Skip to main content
NCBI home page
Chemical Senses logoLink to Chemical Senses
. 2020 Aug 24;45(8):675–685. doi: 10.1093/chemse/bjaa056

Mixtures of Sweeteners and Maltodextrin Enhance Flavor and Intake of Alcohol in Adolescent Rats

Alice Sardarian 1,#, Sophia Liu 1,#, Steven L Youngentob 2,3, John I Glendinning 1,3,✉
PMCID: PMC7648650  PMID: 32832977

Abstract

Sweet flavorants enhance palatability and intake of alcohol in adolescent humans. We asked whether sweet flavorants have similar effects in adolescent rats. The inherent flavor of ethanol in adolescent rats is thought to consist of an aversive odor, bitter/sweet taste, and burning sensation. In Experiment 1, we compared ingestive responses of adolescent rats to 10% ethanol solutions with or without added flavorants using brief-access lick tests. We used 4 flavorants, which contained mixtures of saccharin and sucrose or saccharin, sucrose, and maltodextrin. The rats approached (and initiated licking from) the flavored ethanol solutions more quickly than they did unflavored ethanol, indicating that the flavorants attenuated the aversive odor of ethanol. The rats also licked at higher rates for the flavored than unflavored ethanol solutions, indicating that the flavorants increased the naso-oral acceptability of ethanol. In Experiment 2, we offered rats chow, water, and a flavored or unflavored ethanol solution every other day for 8 days. The rats consistently consumed substantially more of the flavored ethanol solutions than unflavored ethanol across the 8 days. When we switched the rats from the flavored to unflavored ethanol for 3 days, daily intake of ethanol plummeted. We conclude that sweet and sweet/maltodextrin flavorants promote high daily intake of ethanol in adolescent rats (i.e., 6–10 g/kg) and that they do so in large part by improving the naso-oral sensory attributes of ethanol.

Keywords: adolescent rats, ethanol, flavor, brief-access lick test, daily intake

Introduction

Ethanol is consumed avidly throughout the world in a variety of beverages, including wine, beer, and spirits. While adults are the primary consumers, adolescents consume large quantities and have a higher risk for overconsumption (Bates and Labouvie 1997; Wechsler et al. 2000). What makes the latter observation surprising is that adolescents generally dislike the inherent flavor of ethanol (Samson et al. 1989; Moore and Weiss 1995). The flavor includes a sharp odor, bitter taste, and capsaicin-like burning sensation (Nolden and Hayes 2015). The beverage industry has developed a variety of premixed products (e.g., alcopops and sweet cider), which contain sweet and fruity flavorants, and relatively low (5–14%) concentrations of ethanol (Hughes et al. 1997; Romanus 2000; Fortunato et al. 2014; Albers et al. 2015). Because the sweet and fruity flavorants increase the naso-oral acceptability of the ethanol beverage (Copeland et al. 2007), they may promote ethanol consumption by adolescents.

Rats are an excellent model system for understanding the factors that regulate ethanol consumption during adolescence. Like humans, adolescent rats consume more flavored ethanol than adult rats (Brunell and Spear 2005; Doremus et al. 2005; Vetter et al. 2007; Vetter-O’Hagen et al. 2009; Broadwater et al. 2011). To explain the age-related difference in intake, prior work has focused on the contribution of the reinforcing postingestive pharmacological actions of ethanol (Li et al. 1993). This work revealed, for instance, that adolescent rats are less sensitive than adult rats to the aversive postingestive (Vetter-O’Hagen et al. 2009) and intoxicating (Broadwater et al. 2011; Hosova and Spear 2019) actions of ethanol. It is possible that the adolescent flavor system also contributes to the high daily intake of ethanol. The inherent flavor of ethanol in rodents is thought to consist of an aversive odor (Nachman et al. 1971), bitter/sweet taste (Di Lorenzo et al. 1986), and capsaicin-like burning sensation (Trevisani et al. 2002; Ellingson et al. 2009; Glendinning et al. 2017). However, we are not aware of any studies that specifically evaluated the impact of flavorants on ethanol intake in adolescent rats. Instead, most investigators have simply measured the intake of flavored ethanol without including an ethanol-alone comparison group. In these prior studies, the flavorants included glucose and saccharin (Kulkosky 1979; Ji et al. 2008); sucrose and saccharin (Walker et al. 2008; Broadwater et al. 2013); saccharin (Brunell and Spear 2005; Doremus et al. 2005); or BOOST, a sugar-sweetened chocolate drink (Hosova and Spear 2017, 2019). Because sugars elicit a sweet taste and salient odor sensation in rodents (Rhinehart-Doty et al. 1994; Schier et al. 2019; Glendinning et al. 2020), they may have improved the naso-oral acceptability of ethanol and thereby increased daily intake.

To assess the impact of flavorants on the naso-oral acceptability of (or avidity for) ethanol solutions, one can use the brief-access lick test (Youngentob and Glendinning 2009; Tang et al. 2018). This test measures licking responses to small solution volumes, minimizing the contribution of any postingestive actions of the ingested solution. It also measures ingestive behaviors while the test solutions are stimulating naso-oral chemosensory cells. By analyzing these behaviors, one can distinguish appetitive and consummatory components of the ingestive process. The appetitive component can be defined as the latency to initiate licking from a sipper tube once the shutter has opened. Because this measure reflects behavior exhibited prior to contacting the test solution, it is necessarily mediated by odor cues. The shorter the latency, the more acceptable the test solution (Rhinehart-Doty et al. 1994). The consummatory component can be defined as the rate at which the rat licks during a brief trial; this component is mediated by olfactory, trigeminal (oral and nasal), and taste inputs. The higher the lick rate, the more acceptable the test solution (Davis 1973; Smith and Sclafani 2002).

When adult rats were exposed intermittently (i.e., every other day) to 20% ethanol without added flavorants (hereafter, unflavored), they not only displayed an increased avidity for the unflavored ethanol (as measured during brief-access lick tests; Loney and Meyer 2018) but also a 3–4-fold increase in daily intake (Simms et al. 2008). In contrast, when adolescent rats were exposed intermittently to unflavored 10% ethanol, they displayed an increased avidity for the unflavored ethanol but no associated increase in daily intake (Tang et al. 2018). The latter finding points to a disconnect between naso-oral acceptability and daily intake of unflavored ethanol in adolescent rats. Here, we examined the relationship between naso-oral acceptability and daily intake of flavored ethanol in adolescent rats.

We conducted 2 experiments. In Experiment 1, we measured the impact of 4 flavorants (see Table 1) on the naso-oral acceptability of 10% ethanol using brief-access lick tests. In Experiment 2, we asked whether the same flavorants increased voluntary daily intake of 10% ethanol over 8 test days. To determine whether consumption of the flavored ethanol solutions increased daily intake of unflavored ethanol, we switched the rats to unflavored ethanol and examined daily intake over 3 additional test days.

Table 1.

