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Isomaltulose, a slowly digested isocaloric analog of sucrose, and allulose, a noncaloric fructose analog, are promoted as "healthful" sugar alternatives in human food products. Here we investigated the appetite and preference conditioning actions of these sugar analogs in inbred mouse strains. In brief-access lick tests (Experiment 1), C57BL/6 (B6) mice showed similar concentration dependent increases in licking for allulose and fructose, but less pronounced concentration-dependent increases in licking for isomaltulose than sucrose. In Experiment 2, B6 mice were given one-bottle training with a CS+ flavor (e.g., grape) mixed with 8% isomaltulose or allulose and a CS- flavor (e.g., cherry) mixed in water followed by two-bottle CS flavor tests. The isomaltulose mice showed only a weak CS+ flavor preference but a strong preference for the sugar over water. The allulose mice strongly preferred the CS- flavor and water over the sugar. The allulose avoidance may be due to gut discomfort as reported in humans consuming high amounts of the sugar. Experiment 3 found that the preference for 8% sucrose over 8% isomaltulose could be reversed or blocked by adding different concentrations of a noncaloric sweetener mixture (sucralose + saccharin, SS) to the isomaltulose. Experiment 4 revealed that the preference of B6 or FVB/N mice for isomaltulose+0.01%SS or sucrose over 0.1%SS increased after separate experience with the sugars and SS. This indicates that isomaltulose, like sucrose, has postoral appetition effects that enhances the appetite for the sugar. In Experiments 5 and 6, the appetition actions of the two sugars were directly compared by giving mice isomaltulose+0.05%SS vs. sucrose choice tests before and after separate experience with the two sugars. In general, the initial preference the mice displayed for isomaltulose+0.05%SS was reduced or reversed after separate experience with the two sugars although some strain and sex differences were obtained. This indicates that isomaltulose has weaker postoral appetition effects than sucrose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

When offered glucose and fructose solutions, rodents consume more glucose solution because it produces stronger postoral reinforcement. Intake of these sugars also conditions a higher avidity for glucose relative to fructose. We asked which chemosensory cue mediates the learned avidity for glucose. We subjected mice to 18 days of sugar training, offering them 0.3, 0.6, and 1 M glucose and fructose solutions. Before and after training, we measured avidity for 0.3 and 0.6 M glucose and fructose in brief-access lick tests. First, we replicated prior work in C57BL/6 mice. Before training, the mice licked at a slightly higher rate for 0.6 M fructose; after training, they licked at a higher rate for 0.6 M glucose. Second, we assessed the necessity of the glucose-specific ATP-sensitive K + (K ATP ) taste pathway for the learned avidity for glucose, using mice with a nonfunctional K ATP channel [regulatory sulfonylurea receptor (SUR1) knockout (KO) mice]. Before training, SUR1 KO and wild-type mice licked at similar rates for 0.6 M glucose and fructose; after training, both strains licked at a higher rate for 0.6 M glucose, indicating that the K ATP pathway is not necessary for the learned discrimination. Third, we investigated the necessity of olfaction by comparing sham-treated and anosmic mice. The mice were made anosmic by olfactory bulbectomy or ZnSO 4 treatment. Before training, sham-treated and anosmic mice licked at similar rates for 0.6 M glucose and fructose; after training, sham-treated mice licked at a higher rate for 0.6 M glucose, whereas anosmic mice licked at similar rates for both sugars. This demonstrates that olfaction contributes significantly to the learned avidity for glucose.

