches). The second was the total number of active lever presses (active lever approaches). Inactive lever presses were assessed as a measure of non-specific responding. The first consummatory behavior was the number of dipper presentations into the access area (reinforcers delivered). The second consummatory behavior was numbers of head entries into the dipper access area when the dipper was present (reinforcers consumed). It is important to note that we did not did not verify consumption by weighing the fluid reservoir. We assumed if the animal works to obtain a fluid delivery and enters its head into the dipper access area then it is doing so to ingest the fluid.

2.8 Statistical Analysis

Alcohol intake during DID was analyzed using a two way mixed design ANOVA with sex as the between group factor and week as the repeated measure factor. Males and females were compared on appetitive and consummatory behaviors in alcohol or sucrose operant self-administration using Student’s t tests. The effect size Cohen’s d was calculated based on the group means and the average standard deviation [33]. This was performed because the large differences in measures between alcohol and sucrose groups precluded incorporating solution group as a factor in the overall analyses. Final ratios completed were compared between males and females using the Mann-Whitney U test. Statistical analyses were performed using SAS software 9.4 with statistical significance defined as p<0.05. Data are primarily presented as mean ± s.e.m; however, data for final ratio completed are presented as median ± interquartile range.

3. Results

3.1. Alcohol drinking in the dark consumption

The mean weekly alcohol intake consumed (converted to g/kg) during DID is shown in Fig. 1. A two way mixed design ANOVA yielded significant main effects of time, F(24,456)=6.44, p<0.001, and sex, F(1,19)=5.86, p<0.05. There was also a significant time × sex interaction, F(24,456)=3.98, p<0.001. Overall, males consumed between 4 and 7 g/kg and females consumed between 4 and 9 g/kg across weeks of the study. The significant main effect of time and its interaction with sex likely reflect that female rats showed greater variability in intake over weeks compared to males as seen in Fig. 1.

Figure 1.

Figure 1

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Alcohol intake of male and female during overnight drinking in the dark. Data are plotted as mean (± SEM) weekly alcohol consumption (g/kg) for entire length of the study. An asterisk (*) represents a significant difference between males and females (p<0.05).

3.2 Appetitive responses

Sex differences in dipper approaches for alcohol are shown in Fig. 2A. Female rats displayed significantly more head entries for alcohol when compared to males, t(16)=2.63, p<0.05; Cohen’s d = 1.11. Similarly, females also showed greater head entries for sucrose solution compared to males, t(12)=2.96, p<0.05; Cohen’s d = 1.72 (Fig. 3A).

Figure 2.

Figure 2

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Appetitive responses for alcohol under a PR schedule of reinforcement; n = 7 female n = 11 male. Data for appetitive responses are primarily presented as mean (± SEM). (A) Data are plotted as the average number of dipper approaches during the PR session. (B) Data are plotted as the average number of active lever presses during the PR session. (C) Data for final ratios completed are plotted as median (± interquartile range). An asterisk (*) represents a significant difference between males and females at p<0.05, ** indicates sex differences at p<0.01, and *** indicates sex differences at p<0.001.

Figure 3.

Figure 3

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Appetitive responses for sucrose under a PR schedule of reinforcement; n = 6 female n = 8 male. Data for appetitive responses are primarily presented as mean (± SEM). (A) Data are plotted as the average number of dipper approaches during the PR session. (B) Data are plotted as the average number of active lever presses during the PR session. (C) Data for final ratios completed are plotted as median (± interquartile range). An asterisk (*) represents a significant difference between males and females at p<0.05, and ** indicates sex differences at p<0.01.

Sex differences in active lever presses for alcohol are shown in Fig. 2B. Females pressed the active lever significantly more than males in both the alcohol, t(16)=4.09, p<0.001; Cohen’s d = 1.76, and sucrose, t(12)=3.21, p<0.01; Cohen’s d = 1.84 (Fig. 3B), groups. There were no sex differences on number of inactive lever presses (data not shown).

Females completed higher final ratios compared to males, p<0.01, in the alcohol responding groups as shown in Fig. 2C. Females also completed higher final ratios compared to males, p<0.05, in the sucrose responding groups as shown in Fig. 3C.

3.3 Consummatory responses

Sex differences in numbers of alcohol reinforcers delivered are shown in Fig 4A and in numbers of sucrose reinforcers delivered are shown in Fig. 5A. Females in the alcohol group exhibited higher dipper presentations compared to males, t(16)=5.73, p<0.001; Cohen’s d = 2.64. Females in the sucrose group exhibited higher dipper presentations than males, t(12)=3.80, p<0.01; Cohen’s d = 2.10.

Figure 4.