Composition of the test solutions and their caloric density

Chemical constituents (%, weight/volume)
Test solution Ethanol Saccharin Sucrose Maltodextrin kcal/g solution
E 10 — — — 0.70
SS — 0.125 3 — 0.12
E + SS 10 0.125 3 — 0.82
SSM — 0.2 1 1 0.08
E + SSM 10 0.2 1 1 0.78
E + SSM2 10 0.2 2 2 0.86
E + SSM4 10 0.2 4 4 1.02
Open in a new tab

Materials and methods

Animals and maintenance

We purchased adolescent Long Evans Hooded rats from Envigo (http://www.envigo.com), weighing 70–94 g, and began testing them 4 days after arrival (i.e., postnatal day 30). Given that adolescent rats (i.e., postnatal days 30–46) display similar behavioral and neurobiological changes as adolescent humans, they are used widely as a model of adolescence (Spear 2000).

We used different rats in Experiments 1 and 2. All of them were naïve to the test solutions (see below) prior to testing. There were approximately equal numbers of males and females in each treatment group. The rats were housed individually in standard polycarbonate cages in a temperature- and humidity-controlled vivarium on a 12-h light/dark cycle. Water was provided through open-ended sipper tubes (hole diameter = 3.3 mm), and laboratory chow (5001, PMI Nutrition International) was available through the cage lid. Rats were weighed weekly. Food and water were provided ad libitum, unless specified otherwise.

All experimental procedures were approved by the Institutional Animal Care and Use Committees of Columbia University. The protocols were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Test solutions

Test chemicals were purchased from Sigma-Aldrich (sucrose, ≥99.5% pure; and sodium saccharin, ≥99% pure), Decon Laboratories (ethanol, 200 proof), and Medica Nutrition (maltodextrin; product name: SolCarb; 94.5% carbohydrate, <0.3% salts). The maltodextrin contained a mixture of oligosaccharides and polysaccharides. All chemicals were dissolved in deionized water and presented at room temperature. The flavorants were mixtures of saccharin and sucrose or saccharin, sucrose, and maltodextrin. Maltodextrin consists of D-glucose units in polymers of variable length, typically 3–17 glucose units; it has a palatable taste to rats that is distinct from that of sucrose and saccharin, and rats prefer solutions containing sucrose + maltodextrin to those containing sucrose or maltodextrin alone (Sclafani et al. 1998).

We used 10% ethanol (henceforth, E) because it has been used in most prior studies of voluntary E intake by adolescent rats (Vetter et al. 2007; Broadwater et al. 2013; Hosova and Spear 2017). One of the flavorant mixtures (0.125% saccharin and 3% sucrose; henceforth, SS) has been used previously in studies of flavored E intake by adolescent rats (Ji et al. 2008; Broadwater et al. 2013). The other flavorant mixture (0.2% saccharin, 1% sucrose, and 1% maltodextrin; henceforth, SSM) has been found to stimulate high daily intake in adult rats (Sclafani et al. 1998). We tested 2 additional formulations of SSM, which contained higher concentrations of sucrose and maltodextrin (see Table 1). We included the latter SSM formulations to test the impact of increasing sweet/maltodextrin taste intensity and caloric content on oral acceptability and daily intake. We calculated the caloric density of each solution, assuming that the carbohydrates and E contain 4 and 7 kcal/g, respectively (Table 1).

Initial ingestive responses to flavored versus unflavored ethanol (Experiment 1)

To measure the oral acceptability of the test solutions in Table 1, we measured the initial ingestive responses of individual rats to 2 test solutions during brief-access lick tests. We examined 2 components of the ingestive response: latency to initiate licking and lick rate. We conducted the brief-access lick tests in a gustometer (Davis MS160-Mouse; DiLog Instruments).

We subjected 3 groups of rats to a series of brief-access lick tests. One group (2 separate shipments of 8 rats) was subjected to 5 lick tests in the following order: E versus water, E versus E + SSM, E versus E + SSM2, E versus E + SSM4, and then E versus E + SS. A second group (one shipment of 12 rats) was subjected to 2 lick tests in the following order: SS versus SSM and, then, E + SS versus E + SSM. A third group (one shipment of 6 rats) was subjected to 2 lick tests in the following order: water versus SS and, then, water versus SSM.

Gustometer training

Each rat received 3 training sessions in the gustometer with water. These training sessions familiarized the rat with the gustometer and taught it to obtain water from the sipper tube. Each training session began once the shutter opened and the rat took its first lick; it lasted 30 min. On Training Day 1, the rat could drink freely from a single sipper tube throughout the session. On Training Days 2 and 3, the rat could only drink from a sipper tube during sequential 10-s trials with intertrial intervals of 7.5 s.

To motivate licking during each training session, we water deprived the rats for 22.5 h prior to each session. Afterward, the rat was returned to its home cage and given 1 h of ad libitum access to water; then, it was water deprived for another 22.5 h but had ad libitum access to food.

Gustometer testing

During each brief-access lick test, we presented the rat with 2 test solutions (e.g., A and B). Only a single test solution was provided during each 10-s trial, however. The trial began when the shutter opened and the rat initiated licking from the sipper tube dispensing Solution A; it ended 10 s later when the shutter closed. Following a 7.5-s interval, the rat was presented with the sipper tube dispensing Solution B. In this manner, we presented the 2 test solutions repeatedly in an alternating manner. The rat could initiate up to 102 trials (51 for each test solution) across the 30-min test session. Each rat was subjected to only one test session with a given pair of test solutions.

We employed 2 deprivation schedules, depending on the pair of test solutions used in the brief-access lick tests. For the lick tests that involved at least one ethanol-containing test solution, we made the rats thirsty prior to testing. To this end, we removed the water bottles from each rat’s home cage (but not chow) 22.5 h before the lick test. Prior studies revealed that this water-deprivation procedure causes adolescent rats to initiate large numbers of trials and exhibit robust concentration-dependent decreases in licking for aversive substances like ethanol, NaCl, and quinine (Youngentob and Glendinning 2009; Tang et al. 2018). For brief-access lick tests that involved flavorants but no ethanol, we made the rats hungry prior to testing. To this end, we removed the chow (but not the water) and provided rats with fresh bedding 23.5 h before the lick test. This food-deprivation procedure causes adolescent rats to initiate large numbers of trials and generate robust concentration-dependent increases in licking for palatable substances like sucrose (Tang et al. 2018). After completing a brief-access lick test, each rat was returned to its home cage and given 24 h of ad libitum access to food and water.

Data analysis

We asked how the ingestive response of each rat to the pair of test solutions changed across the initial 20 trials (i.e., initial 10 trials per test solution) of the brief-access lick test. We measured 2 components of the ingestive response: latency to initiate licking (i.e., interval between shutter opening and the initiation of licking) and lick rate (i.e., numbers of licks per 10-s trial). A Shapiro–Wilk’s test indicated that each of the ingestive measures was normally distributed (in all lick tests, P > 0.05), permitting the use of parametric statistical procedures. First, we analyzed ingestive responses across the initial 10 trials with each test solution using 2-way repeated-measures analysis of variance (ANOVA). The independent variables were test solution and consecutive trial. Second, we examined the immediate response of the rats to test solutions by comparing ingestive responses during the first trial with each solution using paired t-test. We analyzed the lick tests involving ethanol-containing test solutions (n = 6) separately from those involving ethanol-free test solutions. To control the Type I error rate for a given ingestive measure, we used Bonferroni correction. Accordingly, the alpha level for tests involving ethanol-containing test solutions was 0.05/6 (=0.0083) and for tests involving ethanol-free test solutions was 0.05/3 (=0.017). In this and the next experiment, we performed all statistical analyses with GraphPad Prism, v8.2 (https://www.graphpad.com/scientific-software/prism/).