A recent study indicated that CAST/EiJ and C57BL/6J mice differ in their taste preferences for maltodextrin but display similar sucrose preferences. The present study revealed strain differences in preferences for the constituent sugars of sucrose. Whereas B6 mice preferred 8% glucose to 8% fructose in 2-day tests, the CAST mice preferred fructose to glucose. These preferences emerged with repeated testing which suggested post-oral influences. In a second experiment, 2-day choice tests were conducted with the sugars versus a sucralose + saccharin (SS) mixture which is highly preferred in brief access tests. B6 mice strongly preferred glucose but not fructose to the non-nutritive SS whereas CAST mice preferred SS to both glucose and fructose even when food restricted. This implied that CAST mice are insensitive to the postoral appetite stimulating actions of the 2 sugars. A third experiment revealed, however, that intragastric glucose and fructose infusions conditioned significant but mild flavor preferences in CAST mice, whereas in B6 mice glucose conditioned a robust preference but fructose was ineffective. Thus, unlike other mouse strains and rats, glucose is not more reinforcing than fructose in CAST mice. Their oral preference for fructose over glucose may be related to a subsensitive maltodextrin receptor or glucose-specific receptor which is stimulated by glucose but not fructose. The failure of CAST mice to prefer glucose to a non-nutritive sweetener distinguishes this strain from other mouse strains and rats., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies indicate that C57BL/6J (B6) and FVB inbred mouse strains differ in post-oral fructose conditioning. This was demonstrated by their differential flavor conditioning response to intragastric fructose and their preference for fructose versus a non-nutritive sweetener. The present study extended this analysis to SWR and BALB/c inbred strains which are of interest because they both show robust flavor conditioning responses to fructose. In the first experiment, ad-libitum fed mice were given a series of 2-day, two-bottle preference tests between 8% fructose and a more preferred, but non-nutritive 0.1% sucralose +0.1% saccharin (S+S) solution (tests 1 & 4), and fructose or S+S versus water (tests 2 and 3). In test 1, SWR mice preferred S+S to fructose, and in tests 2 and 3, they preferred both sweeteners to water. In test 4, SWR mice switched their preference and consumed more fructose than S+S. In contrast, ad-libitum fed BALB/c mice strongly preferred S+S to fructose in both tests 1 and 4, although they preferred both sweeteners to water in tests 2 and 3. Food-restricted BALB/c mice also preferred the non-nutritive S+S to fructose in tests 1 and 4. The experience-induced fructose preference reversal observed in SWR, but not BALB/c mice indicates that fructose has a post-oral reinforcing effect in SWR mice as in FVB mice. Because B6 and FVB mice prefer glucose to fructose based on the post-oral actions of the two sugars, the second experiment compared the preferences of SWR and BALB/c mice for 8% glucose and fructose solutions. Ad-libitum fed and food-restricted SWR mice strongly preferred glucose to fructose. In contrast, ad-libitum fed BALB/c mice were indifferent to the sugars, perhaps because of their overall low intakes. Food-restricted BALB/c mice, however, strongly preferred glucose. These findings indicate that SWR and BALB/c mice differ in their preference response to the post-oral actions of fructose., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Intragastric (IG) flavor conditioning studies in rodents indicate that isocaloric sugar infusions differ in their reinforcing actions, with glucose and sucrose more potent than fructose. Here we determined if the sugars also differ in their ability to maintain operant self-administration by licking an empty spout for IG infusions. Food-restricted C57BL/6J mice were trained 1 h/day to lick a food-baited spout, which triggered IG infusions of 16% sucrose. In testing, the mice licked an empty spout, which triggered IG infusions of different sugars. Mice shifted from sucrose to 16% glucose increased dry licking, whereas mice shifted to 16% fructose rapidly reduced licking to low levels. Other mice shifted from sucrose to IG water reduced licking more slowly but reached the same low levels. Thus IG fructose, like water, is not reinforcing to hungry mice. The more rapid decline in licking induced by fructose may be due to the sugar's satiating effects. Further tests revealed that the Glucose mice increased their dry licking when shifted from 16% to 8% glucose, and reduced their dry licking when shifted to 32% glucose. This may reflect caloric regulation and/or differences in satiation. The Glucose mice did not maintain caloric intake when tested with different sugars. They self-infused less sugar when shifted from 16% glucose to 16% sucrose, and even more so when shifted to 16% fructose. Reduced sucrose self-administration may occur because the fructose component of the disaccharide reduces its reinforcing potency. FVB mice also reduced operant licking when tested with 16% fructose, yet learned to prefer a flavor paired with IG fructose. These data indicate that sugars differ substantially in their ability to support IG self-administration and flavor preference learning. The same post-oral reinforcement process appears to mediate operant licking and flavor learning, although flavor learning provides a more sensitive measure of sugar reinforcement., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sugar appetite is influenced by unlearned and learned preferences in rodents. The present study examined whether dopamine (DA) D1 (SCH23390: SCH) and opioid (naltrexone: NTX) receptor antagonists differentially altered the expression and acquisition of fructose-conditioned flavor preferences (CFPs) in BALB/c and SWR mice. In expression experiments, food-restricted mice alternately (10 sessions, 1h) consumed a flavored (e.g., cherry) 8% fructose+0.2% saccharin solution (CS+) and a differently-flavored (e.g., grape) 0.2% saccharin solution (CS-). Two-bottle CS choice tests (1h) occurred 0.5h following vehicle: SCH (200 or 800 nmol/kg) or NTX (1 or 5mg/kg). SCH, but not NTX significantly reduced CS+ preference in both strains. In acquisition experiments, 0.5h prior to 10 acquisition training sessions, vehicle, SCH (50 nmol/kg), NTX (1 mg/kg) or Limited Control vehicle treatments were administered, followed by two-bottle CS choice tests without injections. SCH and NTX reduced training intakes in both strains. BALB/c mice displayed hastened extinction of the fructose-CFP following training with SCH, but not NTX. SCH eliminated fructose-CFP acquisition in SWR mice, whereas NTX hastened extinction of the CFP. These results are compared to previous drug findings obtained with sucrose-CFPs in SWR and BALB/c mice, and are discussed in terms of differential effects of these sugars on oral and post-oral conditioning., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sugar and fat intake in rodents are mediated in part by brain dopamine (DA) and opioid neurotransmitter systems although important strain differences exist. Thus, whereas sucrose intake of BALB/c and SWR mice was reduced by DA D1 (SCH23390: SCH) receptor antagonism, opioid (naltrexone: NTX) receptor antagonism reduced intake only in BALB/c mice. Both SCH and NTX reduced fat (Intralipid) intake in SWR, but not BALB/c mice. The present study extended this pharmacological analysis to caloric and non-caloric sweeteners by examining whether fructose (8%) or saccharin (0.2%) intakes were differentially suppressed in BALB/c and SWR mice by SCH (50-1600nmol/kg) or NTX (0.01-5mg/kg) over a 5- to 120-min time course. SCH significantly reduced fructose (200-1600nmol/kg) and saccharin (50-1600nmol/kg) intakes in both strains as did NTX (0.1-5mg/kg). Antagonist ID40 potencies were <50nmol/kg for SCH and 0.9mg/kg for NTX in inhibiting saccharin intake, and 1234nmol/kg for SCH and 5mg/kg for NTX in inhibiting fructose intake in BALB/c mice. For SWR mice, the ID40 potencies were <50nmol/kg for SCH and 0.02mg/kg for NTX in inhibiting saccharin intake, and 298nmol/kg for SCH and 2.6mg/kg for NTX in inhibiting fructose intake. Thus, saccharin intake was similarly reduced by SCH and NTX in BALB/c and SWR mice, but greater potencies of opioid (1.9-fold) and DA D1 (4-fold) receptor antagonism of fructose intake were observed in SWR relative to BALB/c mice, indicating strong strain differences., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Recent studies indicate that, unlike glucose, fructose has little or no post-oral preference conditioning actions in C57BL/6J (B6) mice. The present study determined whether this is also the case for FVB mice, which overconsume fructose relative to B6 mice. In experiment 1, FVB mice strongly preferred a noncaloric 0.1% sucralose + 0.1% saccharin (S+S) solution to 8% fructose in a 2-day choice test but switched their preference to fructose after separate experience with the two sweeteners. Other FVB mice displayed a stronger preference for 8% glucose over S+S. In a second experiment, ad libitum-fed FVB mice trained 24 h/day acquired a significant preference for a flavor (CS+) paired with intragastric (IG) self-infusions of 16% fructose over a different flavor (CS-) paired with IG water infusions. IG fructose infusions also conditioned flavor preferences in food-restricted FVB mice trained 1 h/day. IG infusions of 16% glucose conditioned stronger preferences in FVB mice trained 24- or 1 h/day. Thus, fructose has post-oral flavor conditioning effects in FVB mice, but these effects are less pronounced than those produced by glucose. Further studies of the differential post-oral conditioning effects of fructose and glucose in B6 and FVB mice should enhance our understanding of the physiological processes involved in sugar reward., (Copyright © 2014 the American Physiological Society.)