Figure 4

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Consummatory responses for alcohol under a PR schedule of reinforcement; n = 7 female n = 11 male. Data for consummatory responses are primarily presented as mean (± SEM). (A) Data are plotted as the average number of alcohol reinforcers delivered during the PR session. (B) Data are plotted as the average number of alcohol reinforcers consumed during the PR session. Asterisks (***) represent a significant difference between males and females at p<0.001.

Figure 5.

Figure 5

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Consummatory responses for sucrose under a PR schedule of reinforcement; n = 6 female n = 8 male. Data for consummatory responses are primarily presented as mean (± SEM). (A) Data are plotted as the average number of sucrose reinforcers delivered during the PR session. (B) Data are plotted as the average number of sucrose reinforcers consumed during the PR session. Asterisks (**) represent a significant difference between males and females at p<0.01.

Sex differences in the number of reinforcers consumed are shown in Figs. 4B and 5B. In the alcohol group, there were no significant differences between the sexes in the number of reinforcers consumed, t(16)=1.95, p=0.06. There were also no significant differences between sexes in the number of sucrose reinforcers consumed, t(12)=1.76, p>0.10.

3.4. Magnitude of sex differences

Effect sizes of sex differences on appetitive and consummatory measures during the PR test are shown in Table 1. Greater sex effects were seen on consummatory behaviors in alcohol-responding vs sucrose groups. Conversely, greater sex effects were seen on appetitive behaviors in the sucrose-seeking vs alcohol groups. Overall, in both sucrose- and alcohol groups, greater sex effects were seen in appetitive behaviors relative to consummatory behaviors.

Table 1.

Baseline Locomotor Activity1 after Vehicle (PBS) Injection

METH Dose Group Female (mean ± SEM) Male (mean ± SEM) P-value2
1 mg/kg 7045.60 ± 417.27 4918.78 ± 950.52 0.14
4mg/kg 5121.80 ± 420.58 5862.40 ± 370.21 0.22
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1

Baseline activity during 30 min. session

2

Student’s t-test

4. Discussion

The results of the present study showed that compared to males, females displayed increased alcohol consumption during DID and elevated levels of appetitive and consummatory responses for alcohol under a PR schedule of reinforcement. Additionally, we observed that females also showed greater appetitive and consummatory responses for a 3% sucrose solution compared to males. Importantly, in both the sucrose and alcohol groups, effect sizes indicated that the magnitude of the sex differences in appetitive behaviors was stronger compared to consummatory behaviors. To our knowledge, this is the first operant self-administration study that assessed both appetitive and consummatory responding for alcohol using a PR schedule in outbred female rodents.

We observed that females consumed more alcohol during DID and displayed greater variability in intake over weeks compared to males. Female rats also showed greater amounts of appetitive and consummatory behaviors for alcohol during a 3 hr PR self-administration session relative to male rats. Specifically, females displayed higher numbers of active lever presses, total head entries, alcohol deliveries, and final ratios completed compared to males. These findings are in agreement with previously identified sex differences in murine models of alcohol consumption. It is well known that female rodents consume greater amounts of alcohol [16–19] and will escalate their alcohol intake [22] compared to males in two bottle choice situations; however, few studies have examined sex differences in operant oral alcohol self-administration. The results of the present study are in accordance with work by Bertholomey and colleagues [34] who showed that female Sprague-Dawley rats responding for a sweetened 10% alcohol solution displayed greater active lever presses, reinforcers earned, and alcohol intake compared to males during fixed ratio 1 (FR1) sessions. In addition, these females acquired alcohol self-administration faster than males. Although there are differences in experimental methodologies employed between that study and ours, such as their use of sweetened alcohol as a reinforcer and a FR1 schedule of reinforcement, we replicate and extend their findings to include both elevated appetitive and consummatory behaviors for unsweetened 10% alcohol in female Sprague-Dawley rats under a PR schedule of reinforcement.

Sex differences in consummatory behaviors during operant alcohol self-administration have also been reported in rats genetically bred to prefer alcohol [23]. In that study, alcohol-preferring females showed higher consumption of an unsweetened 10% alcohol solution at the 30 day time block during a 60 day FR training period, while males showed higher intake at the 50 day time block [23]. There were no sex differences in alcohol intake or alcohol deliveries reported during a PR session. Other self-administration parameters indicative of appetitive behaviors (i.e., active lever presses and head entries) were not reported for FR1 or PR sessions in these previous studies. However, given that sex differences in alcohol consumption have been reported in alcohol-preferring rats implies that a genetic propensity to consume alcohol could mask underlying sex differences in appetitive and consummatory behaviors for alcohol. Such differences may be more readily apparent by employing more genetically diverse rodent strains as we show in the present study. Indeed, we suggest that using outbred strains and measuring appetitive and consummatory behaviors during operant oral self-administration sessions has great utility to further understand the role of sex in animal models of AUD.