Daily intake of flavored versus unflavored ethanol (Experiment 2)

Each day, the rats received a baseline diet of chow and water ad libitum. During Phase 1, we supplemented this baseline diet with one of the test solutions described in Table 1. For control rats, the test solution was E. For experimental rats, the test solution was E + SS, E + SSM, E + SSM2, E + SSM4, SS, or SSM. We exposed the control and experimental rats to their respective test solution for a total of 8 days. However, the test solutions were presented intermittently (i.e., every other day) because this presentation schedule has been found to promote higher intake than chronic exposure in adult rats (Simms et al. 2008). Accordingly, each rat received its respective test solution on Days 1, 3, 5, 7, 9, 11, 13, and 15 of the experiment. During Phase 2, we supplemented the diet of both control and experimental rats with E intermittently for a total of 3 days (i.e., Days 17, 19, and 21 of the experiment).

For each test day, we measured daily intake of water and test solution (to the nearest 0.1 g) by recording the change in weight of the drinking bottles using an electronic balance interfaced to a computer. To control for any side preference, we alternated the left–right position of the taste solution and water across successive testing days. We estimated daily fluid spillage by recording the change in weight of bottles containing each test solution in an empty cage. To correct for fluid spillage, we subtracted the estimated spill from the quantity consumed each day.

Data analysis

To evaluate the normality of daily intakes of each test solution over time, we used Shapiro–Wilk’s test, separately for each test solution and phase of testing. We found that daily intake of all test solutions over time deviated significantly from normality (in all instances, P < 0.012), requiring the use of nonparametric statistics. To test for time-dependent changes in the intake of each test solution, we ran a Friedman test on daily intakes (in grams) of each test solution across the exposure days, separately for each phase of testing. To compare daily intake of each test solution versus water, we calculated median daily intake (in grams) of the test solution and water across the exposure days, separately for each phase of testing, and compared the median daily intakes of both solutions with the Wilcoxon matched-pairs signed rank test. Because we conducted 2 paired tests (during Phases 1 and 2) for each test solution, we controlled the Type 1 error rate with Bonferroni correction (i.e., alpha = 0.05/2 or 0.025). Finally, we compared daily intake of ethanol from each test solution. To this end, we compared median daily intake of ethanol (in grams per kilogram) from each test solution using Kruskall–Wallis and Dunn’s multiple comparison tests, separately for Phases 1 and 2.

Results

Initial ingestive responses to flavored versus unflavored ethanol (Experiment 1)

In Figure 1, we show how latency to initiate licking (left column of panels) and lick rate (right column of panels) changed across the initial 10 trials of the lick tests involving the ethanol-containing solutions. When offered E and water, the rats initiated licking more quickly for water. This difference was apparent during trial 1 (paired t = 3.74, df = 15, P = 0.002) and across all 10 trials (Table 2). Once the trials began, the rats licked more quickly for water than for E. This difference was significant during trial 1 (paired t = 3.42, df = 15, P = 0.0038) and became more pronounced across the 10 trials (Table 2).

Figure 1.

Figure 1.

Open in a new tab

Licking responses of adolescent rats during brief-access lick tests with 2 test solutions: water and E (n = 16 rats); E and E + SS (n = 16); E and E + SSM (n = 16); E + SS and E + SSM (n = 12); E and E + SSM2 (n = 16); or E and E + SSM4 (n = 16). See Table 1 for a key to the acronyms. In the left column of panels, we show latency to initiate licking and, in the right column of panels, we show lick rate (mean ± standard error). In each panel, we show time-dependent changes in ingestive measures across the initial 10 trials of the test session, separately for water and the test solution. Given that we alternated the presentation of the 2 test solutions during a test session, each panel reflects a total of 20 trials (10 per test solution). All rats were water-deprived prior to testing. In each panel, we compared results from trial 1 across the 2 test solutions with paired t-test. To control the Type I error rate for a given ingestive measure, we divided the alpha level by the number of t-tests that were performed (*P < 0.05/6 = 0.008). See Table 2 for further analysis of these results.

Table 2.

Analysis of the brief-access lick data in Figure 1

Latency to initiate licking Lick rate
Test solutions Source of variation F-ratio df P-value F-ratio df P-value
E and water Test solution 22.8 1, 15 <0.0003 78.9 1, 15 <0.0001
Consecutive trials 2.4 4.5, 67.2 0.051 7.6 4.4, 66.3 <0.0001
Interaction 0.9 4.8, 72.6 0.515 12.9 4.7, 70.2 <0.0001
E and E + SS Test solution 11.9 1, 15 <0.005 20.9 1, 15 <0.001
Consecutive trials 1.3 5.3, 80.6 0.279 3.0 5.0, 75.3 0.016
Interaction 1.2 4.7, 69.9 0.287 1.2 3.9, 59 0.300
E and E + SSM Test solution 2.1 1, 15 0.173 10.4 1, 15 0.006
Consecutive trials 2.8 2.2, 33.5 0.067 6.4 4.7, 71.1 <0.0001
Interaction 1.1 3.8, 57.1 0.350 4.0 5.5, 81.9 0.002
E + SS and E + SSM Test solution 3.2 1, 11 0.102 27.0 1, 11 0.0003
Consecutive trials 1.9 5.9, 54.9 0.105 7.0 3.3, 36.1 0.0006
Interaction 1.6 5.4, 59.6 0.158 0.7 2.4, 26.9 0.519
E and E + SSM2 Test solution 13.5 1, 15 0.002 123.1 1, 15 <0.0001
Consecutive trials 1.8 5.4, 81.3 0.114 5.8 4.9, 73.5 0.0002
Interaction 1.4 5.8, 88.1 0.223 8.4 4.7, 70.3 <0.0001
E and E + SSM4 Test solution 27.2 1, 15 0.0001 42.4 1, 15 <0.0001
Consecutive trials 0.9 4.4, 66.5 0.467 0.9 3.9, 58.7 0.449
Interaction 0.3 4.6, 68.7 0.877 1.4 2.9, 44.1 0.265
Open in a new tab

In each lick test, the rat was offered two test solutions. We examined how (a) latency to initiate licking and (b) lick rate for each test solution changed across the initial 20 trials of the lick test (mean ± standard error). We alternated the presentation of each of the test solution, resulting in a total of 10 trials per test solution. For each dependent measure and pair of test solutions, we ran a 2-way repeated-measure ANOVA. We controlled for sphericity by adjusting dfs with the Greenhouse–Geisser correction.