The present study determined if mice, like rats, differ in their flavor conditioning responses to intragastric (IG) infusions of three common monosaccharide sugars. In Experiment 1, C57BL/6J mice were trained to drink a flavored saccharin solution (the CS+) paired with intragastric (IG) self-infusions of 16% glucose, fructose or galactose and a different flavored solution (the CS-) paired with IG water infusions during 22 h/day training sessions. The glucose infusions increased CS+ intakes during training and produced a strong CS+ preference (~87%) in two-bottle choice tests. In contrast, the fructose and galactose infusions reduced CS training intakes and did not condition a CS+ preference. Experiment 2 determined if reducing fructose and galactose concentration would enhance conditioning. However, IG infusions of 8% sugar also failed to condition CS+ preferences. The robust conditioning response to IG glucose confirms results obtained with rats, but the indifference of mice to IG fructose and galactose contrasts with preference and avoidance responses observed in rats. The effectiveness of glucose to condition preferences suggests an important role for glucose-specific sensors rather than gut "sweet" taste receptors in the postoral modulation of carbohydrate appetite., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Genetic factors strongly influence the intake and preference for sugar and saccharin solutions in inbred mouse strains. The present study determined if genetic variance also influences the learned preferences for flavors added to sugar solutions. Conditioned flavor preferences (CFPs) are produced in rodents by adding a flavor (CS+) to a sugar solution and a different flavor (CS-) to a saccharin solution (CS-) in one-bottle training trials; the CS+ is subsequently preferred to the CS- when both are presented in saccharin solutions in two-bottle tests. With some sugars (e.g., sucrose), flavor preferences are reinforced by both sweet taste and post-oral nutrient effects, whereas with other sugars (e.g., fructose), sweet taste is the primary reinforcer. Sucrose and fructose were used in three experiments to condition flavor preferences in one outbred (CD-1) and eight inbred strains which have "sensitive" (SWR/J, SJL/J, C57BL/10J, C57BL/6J) or "sub-sensitive" (DBA/2J, BALB/cJ, C3H/HeJ, 129P3/J) sweet taste receptors (T1R2/T1R3). Food-restricted mice of each strain were trained (1 h/day) to drink flavored 16% sucrose (CS+ 16S, Experiment 1), 16% fructose (CS+ 16F, Experiment 2) or 8% fructose+0.2% saccharin (CS+ 8F, Experiment 3) solutions on five alternate days and a differently flavored saccharin solution (0.05% or 0.2%, CS-) on the other five alternating days. The CS+ and CS- flavors were presented in 0.2% saccharin for two-bottle testing over six days. All strains preferred the CS+ 16S to CS- although there were significant strain differences in the magnitude and persistence of the sucrose preference. The strains also differed in the magnitude and persistence of preferences for the CS+ 16F and CS+ 8F flavors over the CS- with two strains failing to prefer the fructose-paired flavors. Sucrose conditioned stronger preferences than did fructose which is attributed to differences in the taste and post-oral actions of the sugars. These differential training intakes may not have influenced the sucrose-CFP because of the post-oral reinforcing actions of sucrose. Overall, sweet sensitive and sub-sensitive mice did not differ in sucrose-CFP, but unexpectedly, the sub-sensitive mice displayed stronger fructose-CFP. This may be related to differential training intakes of CS+ and CS- solutions: sweet sensitive mice consumed more CS- than CS+ during training while sub-sensitive mice consumed more CS+., (Copyright © 2011 Elsevier Inc. All rights reserved.)

High fructose corn syrup (HFCS) has replaced sucrose in many food products, which has prompted research comparing these two sweeteners in rodents. The present study examined the relative palatability of HFCS and sucrose for rats, offering 11% carbohydrate solutions to match the content of common beverages for human consumption. The animals initially preferred HFCS to sucrose but after separate experience with each solution they switched to sucrose preference. Approximating the composition of HFCS with a mixture of fructose and glucose (55:45) yielded a solution that was less attractive than sucrose or HFCS. However, HFCS contains a small amount of glucose polymers, which are very attractive to rats. A 55:42:3 mixture of fructose, glucose and glucose polymers (Polycose) was equally preferred to HFCS and was treated similarly to HFCS in comparisons vs. sucrose. Post-oral effects of sucrose, which is 50% fructose and 50% glucose, may be responsible for the shift in preference with experience. This shift, and the relatively small magnitude of differences in preference for HFCS and sucrose, suggest that palatability factors probably do not contribute to any possible difference in weight gain responses to these sweeteners., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We examined sugar-induced obesity in mouse strains polymorphic for Tas1r3, a gene that codes for the T1R3 sugar taste receptor. The T1R3 receptor in the FVB and B6 strains has a higher affinity for sugars than that in the AKR and 129P3 strains. In Experiment 1, mice had 40days of access to lab chow plus water, sucrose (10 or 34%), or fructose (10 or 34%) solutions. The strains consumed more of the sucrose than isocaloric fructose solutions. The pattern of strain differences in caloric intake from the 10% sugar solutions was FVB>129P3=B6>AKR; and that from the 34% sugar solutions was FVB>129P3>B6>/=AKR. Despite consuming more sugar calories, the FVB mice resisted obesity altogether. The AKR and 129P3 mice became obese exclusively on the 34% sucrose diet, while the B6 mice did so on the 34% sucrose and 34% fructose diets. In Experiment 2, we compared total caloric intake from diets containing chow versus chow plus 34% sucrose. All strains consumed between 11 and 25% more calories from the sucrose-supplemented diet. In Experiment 3, we compared the oral acceptability of the sucrose and fructose solutions, using lick tests. All strains licked more avidly for the 10% sucrose solutions. The results indicate that in mice (a) Tas1r3 genotype does not predict sugar-induced hyperphagia or obesity; (b) sucrose solutions stimulate higher daily intakes than isocaloric fructose solutions; and (c) susceptibility to sugar-induced obesity varies with strain, sugar concentration and sugar type., (Copyright 2010 Elsevier Inc. All rights reserved.)