We also demonstrated that females and males differ in appetitive and consummatory responses for a 3% sucrose solution. Specifically, females show greater numbers of active lever presses, total head entries, sucrose deliveries, and achieved higher final ratios completed compared to males. Interestingly, there were no significant differences between males and females on sucrose reinforcers consumed. Effect sizes for sex were greater for appetitive measures of sucrose-seeking relative to alcohol, however, this was not the case for consummatory behaviors. Several studies have shown that female rodents display a higher preference for sweetened solutions compared to males [35–37]. However, previous operant sucrose self-administration have reported inconsistent findings in tests for potential sex differences. For example, females earned more saccharin reinforcers than males under a FR1 schedule [34] while males exhibited higher active lever presses for sucrose compared to females under FR1 [38] and FR3 [39] schedules. Another study reported no sex differences in sucrose pellets delivered on a PR schedule in adolescent rats [40]. The concentration of sucrose used in the above studies vary widely, which may account, at least in part, for some of these inconsistent findings. It is also important to note that the caloric content in alcohol and sucrose may have limited the consummatory behaviors observed in this study. The issue of caloric and reward satiation may be unique to alcohol relative to other drugs of abuse.

Sex differences have been observed in operant self-administration of several classes of drugs of abuse. Across most of these drug classes, female rodents acquire the operant more quickly [8] and self-administer greater amounts of cocaine on a PR schedule during maintenance [41, 42] and reinstatement [43] procedures. Although there is evidence of sex differences in multiple aspects of addiction-like behaviors, females are understudied in animal models of AUD. This is especially evident in operant alcohol self-administration studies where we suggest that appetitive and consummatory responses for alcohol can be assessed in the same session.

Data from the present study are consistent with the body of literature indicating sex differences in two-bottle choice alcohol self-administration but also adds some new insights. First, the present study used an operant self-administration procedure to test for sex differences to seek and consume alcohol. Second, we employed a PR schedule of reinforcement that is a reliable measure of reinforcer efficacy and compulsive-like responding associated with addiction. Third, the use of an outbred rat strain better parallels a genetically diverse population, such as humans, and provides an excellent opportunity to assess individual differences. Fourth, to determine if the sex effects are selective for alcohol, the magnitude of the sex differences in alcohol-motivated behavior were compared to a sucrose-responding group. Fifth, similarities in the sex effect for alcohol and sucrose is advantageous for future studies testing for sex-specificity of pharmacological agents because the baseline sex difference would be the same. Lastly, we demonstrate the value of incorporating measures of head entries as an appetitive behavior and that head entry data can be obtained during the same sessions in which consummatory behaviors or other appetitive behaviors are assessed.

The strengths of our study are also accompanied by an important limitation. We did not monitor the estrous cycle in alcohol or sucrose responding females. There is evidence in support of [44] and against [45–47] the influence of ovarian hormones on alcohol self-administration. Previous work using Sprague-Dawley females showed no effect of the estrous cycle on alcohol responding under an FR1 schedule [34]. A lack of effect of the estrous cycle was also seen in Long Evans and Wistar rats under an FR1 schedule [48]. Thus, the differences between alcohol responding males and females observed in our study are likely due to organizational rather than activational effects of gonadal hormones.

6. Conclusions

In summary, we provide evidence that outbred female rodents show elevated and more variable alcohol intake in a chronic, overnight drinking procedure and displayed greater appetitive and consummatory behaviors for an unsweetened 10% alcohol solution and a 3% sucrose solution under an operant self-administration PR schedule. These results have important clinical implications given evidence that alcohol use in women is increasing [3] and that women experience more adverse health consequences related to alcohol use [4–7]. Operant procedures that incorporate both appetitive and consummatory parameters will be useful in identifying individual differences in AUD and determining if treatments should be targeted at different phases of the treatment process depending on whether reducing craving or consumption is the treatment goal. Further, data from the present study show that sex differences are greater for appetitive vs consummatory measures. Insights derived from research employing animals of both sexes is necessary to understand the differences in the neurobiology of AUD and to identify more effective treatments.

Highlights.

  • Female rats show greater appetitive and consummatory behaviors than males

  • Sex effect for appetitive alcohol behaviors is stronger than for sucrose

  • Sex differences in alcohol-responding are greater for consummatory behaviors

  • Measuring both appetitive and consummatory behaviors is useful

Acknowledgments

The authors would like to acknowledge Kevin Winoske for excellent technical assistance and Drs. Richard Meisch and Odochi Ohia-Nwoko for valuable input on earlier versions of the manuscript. This work was supported by the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (AA013476, TAK).

Footnotes

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