When offered E and E + SS, the rats initiated licking more quickly for E + SS. This difference was not significant during trial 1 (paired t = 0.12, df = 15, P = 0.991) but was across all 10 trials (Table 2). Once the lick trials began, the rats licked at a faster rate for E + SS. This difference was apparent both during trial 1 (paired t = 4.15, df = 15, P = 0.0009) and across all 10 trials (Table 2).

When offered E and E + SSM, the rats initiated licking for both solutions with similar latencies across the 10 trials (Table 2). Once the lick trials began, however, the rats licked more quickly for E + SSM than E. This difference was not evident, however, until trials 5–10 (Figure 1; Table 2).

When offered E + SS and E + SSM, the rats initiated licking for both solutions at a similar latency across all 10 trials (Table 2). One the lick trials began, however, the rats licked at a faster rate for E + SSM than E + SS during trials 6–10 (Table 2; Figure 1).

When offered E and E + SSM2, the rats initiated licking more quickly for E + SSM2. This difference was not significant during trial 1 (paired t = 1.60, df = 15, P = 0.131) but was across all 10 trials (Table 2). Once the lick trials began, the rats licked more quickly for E + SSM2 than E. This difference was significant during trial 1 (paired t = 4.14, df = 15, P = 0.0009) and became more pronounced across the 10 trials (Table 2).

When offered E and E + SSM4, the rats initiated licking more quickly for E + SSM4. There was a trend for this difference to manifest itself during trial 1 (paired t = 1.99, df = 15, P = 0.0681), but it was significant across all 10 trials (Table 2). Once the lick trials began, the rats licked more quickly for E + SSM4 than E. This difference was significant both during trial 1 (paired t = 4.15, df = 15, P = 0.0009) and across all 10 trials (Table 2).

When offered water and SS, the rats initiated licking more quickly for SS (Supplementary Figure 1). This difference was not significant during trial 1 (paired t = 1.48, df = 5, P = 0.199) but was across all 10 trials (Supplementary Table 1). Once the trials began, the rats licked at a markedly higher rate for SS. This difference was significant during trial 1 (paired t = 6.55, df = 5, P = 0.0012) and across all 10 trials (Supplementary Table 1).

When offered water and SSM, the rats initiated licking more quickly for SSM (Supplementary Figure 1). This difference was not significant during trial 1 (paired t = 1.48, df = 5, P = 0.199), but it was across all 10 trials (Supplementary Table 1). Once the trials began, the rats licked at a substantially higher rate for SSM. This difference was evident both during trial 1 (paired t = 4.30, df = 11, P = 0.0077) and across all 10 trials (Supplementary Table 1).

When offered SS and SSM, the rats initiated licking more quickly for SS (Supplementary Figure 1). This difference was not evident during trial 1 (paired t = 0.34, df = 11, P = 0.739), but it was across all 10 trials (Supplementary Table 1). Once the trials began, however, the rats licked more quickly for SSM. This difference was significant both during trial 1 (paired t = 6.55, df = 5, P = 0.0012) and across all 10 trials (Supplementary Table 1).

Finally, during the 6 brief-access lick tests in Figures 1 and 3 brief-access lick tests in Supplementary Figure 1, the rats initiated a total of 33–49 trials (or about 16–25 trials for each test solution) during each test. The fact that the rats initiated so many trials for each test solution demonstrates that the rats were highly motivated to perform during the lick tests.

Figure 3.

Figure 3.

Open in a new tab

Median daily intake of ethanol (in grams per kilogram rat) during Experiment 2. We show daily ethanol intake by 6 groups of rats. The rats from each group were offered (a) 1 of the 6 ethanol-containing test solutions during Phase 1 and (b) unflavored ethanol during Phase 2. See Table 1 for a key to the acronyms. Each point represents the median daily ethanol intake by a given rat across a given phase of testing and each horizonal line represents the median daily intake across all rats in a group. Within each panel, we compare median daily ethanol intake from unflavored ethanol to that from each of the flavored ethanol solutions using Dunn’s multiple comparison test (*P < 0.05).

Daily intake of flavored versus unflavored ethanol (Experiment 2)

In Figure 2, we show daily intakes of water and each ethanol-containing test solution across Phases 1 and 2 of the experiment. There was considerable variation in daily intake of the flavored ethanol solutions both within the same rat across successive days and between different rats across any given day.

Figure 2.

Figure 2.

Open in a new tab

Daily intake (in grams) of water and 1 of the ethanol-containing test solutions across the 8 days of Phase 1 and the 3 days of Phase 2 (Experiment 2). During Phase 1, the ethanol-containing test solution was (a) E (n = 7 rats), (b) E + SS (n = 7), (c) E + SSM (n = 7), (d) E + SSM2 (n = 8), or (e) E + SSM4 (n = 8). During Phase 2, the test solution was E in Panels A–E. See Table 1 for a key to the acronyms. In each panel, we present daily intake by each rat (thin lines) and median daily intake by all rats (thick line). See Table 3 for the analysis of time-dependent changes in intake and Table 4 for a comparison of daily intake of water versus each of the test solutions.

The control rats received water and E (Figure 2a). During Phases 1 and 2, their daily intake of E was stable across exposure days (Table 3), and they consumed substantially less E than water (Table 4).

Table 3.

Test for time-dependent changes in daily intake of each ethanol-containing test solution

Phase 1 (Days 1–8) Phase 2 (Days 9–11)
Test solution n Friedman test statistic P-value Friedman test statistic P-value
E 7 13.35 0.064 3.74 0.172
E + SS 7 10.32 0.171 2.15 0.381
E + SSM 7 7.42 0.387 3.58 0.178
E + SSM2 8 31.88 <0.001* 3.94 0.156
E + SSM4 8 39.80 <0.001* 0.75 0.794
Open in a new tab

See Figure 2 for an illustration of the data and Table 1 for a key to the acronyms. We analyzed daily intake of the test solutions, separately for Phases 1 and 2, with Friedman test. Because we conducted two Friedman tests for each test solution (during Phases 1 and 2), we had to control the Type 1 error rate with Bonferroni correction (*P < 0.05/2 = 0.025).

Table 4.

Comparison of daily intake of water versus each ethanol-containing test solution during Phases 1 and 2

Phase 1 (Days 1–8) Phase 2 (Days 9–11)
Test solutions n Wilcoxon test statistic P-value Wilcoxon test statistic P-value
Water vs E 7 −28 0.016* −28 0.016*
Water vs. E + SS 7 +12 0.375 −28 0.016*
Water vs. E + SSM 7 +28 0.016* −28 0.016*
Water vs. E + SSM2 8 −18 0.250 −36 0.008*
Water vs. E + SSM4 8 +6 0.742 −36 0.008*
Open in a new tab

See Figure 2 for an illustration of the data and Table 1 for a key to the acronyms. For each rat, we determined median daily intake of water and test solution separately for Phases 1 and 2. Then, we compared median daily intake of water and test solution using Wilcoxon matched-pairs signed rank test. Because we conducted two Wilcoxon tests for each test solution (during Phases 1 and 2), we had to control the Type 1 error rate with Bonferroni correction (*P < 0.05/2 = 0.025).