Rats learn to prefer a flavor mixed into a fructose-saccharin solution over a different flavor mixed into a saccharin-only solution which is considered to be a form of flavor-flavor conditioning. Fructose-conditioned flavor preferences are impaired by systemic dopamine D1 and to a lesser degree, D2 receptor antagonism as well as by NMDA, but not opioid, receptor antagonism. Given the emerging role of the endocannabinoid system in mediating hedonically-driven food intake, the present study examined whether systemic administration of the inverse CB-1 receptor agonist, AM-251 would alter fructose-conditioned flavor preferences. In Experiment 1, food-restricted rats were trained over 10 sessions (30 min/day) to drink a fructose-saccharin solution mixed with one flavor (CS+/Fs) and a less-preferred saccharin-only solution mixed with another flavor (CS-/s). Subsequent two-bottle tests with the two flavors in saccharin (CS+/s, CS-/s) occurred 15 min following counterbalanced pairs of AM-251 doses of 0, 0.1, 1 or 3 mg/kg. Preference for CS+/s over CS-/s following vehicle treatment (74%) was significantly reduced by the 0.1 (67%) and 1 (65%) AM-251 doses, whereas CS+/s, but not CS-/s intake was significantly reduced by the 1 and 3 mg/kg AM-251 doses. In Experiment 2, rats received systemic injections of AM-251 (1 mg/kg) or vehicle prior to the 10 CS+/Fs and CS-/s training sessions. In subsequent two-bottle tests (drug-free) the AM-251 and control groups displayed similar preferences for the CS+ flavor (66% vs. 69%). Experiment 3 demonstrated that AM-251 significantly decreased chow intake (24 h), and 1-h intakes of fructose-saccharin and saccharin-only solutions in ad libitum-fed rats. These data indicate that functional CB-1 receptor antagonism significantly reduces the expression, but not the acquisition of fructose-conditioned flavor-flavor preferences. The endogenous endocannabinoid system is therefore implicated in the maintenance of this form of learned flavor preferences.

Systemic administration of dopamine D1 (SCH23390) and less so D2 (raclopride) receptor antagonists significantly reduce acquisition and expression of fructose-conditioned flavor preferences (CFP). Because dopamine in the nucleus accumbens shell (NAcS) is implicated in food reward, the present study examined whether NAcS D1 or D2 antagonists altered acquisition and/or expression of fructose-CFP. In Experiment 1, food-restricted rats with bilateral NAcS cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+/Fs) and a less-preferred 0.2% saccharin solution with mixed another flavor (CS-/s). Unlimited two-bottle tests with the two flavors in saccharin (0.2%: CS+/s, CS-/s) occurred 10 min following total bilateral NAcS doses of 0, 12, 24 or 48 nmol of SCH23390 or raclopride. Preference for CS+/s over CS-/s following vehicle treatment (76%) was significantly reduced by SCH23390 (48 nmol, 62%) and raclopride (24 nmol, 63%). In Experiment 2, rats received bilateral NAcS injections (12 nmol) of SCH23390 or raclopride on one-bottle training (16 ml) days. Yoked control rats received vehicle and were limited to the CS intakes of the D1 and D2 groups, whereas untreated controls without injections received their CS ration during training. Subsequent unlimited two-bottle tests revealed initial preferences of CS+/s over CS-/s in all groups that remained stable in untreated and yoked controls, but were lost over the six tests sessions in D1 and D2 groups. These data indicate that NAcS D1 and D2 antagonists significantly attenuated the expression of the fructose-CFP and did not block acquisition, but hastened extinction of fructose-CFP.

The effects of the general opioid antagonist, naltrexone, on the acquisition and expression of flavor preferences conditioned by the sweet taste of fructose were examined. Food-restricted rats were trained over eight daily alternating one-bottle sessions (2 h) to drink an 8% fructose solution containing one novel flavor (CS+/F) and a less preferred 0.2% saccharin solution containing a different flavor (CS-/S). Four groups of rats were treated daily with either saline (control group) or naltrexone doses of 0.1, 1.0, or 5.0 mg/kg during training. Preferences were assessed in two-bottle tests with the CS+/S and CS-/S flavors presented in 0.2% saccharin solutions following saline injections. Naltrexone dose-dependently reduced fructose and saccharin intakes during training, confirming the drug's well-known suppressive effect on the intake of sweet solutions. Despite their reduced training intakes, the naltrexone groups displayed preferences for the CS+/S over the CS-/S (72-86%) that were similar to that of the control group (78%). The effect of naltrexone on the expression of the CS+/S flavor preference was evaluated by treating control rats with naltrexone (0.1-5 mg/kg) prior to CS+/S vs. CS-/S choice tests. The drug doses produced a dose-dependent reduction in CS+/S intake but did not significantly attenuate the CS+/S preference. These data are consistent with the relative inability of naltrexone to reduce flavor-flavor conditioning by sucrose in sham-feeding rats and flavor-nutrient conditioning in rats receiving intragastric sucrose infusions. In contrast, dopamine antagonists reduce both sucrose- and fructose-conditioned flavor preferences, which indicates the sensitivity of these conditioning paradigms to neuropharmacological manipulations. These data indicate that the endogenous opioid system, unlike the dopamine system, does not play a major role in either the acquisition or expression of flavor preference learning as measured in two-bottle choice tests.

Previous studies indicate that fructose postingestive reward for flavor preference learning is weaker than that of glucose. The present experiments explored the effects of several variables that modulate the response to fructose. In Experiment 1, ad libitum fed male rats were trained in 22 h sessions with one flavor (the CS+) paired with intragastric infusions of 7.18% fructose and another flavor (the CS-) paired with intragastric water infusion. Subsequent preference for the CS+ relative to the CS- was 90% with saccharin-sweetened flavors and only 67% with nonsweet flavors. Experiments 2 (males) and 3 (females) examined the effects of taste quality on conditioning with 16% fructose infusions. Males and females both preferred the sweet CS+ flavor (71-72%). In contrast, males avoided the nonsweet CS+ flavor (31%) and females were indifferent (47%). The different preference patterns were accompanied by differences in sweet and nonsweet training intakes and bout patterns, suggesting stimulation of intake with sweet flavor and 7.18% fructose, and satiating effects of 16% fructose. The sex difference in response to nonsweet flavors may reflect a greater sensitivity of male rats to fructose's postingestive satiating or aversive effects. Possible mechanisms for the sweet-taste enhancement of conditioning include increasing CS intakes in training, facilitating fructose metabolism and increasing flavor salience.