The experimental rats received water and a flavored ethanol solution (Figures 2b–2e). During Phase 1, daily intake of E + SS and E + SSM was stable over time, whereas daily intake of E + SSM2 and E + SSM4 increased systematically over time (Table 3). The rats consumed similar amounts of 1) water and E + SS, 2) water and E + SSM2, and 3) water and E + SSM4 but 4) lower amounts of water than E + SSM (Table 4). During Phase 2, the rats all received water and E. They exhibited stable daily intakes of E (Table 3) and consumed significantly less E than water (Table 4).

In Figure 3a, we show median daily intakes of ethanol (in grams per kilogram of rat) from each test solution across Phase 1 (Figure 3a). A Kruskal–Wallis ANOVA revealed a significant main effect of test solution on daily ethanol intake (Kruskal–Wallis statistic = 17.9, P < 0.002). The experimental rats obtained more ethanol per day from E + SS, E + SSM, and E + SSM4 than the control rats obtained from E according to a Dunn’s multiple comparison test (P < 0.05). Indeed, the experimental rats ingested a median of about 10 g/kg of ethanol per day from these flavored ethanol solutions, whereas the control rats ingested a median of 0.6 g/kg of ethanol per day from the unflavored ethanol—an approximate 16-fold difference in daily intake. There was also a strong trend for the rats to obtain more ethanol from E + SSM2 than E, but the difference was not significant (P = 0.065). It is notable that increasing the concentration of sucrose and maltodextrin (and, hence, sweet/maltodextrin taste intensity and caloric density) in the SSM formulations did not cause a corresponding increase in daily ethanol intake.

In Figure 3b, we show median daily intakes of ethanol (in grams per kilogram) from the unflavored ethanol solution across Phase 2. There was no effect of the test solution to which the rat had been exposed during Phase 1 (Kruskal–Wallis statistic = 1.7, P > 0.79). The control and experimental rats all consumed only small quantities of ethanol (0.6–0.8 g/kg) each day. Thus, the consumption of high quantities of flavored ethanol during Phase 1 did not increase the consumption of unflavored ethanol during Phase 2.

In Supplementary Figure 2, we show how daily intake of SS or SSM during Phase 1 impacted daily intake of E during Phase 2. Daily intake of SS (Friedman statistic = 53.23, P < 0.0001) and SSM (Friedman statistic = 35.27, P < 0.0001) increased systematically over Phase 1. Furthermore, the rats consumed substantially more SS (Wilcoxon statistic = 120, P < 0.0001) and SSM (Wilcoxon statistic = 114, P < 0.0004) than water. During Phase 2, daily intake of E did not change systematically over time in rats previously exposed to SS (Friedman statistic = 4.79, P = 0.091) or SSM (Friedman statistic = 0.93, P = 0.63). Furthermore, the rats previously exposed to SS (Wilcoxon statistic = −102, P = 0.002) and SSM (Wilcoxon statistic = −114, P = 0.0003) consumed significantly less E than water. These results reveal that high daily intakes of SS or SSM during Phase 1 did not promote high daily intakes of unflavored ethanol during Phase 2. In addition, the fact that daily intake of SS and SSM was substantially higher than daily intake of E + SS and E + SSM (in Figure 2) shows that the presence of ethanol strongly inhibited daily intake of SS and SSM.

Discussion

Naso-oral acceptability of flavored versus unflavored ethanol

Odors emitted from the test solutions had robust impacts on the appetitive phase of ingestion during the brief-access lick tests. For instance, the adolescent rats initiated licking more quickly for water than for E even during trial 1. This finding is consistent with a prior report that the odor of ethanol is inherently aversive to rodents (Nachman et al. 1971). The rats also initiated licking more quickly for 1) SS and SSM than water and 2) E + SS, E + SSM2, and E + SSM4 than E. These latter findings show that odor cues from the flavorants influenced ingestive responses of the rats both when the flavorants were presented alone and mixed with ethanol. That the latency to initiate licking for E + SSM and E did not differ indicates that the odor cues from SSM were not salient in the presence of 10% ethanol.

We can propose 2 nonmutually exclusive explanations for why the adolescent rats were more attracted to the odor of flavored than unflavored ethanol solutions. First, prior studies have revealed that when rats are presented with a binary mixture of odors, one odor often partially masks the other odor (Bell et al. 1987; Laing et al. 1989). Here, the odor of the flavorants (e.g., SS) could have partially masked the odor of the ethanol, making it less aversive. Second, Coppola and Slotnick (2018) reported that mice learn rapidly to associate the odor of quinine and denatonium benzoate with their bitter taste (often after a single trial) and, subsequently, avoid these bitter stimuli based on olfaction alone. Here, the rats could have learned to associate the odors from one test solution (e.g., E + SS) with its more pleasant naso-oral sensations, relative to ethanol alone, and subsequently approached E + SS more readily. Because there was no difference in latency to initiate licking for the flavored and unflavored ethanol solutions during trial 1 of the lick tests, our results would appear to support the associative learning explanation. It is also possible, however, that lack of odor discrimination during trial 1 reflects the fact that the difference in odor quality between, for instance, E and E + SS was subtle. If so, then this would explain why the rats discriminated the odor of these solutions during most but not all of the initial 10 trials.

Further work is needed to explain the nature of the odor cues emitted from the flavorants. The odor cues could have been derived from the flavorants themselves, contaminants in the flavorants, or a combination of both (Rhinehart-Doty et al. 1994; Coppola and Slotnick 2018; Glendinning et al. 2020). Irrespective of the nature of these odor cues, the fact that they could be detected reliably in the presence of ethanol suggests that they are salient to adolescent rats. Elsewhere, we reported that mice can detect odor cues from glucose and fructose solutions even when mixed with amyl acetate (Glendinning et al. 2020), supporting the idea that the odor cues from sugars can be detected in the presence of other odorants.

The adolescent rats licked at higher rates for flavored than unflavored ethanol solutions. In some instances (e.g., E + SS, E + SSM2, and E + SSM4), there was a difference in lick rate during trial 1. This indicates that the higher acceptability of these flavored ethanol solutions was, at least in part, unlearned. Given that lick rate increases with the naso-oral acceptability of chemical solutions in rats (Davis 1973; Rhinehart-Doty et al. 1994; Smith and Sclafani 2002), it follows that the flavorants increased the naso-oral acceptability of ethanol. They could have done so in 5 nonmutually exclusive ways. First, the rats were attracted to the orosensory properties of the flavorants per se. Second, retronasal odors (i.e., volatiles that arise from the oral cavity during eating and drinking) and taste both share common processing circuitry (Blankenship et al. 2019). Accordingly, it is possible that retronasal odors from the flavorants improved the acceptability of ethanol’s orosensory properties. Third, given that sucrose and saccharin can inhibit the bitter taste of quinine (Kroeze and Bartoshuk 1985; Formaker and Frank 1996; Talavera et al. 2008), it is possible that they inhibited the bitter taste of ethanol in the present study. Fourth, ethanol can enhance the sweet taste of sucrose in humans (Martin and Pangborn 1970). This observation may reflect the fact that, at least in rats, sucrose and ethanol stimulate many of the same taste-responsive neurons in the nucleus of the solitary tract (Lemon et al. 2004). If so, then the ethanol-enhanced sweetness of the flavorants could have inhibited the bitterness of the ethanol more effectively. Fifth, sucrose inhibits the trigeminally mediated burning sensations from capsaicin in humans (Smutzer et al. 2018). Accordingly, the flavorants may have partially inhibited the burning sensation from ethanol.