The effects of dopamine (DA) D(1) and D(2) receptor antagonists on the acquisition and expression of flavor-preferences conditioned by the sweet taste of fructose were examined. Food-restricted rats were trained over eight alternating one-bottle sessions to drink an 8% fructose solution containing one novel flavor (CS+) and a less preferred 0.2% saccharin solution containing a different flavor (CS-). Three groups of rats were treated daily with either vehicle (control group), SCH23390 (200 nmol/kg; D(1) group), or raclopride (200 nmol/kg; D(2) group) during training. Additional groups of vehicle-treated rats had their daily training intakes matched to that of the D(1) and D(2) groups. Preferences were assessed in two-bottle tests with the CS+ and CS- flavors presented in 0.2% saccharin solutions following doses of 0, 50, 200, 400, or 800 nmol/kg of either D(1) or D(2) antagonists. The D(1) and D(2) groups, unlike the control and yoked-control groups, failed to display a significant CS+ preference in the two-bottle tests following vehicle treatment. In addition, treatment with SCH23390 prior to the two-bottle tests blocked the expression of the CS+ preference in the control groups. Pretest raclopride treatment attenuated the CS+ preference at some dose levels. Raclopride also attenuated the preference for fructose in rats given two-bottle training with the CS+/fructose (CS+/F) and CS-/saccharin (CS-/S) solutions. These findings indicate that D(1) and D(2) antagonists block flavor-preference conditioning by sweet taste and that D(1), and to a lesser extent D(2), receptor antagonists attenuate the expression of a previously acquired preference.

Recent studies suggest that preferences are conditioned by nutritive (sucrose) but not by non-nutritive (sucralose) sweeteners in mice. Here we compared the effectiveness of nutritive and non-nutritive sweeteners to condition flavor preferences in three mouse strains. Isopreferred sucrose and sucralose solutions both conditioned flavor preferences in C57BL/6J (B6) mice but sucrose was more effective, consistent with its post-oral appetition action. Subsequent experiments compared flavor conditioning by fructose, which has no post-oral appetition effect in B6 mice, and a sucralose + saccharin mixture (SS) which is highly preferred to fructose in 24-h choice tests. Both sweeteners conditioned flavor preferences but fructose induced stronger preferences than SS. Training B6 mice to drink a flavored SS solution paired with intragastric fructose infusions did not enhance the SS-conditioned preference. Thus, the post-oral nutritive actions of fructose do not explain the sugar's stronger preference conditioning effect. Training B6 mice to drink a flavored fructose solution containing SS did not reduce the sugar-conditioned preference, indicating that SS does not have an off-taste that attenuates conditioning. Although B6 mice strongly preferred flavored SS to flavored fructose in a direct choice test, they preferred the fructose-paired flavor to the SS-paired flavor when these were presented in water. Fructose conditioned a stronger flavor preference than an isopreferred saccharin solution, indicating that sucralose is not responsible for the limited SS conditioning actions. SS is highly preferred by FVB/NJ and CAST/EiJ inbred mice, yet conditioned only weak flavor preferences. It is unclear why highly or equally preferred non-nutritive sweeteners condition weaker preferences than fructose, when all stimulate the same T1r2/T1r3 sweet receptor. Recent findings support the existence of non-T1r2/T1r3 glucose taste sensors; however, there is no evidence for receptors that respond to fructose but not to non-nutritive sweeteners. [ABSTRACT FROM AUTHOR]

The post-oral actions of glucose stimulate intake and condition flavor preferences in rodents. Hypothalamic melanin-concentrating hormone (MCH) neurons are implicated in sugar reward, and this study investigated their involvement in glucose preference conditioning in mice. In Exp. 1 MCH receptor 1 knockout (KO) and C57BL/6 wildtype (WT) mice learned to prefer 8% glucose over an initially more-preferred non-nutritive 0.1% sucralose + saccharin (S+S) solution. In contrast, the KO and WT mice preferred S+S to 8% fructose, which is consistent with this sugar's weak post-oral reinforcing action. In Exp. 2 KO and WT mice were trained to drink a flavored solution (CS+) paired with intragastric (IG) infusion of 16% glucose and a different flavored solution (CS −) paired with IG water. Both groups drank more CS+ than CS − in training and preferred the CS+ to CS − in a 2-bottle test. These results indicate that MCH receptor signaling is not required for flavor preferences conditioned by the post-oral actions of glucose. This contrasts with other findings implicating MCH signaling in other types of sugar reward processing. [ABSTRACT FROM AUTHOR]

Recent studies suggest that because of their energy value, sugars are more rewarding than noncaloric sweeteners. However, intragastric infusion data indicate that sugars differ in their postoral appetite-stimulating effects. We therefore compared the preference for isocaloric 8% sucrose, glucose, and fructose solutions with that of a non-caloric sweetener solution (0.8% sucralose) in C57BL/6J mice. Brief 2-bottle tests indicated that sucralose was isopreferred to sucrose but more preferred than glucose or fructose. Yet, in long-term tests, the mice preferred sucrose and glucose, but not fructose to sucralose. Additional experiments were conducted with a non-caloric 0.1% sucralose + 0.1% saccharin mixture (S + S), which does not have the postoral inhibitory effects of 0.8% sucralose. The S + S was preferred to fructose in brief and long-term choice tests. S + S was also preferred to glucose and sucrose in brief tests, but the sugars were preferred in long-term tests. In progressive ratio tests, non-deprived and food-deprived mice licked more for glucose but not fructose than for S + S. These findings demonstrate that the nutrient-specific postoral actions, not calories per se, determine the avidity for sugar versus non-caloric sweeteners. Furthermore, sweet taste intensity and potential postoral inhibitory actions must be considered in comparing non-caloric and caloric sweeteners. [ABSTRACT FROM AUTHOR]

Knockout (KO) mice missing the taste signaling protein Trpm5 have greatly attenuated sweetener preferences but develop strong preferences for glucose in 24-h tests, which is attributed to post-oral sugar conditioning. Trpm5 KO mice express mild preferences for galactose but no preferences for fructose in 24-h tests, which suggests that these sugars differ in their post-oral reinforcing effects. Here we investigated sugar-conditioned flavor preferences in Trpm5 KO and C57BL/6J wildtype (B6) mice. The mice were trained to consume a flavored (CS+, e.g. grape) 8% sugar solution and flavored (CS−, e.g., cherry) water on alternating days followed by two-bottle choice tests with CS+ vs. CS− flavors in water and with unflavored sugar vs. water. The KO mice displayed strong preferences (> 80%) for the CS+ glucose and CS+ galactose but not for the CS + fructose flavor. They also preferred glucose and galactose, but not fructose to water. In contrast, the B6 mice preferred all three CS + flavors to the CS− flavor, and all three sugars to water. In tests with the non-metabolizable sugar α-methyl- d -glucopyranoside (MDG), the KO and B6 mice preferred 8% MDG to water but did not prefer the CS+ 8% MDG to CS−. However, they preferred a CS + flavor mixed with 4% MDG over the CS− flavor. Trpm5 KO mice also preferred galactose and MDG to fructose in direct choice tests. The Trpm5 KO data indicate that glucose and, to a lesser extent, galactose and MDG have post-oral reinforcing actions that stimulate intake and preference while fructose has a much weaker effect. The CS+ flavor and sugar preferences of B6 mice may be mediated by the sweet taste and/or post-oral actions of the various sugars. Glucose, galactose, and MDG, but not fructose, are ligands for the sodium–glucose transporter 1 (SGLT1) which is implicated in post-oral sugar conditioning in B6 mice. [ABSTRACT FROM AUTHOR]

Post-oral sugar actions enhance the intake of and preference for sugar-rich foods, a process referred to as appetition. Here, we investigated the role of intestinal sodium glucose cotransporters (SGLTs) in sugar appetition in C57BL/6J mice using sugars and nonmetabolizable sugar analogs that differ in their affinity for SGLT1 and SGLT3. In experiments 1 and 2, food-restricted mice were trained (1 h/day) to consume a flavored saccharin solution [conditioned stimulus (CS-)] paired with intragastric (IG) self-infusions of water and a different flavored solution (CS+) paired with infusions of 8 or 12% sugars (glucose, fructose, and galactose) or sugar analogs (α-methyl-D-glucopyranoside, MDG; 3-O-methyl-D-glucopyranoside, OMG). Subsequent twobottle CS+ vs. CS- choice tests were conducted without coinfusions. Infusions of the SGLT1 ligands glucose, galactose, MDG, and OMG stimulated CS+ licking above CS- levels. However, only glucose, MDG, and galactose conditioned significant CS+ preferences, with the SGLT3 ligands (glucose, MDG) producing the strongest preferences. Fructose, which is not a ligand for SGLTs, failed to stimulate CS+ intake or preference. Experiment 3 revealed that IG infusion of MDG+phloridzin (an SGLT1/3 antagonist) blocked MDG appetition, whereas phloridzin had minimal effects on glucose-induced appetition. However, adding phloretin (a GLUT2 antagonist) to the glucose+phloridzin infusion blocked glucose appetition. Taken together, these findings suggest that humoral signals generated by intestinal SGLT1 and SGLT3, and to a lesser degree, GLUT2, mediate post-oral sugar appetition in mice. The MDG results indicate that sugar metabolism is not essential for the post-oral intake-stimulating and preference-conditioning actions of sugars in mice. [ABSTRACT FROM AUTHOR]

Knockout (KO) mice missing the sweet taste receptor subunit T1r3 or the signaling protein Trpm5 have greatly attenuated sweetener preferences but learn to prefer sucrose in 24-h tests. Here, we examined 24-h preferences of T1r3 KO, Trpm5 KO, and C57BL/6J wild-type (WT) mice for glucose, fructose, galactose, and corn starch. Unlike glucose, fructose has little postoral reward effect in WT mice, whereas conflicting data have been obtained with galactose. Naïve KO mice were initially indifferent to dilute glucose solutions (0.5–4%) but exhibited strong preferences for 8–32% concentrations. In a second test, they strongly preferred (~90%) all glucose concentrations although they drank less sugar than WT mice. Naïve KO mice were indifferent to 0.5–8% fructose and avoided 16–32% fructose. However, the glucose-experienced KO mice displayed significant preferences for all fructose solutions. Naïve KO mice preferred only 8% galactose, whereas WT mice preferred 4–16% galactose, and all mice avoided 32% galactose. Galactose experience enhanced the preference for this sugar in KO and WT mice. Naïve T1r3 KO and WT mice displayed similar preferences for 0.5–32% corn starch, which were enhanced by starch experience. Naïve Trpm5 KO mice did not prefer starch but did so after 1-bottle starch experience. The results confirm the sweet taste deficits of T1r3 KO and Trpm5 KO mice but demonstrate their ability to develop strong glucose and milder galactose preferences attributed to the postoral actions of these sugars. The acquired preference for the non-sweet flavor properties of glucose generalized to those of fructose. The findings further demonstrate that although Trpm5 (but not T1r3) signaling is essential for starch preference, Trpm5 KO mice can learn to prefer starch based on its postoral effects. [ABSTRACT FROM PUBLISHER]

Although widely assumed to have only satiating actions, nutrients in the gut can also condition increases in intake in some cases. Here we studied the time course of post-oral nutrient stimulation of ingestion in food-restricted C57BL/6J mice. In experiment 1, mice adapted to drink a 0.8% sucralose solution 1 h/day, rapidly increased their rate of licking (within 4-6 min) when first tested with an 8% glucose solution and even more so in tests 2 and 3. Other mice decreased their licking rate when switched from sucralose to 8% fructose, a sugar that is sweet like glucose but lacks positive post-oral effects in mice. The glucose-stimulated drinking is due to the sugar's post-oral rather than taste properties, because sucralose is highly preferred to glucose and fructose in brief choice tests. A second experiment showed that the glucose-stimulated ingestion is associated with a conditioned flavor preference in both intact and capsaicin-treated mice. This indicates that the post-oral stimulatory action of glucose is not mediated by capsaicin-sensitive visceral afferents. In experiment 3, mice consumed flavored saccharin solutions as they self-infused water or glucose via an intragastric (IG) catheter. The glucose self-infusion stimulated ingestion within 13-15 min in test 1 and produced a conditioned increase in licking that was apparent in the initial minute of tests 2 and 3. Experiment 4 revealed that IG self-infusions of a fat emulsion also resulted in post-oral stimulation of licking in test 1 and conditioned increases in tests 2 and 3. These findings indicate that glucose and fat can generate stimulatory post-oral signals early in a feeding session that increase ongoing ingestion and condition increases in flavor acceptance and preference revealed in subsequent feeding sessions. The test procedures developed here can be used to investigate the peripheral and central processes involved in stimulation of intake by post-oral nutrients. [ABSTRACT FROM AUTHOR]