Daily intake of flavored versus unflavored ethanol

During Phase 1, the control rats largely avoided unflavored ethanol, consuming substantially greater quantities of water instead. In contrast, the experimental rats generally consumed either equivalent or even larger quantities of the flavored ethanol solutions than water. In fact, they obtained a median of 6–10 g/kg of ethanol from the flavored ethanol solutions, which is comparable to values reported previously (Doremus et al. 2005) for adolescent rats that were offered a mixture of 0.1% saccharin and 10% ethanol. An important feature of our findings is that that adolescent rats did not have to be acclimated to the flavored ethanol solutions to exhibit high daily intakes—for example, through a fading procedure (Samson 1986; Tolliver et al. 1988), intermittent access (Carnicella et al. 2014), or induction of detoxification enzymes (Kalant et al. 1971). On the contrary, the adolescent rats exhibited high daily intakes of the flavored ethanol solutions during the first and all subsequent days of exposure. This likely reflects the fact that the flavored ethanol solutions were attractive to the adolescent rats.

Did postingestive actions of the flavorants enhance daily intake of the flavored ethanol solutions? For example, there are reports (Jones et al. 1979; Roberts et al. 1999; Matthews et al. 2001) that sugars increase the rate of ethanol elimination from the blood when they are coadministered with ethanol. However, this finding is controversial (Czachowski et al. 1999) and there is no direct evidence that the reductions in postprandial blood ethanol promote greater daily intake of ethanol. There are also reports that intragastric infusions of glucose-containing carbohydrates can condition higher daily intake of ethanol and other flavored solutions in rats by activating a postingestive glucose appetition mechanism (Ackroff and Sclafani 2002; Sclafani and Ackroff 2012). Accordingly, it is possible that the postingestive actions of the various SS and SSM flavorants contributed to the enhanced intakes produced by the flavorants. In support of this possibility, intragastric infusions of 2–4% maltodextrin solutions (diluted to 1–2% in the gut) have been shown to condition preferences for an unsweetened flavored solution in rats (Ackroff and Sclafani 1994). In the present study, however, we did not obtain clear evidence that postingestive nutritive actions of the flavorants enhanced daily intake of the flavored ethanol solutions. On the one hand, the observation that daily intake of the most calorically dense test solutions (E + SSM2 and E + SSM4) increased systematically across Phase 1 supports a contribution of postingestive nutritive conditioning. On the other hand, the observation that daily intake of the E + SSM2 and E + SSM4 solution never actually exceeded that of the less calorically dense E + SS and E + SSM solutions contradicts a contribution of postingestive nutritive conditioning.

The adolescent rats consumed about 3 times more SS and SSM than E + SS and E + SSM. This indicates that irrespective of how attractive the flavorants were to adolescent rats, daily intake of the flavored ethanol solutions was limited by ethanol. Indeed, the findings reported herein and elsewhere (Doremus et al. 2005) indicate that adolescent rats will not voluntarily consume ethanol doses greater than 8–10 g/kg/day. This apparent upper limit may reflect a postingestive processing constraint for ethanol. If so, then it would explain why the rats did not consume greater quantities of the flavored ethanol solutions relative to water during Phase 1. Indeed, the adolescent rats ingested only slightly more E + SSM than water and statistically equivalent amounts of the other flavored ethanol solutions and water. The processing constraint would also explain why daily intake of E + SSM, E + SSM2, and E + SSM4 did not increase with carbohydrate concentration and caloric content. In fact, the adolescent rats consumed equivalent quantities of ethanol as part of E + SSM and E + SSM4 but slightly less E + SSM2.

The experimental rats exhibited high daily intakes of the flavored ethanol solutions during Phase 1 but low daily intakes of unflavored ethanol during Phase 2. It is unlikely that this result reflects a negative contrast effect because the control and experimental rats both exhibited similarly low daily intakes of unflavored ethanol during Phase 2. While it is possible that the experimental rats would have consumed more unflavored ethanol if we had employed a saccharin- or sucrose-fading procedure during the transition from Phase 1 to 2 (Samson 1986; Tolliver et al. 1988), a prior study reported that fading produces only small increases in daily intake of unflavored ethanol (Tolliver et al. 1988). Further, it is doubtful that the low daily intake of unflavored ethanol during Phase 2 can be explained by the rats having conditioned an aversion to the naso-oral features of ethanol during Phase 1. This is because exposure to unflavored ethanol solutions has been found to increase (not decrease) rates of licking for unflavored ethanol in both adolescent (Tang et al. 2018) and adult (Loney and Meyer 2018) rats. Instead, we propose that, despite extensive dietary exposure to the reinforcing pharmacological effects of ethanol during Phase 1, the experimental rats still could not overcome their aversion to the naso-oral sensory attributes of unflavored ethanol during Phase 2.

In the present study, the adolescent rats consumed large quantities of ethanol (6–10 g/kg/day) during Phase 1 as part of the flavored ethanol solutions. These high daily intakes of ethanol are typically only seen following extensive acclimatization procedures (e.g., multiple weeks of intermittent exposure; Carnicella et al. 2014). Given that such high rates of ethanol intake can produce alcohol dependency in rats (Carnicella et al. 2014), our findings provide support for the hypothesis that flavored alcoholic beverages provide a gateway to problematic alcohol intake in adolescents. Elsewhere, 2 studies asked whether exposure to flavored ethanol during adolescence promotes the consumption of flavored and unflavored ethanol during adulthood. One study found that the ethanol exposure increased the consumption of flavored but not unflavored ethanol during adulthood (Broadwater et al. 2013), whereas the other found that it decreased the consumption of flavored but not unflavored ethanol during adulthood (Vendruscolo et al. 2010). The discrepant findings from these prior studies require further study. Nevertheless, it is notable that, in both of the prior studies and the present study, exposure to flavored ethanol during adolescence was not associated with increased consumption of unflavored ethanol during adolescence or adulthood.

Conclusions

Our results show that sweet and sweet/maltodextrin flavorants can markedly increase daily intake of 10% ethanol in adolescent rats and that they do so, in large part, by improving the naso-oral sensory attributes of ethanol. This finding indicates that adolescent rats could represent a useful model system for understanding how sweet and fruity flavorants promote ethanol consumption in adolescent humans. To gain insight into why adolescent rats consume more flavored ethanol (in grams per kilogram) than adult rats, future studies should examine the impact of flavorants on naso-oral acceptability and daily intake of 10% ethanol in adult rats. It is possible that flavorants are less effective at improving the naso-oral sensory attributes of ethanol in adults.

Supplementary Material

bjaa056_suppl_Supplemental_Data
Click here for additional data file. (99.1KB, pdf)

Acknowledgments

We thank Anthony Sclafani, Karen Ackroff, and two anonymous reviewers for valuable editorial comments.

Funding

This work was supported by the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health [grant number AA-017823] and a Beckman Scholar Award to A.S. from the Arnold and Mabel Beckman Foundation.

References

  1. Ackroff K, Sclafani A. 1994. Flavor preferences conditioned by intragastric infusions of dilute polycose solutions. Physiol Behav. 55(5):957–962. [DOI] [PubMed] [Google Scholar]
  2. Ackroff K, Sclafani A. 2002. Ethanol flavor preference conditioned by intragastric carbohydrate in rats. Pharmacol Biochem Behav. 74(1):41–51. [DOI] [PubMed] [Google Scholar]
  3. Albers AB, Siegel M, Ramirez RL, Ross C, DeJong W, Jernigan DH. 2015. Flavored alcoholic beverage use, risky drinking behaviors, and adverse outcomes among underage drinkers: results from the ABRAND Study. Am J Public Health. 105(4):810–815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bates ME, Labouvie EW. 1997. Adolescent risk factors and the prediction of persistent alcohol and drug use into adulthood. Alcohol Clin Exp Res. 21(5):944–950. [PubMed] [Google Scholar]
  5. Bell GA, Laing DG, Panhuber H. 1987. Odour mixture suppression: evidence for a peripheral mechanism in human and rat. Brain Res. 426(1):8–18. [DOI] [PubMed] [Google Scholar]
  6. Blankenship ML, Grigorova M, Katz DB, Maier JX. 2019. Retronasal odor perception requires taste cortex, but orthonasal does not. Curr Biol. 29(1):62–69.e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Broadwater M, Varlinskaya EI, Spear LP. 2011. Chronic intermittent ethanol exposure in early adolescent and adult male rats: effects on tolerance, social behavior, and ethanol intake. Alcohol Clin Exp Res. 35(8):1392–1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Broadwater M, Varlinskaya EI, Spear LP. 2013. Effects of voluntary access to sweetened ethanol during adolescence on intake in adulthood. Alcohol Clin Exp Res. 37(6):1048–1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brunell SC, Spear LP. 2005. Effect of stress on the voluntary intake of a sweetened ethanol solution in pair-housed adolescent and adult rats. Alcohol Clin Exp Res. 29(9):1641–1653. [DOI] [PubMed] [Google Scholar]
  10. Carnicella S, Ron D, Barak S. 2014. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol. 48(3):243–252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Copeland J, Stevenson RJ, Gates P, Dillon P. 2007. Young Australians and alcohol: the acceptabllity of ready-to-drink (RTD) alcoholic beverages among 12-30-year-olds. Addiction. 102(11):1740–1746. [DOI] [PubMed] [Google Scholar]
  12. Coppola DM, Slotnick B. 2018. Odor-cued bitter taste avoidance. Chem Senses. 43(4):239–247. [DOI] [PubMed] [Google Scholar]
  13. Czachowski CL, Samson HH, Denning CE. 1999. Blood ethanol concentrations in rats drinking sucrose/ethanol solutions. Alcohol Clin Exp Res. 23(8):1331–1335. [PubMed] [Google Scholar]
  14. Davis JD. 1973. The effectiveness of some sugars in stimulating licking behavior in the rat. Physiol Behav. 11(1):39–45. [DOI] [PubMed] [Google Scholar]
  15. Di Lorenzo PM, Kiefer SW, Rice AG, Garcia J. 1986. Neural and behavioral responsivity to ethyl alcohol as a tastant. Alcohol. 3(1):55–61. [DOI] [PubMed] [Google Scholar]
  16. Doremus TL, Brunell SC, Rajendran P, Spear LP. 2005. Factors influencing elevated ethanol consumption in adolescent relative to adult rats. Alcohol Clin Exp Res. 29(10):1796–1808. [DOI] [PubMed] [Google Scholar]
  17. Ellingson JM, Silbaugh BC, Brasser SM. 2009. Reduced oral ethanol avoidance in mice lacking transient receptor potential channel vanilloid receptor. Behav Genet. 39: 62–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Formaker BK, Frank ME. 1996. Responses of the hamster chorda tympani nerve to binary component taste stimuli: evidence for peripheral gustatory mixture interactions. Brain Res. 727(1-2):79–90. [DOI] [PubMed] [Google Scholar]
  19. Fortunato EK, Siegel M, Ramirez RL, Ross C, DeJong W, Albers AB, Jernigan DH. 2014. Brand-specific consumption of flavored alcoholic beverages among underage youth in the United States. Am J Drug Alcohol Abuse. 40(1):51–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Glendinning JI, Maleh J, Ortiz G, Touzani K, Sclafani A. 2020. Olfaction contributes to the learned avidity for glucose relative to fructose in mice. Am J Physiol Regul Integr Comp Physiol. 318(5):R901–R916. [DOI] [PubMed] [Google Scholar]
  21. Glendinning JI, Tang J, Morales Allende AP, Bryant BP, Youngentob L, Youngentob SL. 2017. Fetal alcohol exposure reduces responsiveness of taste nerves and trigeminal chemosensory neurons to ethanol and its flavor components. J Neurophysiol. 118(2):1198–1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hosová D, Spear LP. 2017. Voluntary binge consumption of ethanol in a sweetened, chocolate-flavored solution by male and female adolescent Sprague–Dawley rats. Alcohol Clin Exp Res. 41(3):541–550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hosová D, Spear LP. 2019. Voluntary elevated ethanol consumption in adolescent Sprague–Dawley rats: procedural contributors and age-specificity. Alcohol. 78:1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hughes K, MacKintosh AM, Hastings G, Wheeler C, Watson J, Inglis J. 1997. Young people, alcohol, and designer drinks: quantitative and qualitative study. BMJ. 314(7078):414–418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ji D, Gilpin NW, Richardson HN, Rivier CL, Koob GF. 2008. Effects of naltrexone, duloxetine, and a corticotropinreleasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats. Behav Pharmacol. 19: 1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jones AW, Goldberg L, Neri A. 1979. Effects of a sugar mixture on blood alcohol parameters and impairment in the intact rat. Acta Pharmacol Toxicol (Copenh). 45(5):345–351. [DOI] [PubMed] [Google Scholar]
  27. Kalant H, LeBlanc AE, Gibbins RJ. 1971. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev. 23(3):135–191. [PubMed] [Google Scholar]
  28. Kroeze JH, Bartoshuk LM. 1985. Bitterness suppression as revealed by split-tongue taste stimulation in humans. Physiol Behav. 35(5):779–783. [DOI] [PubMed] [Google Scholar]
  29. Kulkosky PJ. 1979. Effect of addition of ethanol and NaCl on saccharin + glucose polydipsia. Pharmacol Biochem Behav. 10(2):277–283. [DOI] [PubMed] [Google Scholar]