Nutrient-conditioned flavors preferences are thought to involve an increase in flavor palatability (hedonic evaluation). Consistent with this view is the recent finding that a sweet flavor paired with intragastric glucose infusions elicited more hedonic taste reactivity (TR) responses than did an alternative sweet flavor paired with intragastric water. The generality of this finding was examined by conditioning preferences for inherently avoided nonsweet flavors. Rats were trained in 20 h/day and then 30 min/day sessions with a CS+ flavor (sour citric acid or bitter sucrose octaacetate) paired with intragastric 16% glucose infusion, and the opposite flavor (CS−) paired with intragastric water. Glucose conditioning increased the CS+ acceptance in one-bottle tests and produced a 95% CS+ preference in two-bottle sessions. Yet, TR responses to brief intraoral infusions of the two CS flavors did not differ, even after extensive testing. Subsequent choice tests revealed that a 1% fructose solution was preferred to the CS−, whereas the CS+ was preferred to 1% and 2% fructose and equally preferred to 4%, 8%, and 16% fructose. These results indicate that strong nutrient-conditioned flavor preferences are not always associated with increased flavor palatability as measured by TR tests. Therefore, nonhedonic processes, perhaps increased incentive salience, appear to mediate the enhanced preference and acceptance conditioned by postingestive nutrient actions. [Copyright &y& Elsevier]

Recent findings revealed that intragastric infusions of galactose conditioned a flavor avoidance in adult rats. To determine whether the galactose-conditioned avoidance was due to the infusion procedure, we investigated the flavor conditioning effect of orally consumed galactose. Food-restricted rats drank a flavored galactose solution, a flavored fructose solution and a flavored saccharin solution in separate one-bottle training sessions; grape, cherry and orange flavors were used. Because fructose is sweeter than galactose, saccharin was added to the galactose solution to increase its palatability. Pre- and posttraining preferences for the galactose and fructose solutions were evaluated in two-bottle choice tests. Also, preferences for the sugar-paired flavors were evaluated in two-bottle tests with the flavors presented in saccharin. In Experiment 1, rats were trained with flavored 80 g/L fructose, 80 g/L galactose + 2 g/L saccharin, and 2 g/L saccharin solutions (20 mL/d). Their preference for the flavored galactose solution changed (P < 0.01) from 76% (pretraining) to 19% (posttraining). The rats also avoided (P < 0.05) the flavor paired with the galactose solution in choice tests with the fructose-paired flavor and the saccharin-paired flavor. Similar pre- to posttraining preference reversals were obtained in Experiments 2 and 3, which used 20 g/L galactose and fructose solutions, and 20 g/L galactose and fructose solutions mixed with 20 g/L glucose, respectively. These findings, together with the intragastric infusion data, demonstrate that galactose has aversive postingestive consequences in adult rats even at low concentrations (20 g/L). Unlike lactose intolerance, which is due to intestinal malabsorption, this galactose-induced flavor avoidance is presumably due to the slow and incomplete postabsorptive metabolism of galactose. [ABSTRACT FROM AUTHOR]

Reports on the different postingestive reinforcing effects of glucose and fructose. Association of a conditioned stimulus (CS) with a flavor; Effects on rat preference for CS plus flavor; More reinforcing effects of glucose as compared to fructose.

• T1R2+T1R3 taste receptor primarily mediates sweetener preference in mammals • T1R3 Knockout (KO) mice were indifferent to glucose and fructose in 1-min choice test • T1R3 KO, but not TRPM5 KO mice preferred glucose to fructose in 1-h tests • This supports other evidence for a T1R3-independent glucose taste sensor • Postoral actions greatly enhanced glucose preference in KO mice Knockout (KO) mice missing the sweet taste receptor subunit T1R3 or the signaling protein TRPM5 have greatly attenuated sweetener preferences. Yet both types of KO mice develop preferences for glucose but not fructose in 24-h tests, which has been attributed to the postoral reinforcing actions of glucose. Here we probed for residual sugar taste sensitivity in KO mice. Unlike wildtype (WT) mice, food-restricted T1R3 KO and TRPM5 KO mice displayed little attraction for 8% glucose and 8% fructose in 1-min, two-bottle choice tests. However, in 1-h tests about half of the T1R3 KO mice displayed a significant preference for glucose over fructose (78-84%), while WT mice showed either no or weak preferences (41-56%) for glucose. Following one-bottle training sessions, WT mice display greater glucose preferences although still weaker than those observed in T1R3 KO mice. In contrast, TRPM5 KO mice were indifferent to sugars in 1-h tests but developed a strong preference for glucose over fructose in 24-h tests. T1R3 taste cells contain the sodium glucose cotransporter 1 (SGLT1) and the ATP-gated K+ (K ATP) metabolic sensor, which may mediate the unlearned glucose preference displayed by T1R3 KO mice. Unlike WT mice, many T1R3 KO mice strongly preferred glucose to a non-metabolizable glucose analog (α-methyl-D-glucopyranoside, MDG) in initial 1-h choice tests. Glucose and MDG are both ligands for SGLT1 which indicates that SGLT1 sensing does not mediate the glucose preference of T1R3 KO mice. Instead, K ATP sensing and/or other oral sensors are implicated. The MDG findings also argue against postoral sensing as the primary source of the initial glucose preference displayed by T1R3 KO mice. Why only half of the T1R3 KO mice showed this preference in 1-h tests remains to be determined. All T1R3 KO mice preferred glucose to fructose in 24-h tests, which appears to be due to both oral and postoral glucose sensing. [ABSTRACT FROM AUTHOR]