  30. Laing DG, Panhuber H, Slotnick BM. 1989. Odor masking in the rat. Physiol Behav. 45(4):689–694. [DOI] [PubMed] [Google Scholar]
  31. Lemon CH, Brasser SM, Smith DV. 2004. Alcohol activates a sucrose-responsive gustatory neural pathway. J Neurophysiol. 92(1):536–544. [DOI] [PubMed] [Google Scholar]
  32. Li TK, Lumeng L, McBride WJ, Murphy JM. 1993. An experimental approach to understanding the genetic and neurobiological basis of alcoholism. Trans Am Clin Climatol Assoc. 104:61–72; discussion 72. [PMC free article] [PubMed] [Google Scholar]
  33. Loney GC, Meyer PJ. 2018. Brief exposures to the taste of ethanol (EtOH) and quinine promote subsequent acceptance of EtOH in a paradigm that minimizes postingestive consequences. Alcohol Clin Exp Res. 42(3):589–602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Martin S, Pangborn RM. 1970. Taste interaction of ethyl alcohol with sweet, salty, sour and bitter compounds. J Sci Food Agric. 21(12):653–655. [DOI] [PubMed] [Google Scholar]
  35. Matthews DB, Overstreet DH, Rezvani AH, Devaud LL, Morrow AL. 2001. Effects of sweetened ethanol solutions on ethanol self-administration and blood ethanol levels. Pharmacol Biochem Behav. 68(1):13–21. [DOI] [PubMed] [Google Scholar]
  36. Moore M, Weiss S. 1995. Reasons for non-drinking among Israeli adolescents of four religions. Drug Alcohol Depend. 38(1):45–50. [DOI] [PubMed] [Google Scholar]
  37. Nachman M, Larue C, Le Magnen J. 1971. The role of olfactory and orosensory factors in the alcohol preference of inbred strains of mice. Physiol Behav. 6(1):53–59. [DOI] [PubMed] [Google Scholar]
  38. Nolden AA, Hayes JE. 2015. Perceptual qualities of ethanol depend on concentration, and variation in these percepts associates with drinking frequency. Chemosens Percept. 8(3):149–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rhinehart-Doty JA, Schumm J, Smith JC, Smith GP. 1994. A non-taste cue of sucrose in short-term taste tests in rats. Chem Senses. 19(5):425–431. [DOI] [PubMed] [Google Scholar]
  40. Roberts AJ, Heyser CJ, Koob GF. 1999. Operant self-administration of sweetened versus unsweetened ethanol: effects on blood alcohol levels. Alcohol Clin Exp Res. 23(7):1151–1157. [PubMed] [Google Scholar]
  41. Romanus G. 2000. Alcopops in Sweden—a supply side initiative. Addiction. 95(Suppl 4):S609–S619. [DOI] [PubMed] [Google Scholar]
  42. Samson HH. 1986. Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res. 10(4):436–442. [DOI] [PubMed] [Google Scholar]
  43. Samson HH, Maxwell CO, Doyle TF. 1989. The relation of initial alcohol experiences to current alcohol consumption in a college population. J Stud Alcohol. 50(3):254–260. [DOI] [PubMed] [Google Scholar]
  44. Schier LA, Inui-Yamamoto C, Blonde GD, Spector AC. 2019. T1R2+T1R3-independent chemosensory inputs contributing to behavioral discrimination of sugars in mice. Am J Physiol Regul Integr Comp Physiol. 316(5):R448–R462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sclafani A, Ackroff K. 2012. Role of gut nutrient sensing in stimulating appetite and conditioning food preferences. Am J Physiol Regul Integr Comp Physiol. 302(10):R1119–R1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sclafani A, Thompson B, Smith JC. 1998. The rat’s acceptance and preference for sucrose, maltodextrin, and saccharin solutions and mixtures. Physiol Behav. 63(4):499–503. [DOI] [PubMed] [Google Scholar]
  47. Simms JA, Steensland P, Medina B, Abernathy KE, Chandler LJ, Wise R, Bartlett SE. 2008. Intermittent access to 20% ethanol induces high ethanol consumption in Long–Evans and Wistar Rats. Alcohol Clin Exp Res. 32: 1816–1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Smith JC, Sclafani A. 2002. Saccharin as a sugar surrogate revisited. Appetite. 38(2):155–160. [DOI] [PubMed] [Google Scholar]
  49. Smutzer G, Jacob JC, Tran JT, Shah DI, Gambhir S, Devassy RK, Tran EB, Hoang BT, McCune JF. 2018. Detection and modulation of capsaicin perception in the human oral cavity. Physiol Behav. 194:120–131. [DOI] [PubMed] [Google Scholar]
  50. Spear LP. 2000. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 24(4):417–463. [DOI] [PubMed] [Google Scholar]
  51. Talavera K, Yasumatsu K, Yoshida R, Margolskee RF, Voets T, Ninomiya Y, Nilius B. 2008. The taste transduction channel TRPM5 is a locus for bitter-sweet taste interactions. FASEB J. 22(5):1343–1355. [DOI] [PubMed] [Google Scholar]
  52. Tang J, Youngentob SL, Glendinning JI. 2018. Postnatal exposure to ethanol increases its oral acceptability to adolescent rats. Chem Senses. 43(8):655–664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tolliver GA, Sadeghi KG, Samson HH. 1988. Ethanol preference following the sucrose-fading initiation procedure. Alcohol. 5(1):9–13. [DOI] [PubMed] [Google Scholar]
  54. Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B, Amadesi S, Gray J, Jerman JC, Brough SJ, et al.  2002. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci. 5(6):546–551. [DOI] [PubMed] [Google Scholar]
  55. Vendruscolo LF, Gueye AB, Vendruscolo JC, Clemens KJ, Mormède P, Darnaudéry M, Cador M. 2010. Reduced alcohol drinking in adult rats exposed to sucrose during adolescence. Neuropharmacology. 59(6):388–394. [DOI] [PubMed] [Google Scholar]
  56. Vetter CS, Doremus-Fitzwater TL, Spear LP. 2007. Time course of elevated ethanol intake in adolescent relative to adult rats under continuous, voluntary-access conditions. Alcohol Clin Exp Res. 31(7):1159–1168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Vetter-O’Hagen C, Varlinskaya E, Spear L. 2009. Sex differences in ethanol intake and sensitivity to aversive effects during adolescence and adulthood. Alcohol Alcohol. 44(6):547–554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Walker BM, Walker JL, Ehlers CL. 2008. Dissociable effects of ethanol consumption during the light and dark phase in adolescent and adult Wistar rats. Alcohol. 42(2):83–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wechsler H, Kuo M, Lee H, Dowdall GW. 2000. Environmental correlates of underage alcohol use and related oproblems of college students. Am J Prev Med. 19: 24–29. [DOI] [PubMed] [Google Scholar]
  60. Youngentob SL, Glendinning JI. 2009. Fetal ethanol exposure increases ethanol intake by making it smell and taste better. Proc Natl Acad Sci USA. 106(13):5359–5364. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

bjaa056_suppl_Supplemental_Data
Click here for additional data file. (99.1KB, pdf)

Articles from Chemical Senses are provided here courtesy of Oxford University Press

RESOURCES