Rats can learn to prefer flavors paired with ethanol and various nutrients. The present study examined the relative strengths of flavor preferences conditioned by 5% ethanol and isocaloric solutions of 7.18% sucrose, 7.18% fructose, or 3.26% corn oil. In three experiments, nondeprived rats were trained with different flavored solutions (conditioned stimuli, CS) paired with intragastric (IG) infusions: a CS+E flavor paired with ethanol infusion, a second CS+ paired with a nutrient infusion, and a CS- paired with water infusion. In two-bottle tests, rats strongly preferred a sucrose-paired CS+S over the CS- and over the CS+E. The preference for the CS+E over CS- was weaker. These effects occurred when the rats drank substantially more CS+S than CS+E in training and when training intakes were matched. Similar results were obtained when the nutrient infusion was fructose or corn oil, except that preferences for the CS+F or CS+O over the CS+E were less pronounced than with CS+S. Consistent with the IG results, rats trained to drink flavored sucrose and ethanol solutions preferred the CS+S to CS+E in a flavored water test. These results confirm prior reports of ethanol-conditioned preferences but show that ethanol is less effective than other nutrients at isocaloric concentrations. The marked individual differences in ethanol-conditioned preferences may be related to the impact of the sugar or fat infusions on the reward evaluation of the ethanol-paired flavor. [Copyright &y& Elsevier]

Conditioned flavor preferences (CFP) are elicited by sucrose and fructose relative to saccharin in rats and inbred mice. Whereas dopamine, but not opioid receptor antagonists interfere with the acquisition (learning) and expression (maintenance) of sugar-CFP in rats, these antagonists differentially affect acquisition and expression of sucrose- and fructose-CFP in BALB/c and SWR inbred mice. Given that NMDA receptor antagonism with MK-801 blocks acquisition, but not expression of fructose-CFP in rats, the present study examined whether MK-801 altered the expression and acquisition of sucrose- and fructose-CFP in BALB/c and SWR mice. In expression experiments, food-restricted mice alternately consumed a flavored (CS +, e.g., cherry, 5 sessions) 16% sucrose or 8% fructose + 0.2% saccharin solution and a differently-flavored (CS −, e.g., grape, 5 sessions) 0.2% saccharin solution. 2-Bottle CS choice tests occurred following vehicle or MK-801 at doses of 100 or 200 μg/kg. MK-801 mildly reduced the magnitude of the expression of sucrose- and fructose-CFP in BALB/c mice, and blocked the expression of fructose-, but not sucrose-CFP at the high dose in SWR mice. In acquisition experiments, groups of BALB/c (0, 100 μg/kg) and SWR (0, 100, 200 μg/kg) mice were treated prior to acquisition training sessions that was followed by 2-bottle CS choice tests without injections. MK-801 (100 μg/kg) eliminated acquisition of sucrose- and fructose-CFP in BALB/c, but not SWR mice. The 200 μg/kg MK-801 dose eliminated acquisition of sucrose- and fructose-CFP in SWR mice. Thus, NMDA receptor signaling is essential for the learning of both forms of sugar-CFP in both strains with BALB/c mice more sensitive to MK-801 dose effects. [ABSTRACT FROM AUTHOR]

Abstract: The attraction to sugar-rich foods is influenced by conditioned flavor preferences (CFP) produced by the sweet taste of sugar (flavor–flavor learning) and the sugar's post-oral actions (flavor–nutrient) learning. Brain dopamine (DA) circuits are involved in both types of flavor learning, but to different degrees. This study investigated the role of DA receptors in the lateral hypothalamus (LH) on the flavor–flavor learning produced the sweet taste of fructose. In an acquisition study, food-restricted rats received bilateral LH injections of a DA D 1 receptor antagonist (SCH23390), a D 2 antagonist (RAC, raclopride) or vehicle prior to 1-bottle training sessions with a flavored 8% fructose+0.2% saccharin solution (CS+/F) and a less-preferred flavored 0.2% saccharin solution (CS−). Drug-free 2-bottle tests were then conducted with the CS+ and CS− flavors presented in saccharin. The fructose-CFP did not differ among groups given vehicle (76%), 12nmol SCH (78%), 24nmol (82%) or 24nmol RAC (90%) during training. In an expression study with rats trained drug-free, LH injections of 12 or 24nmol SCH or 12–48nmol RAC prior to 2-bottle tests did not alter CS+ preferences (77–90%) relative to vehicle injection (86%). Only a 48nmol SCH dose suppressed the CS+ preference (61%). The minimal effect of LH DA receptor antagonism upon fructose flavor–flavor conditioning differs with the ability of LH SCH injections to block the acquisition of glucose flavor–nutrient learning. [Copyright &y& Elsevier]

Abstract: Systemic administration of dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked both acquisition and expression of fructose-conditioned flavor preferences (CFP). It is unclear what brain circuits are involved in mediating these effects. The present study investigated DA signaling within the nucleus accumbens shell (NAcS), amygdala (AMY) and medial prefrontal cortex (mPFC) in the acquisition and expression of fructose-CFP. In Experiment 1, separate groups of rats were injected daily in the NAcS or AMY with saline, SCH (24nmol) or RAC (24nmol) prior to training sessions with a flavor (CS+) mixed with 8% fructose and 0.2% saccharin (CS+/F) and a different flavor (CS−) mixed with only 0.2% saccharin. In the two-bottle choice tests with 0.2% saccharin, only rats injected with RAC in the AMY failed to acquire a CS+ preference (45–54%). In Experiment 2, new rats were identically trained, but saline, SCH and RAC were injected in the mPFC. In subsequent two-bottle choice tests, SCH- and RAC-treated rats failed to exhibit a CS+ preference (50–56%). In Experiment 3, new rats were trained with CS+/F and CS− without injections. Subsequent two-bottle choice tests were then conducted following bilateral injections of SCH or RAC in the mPFC at total doses of 0, 12, 24 and 48nmol. Expression of the CS+ preference failed to be affected by either antagonist, indicating that the mPFC is not involved in the maintenance of this preference. These data indicate that the acquisition of fructose-CFP is dependent on DA signaling in the mPFC and AMY. [Copyright &y& Elsevier]

Abstract: In our prior studies, systemic administration of the opioid receptor antagonist naltrexone (NTX) did not block flavor preference conditioning by the sweet taste or post-oral actions of sugar despite reducing intake. Because opioid signaling in the nucleus accumbens (NAc) is implicated in food reward, this study determined if NTX administered into the NAc would block the expression of sugar-conditioned preferences. In Experiment 1, food-restricted rats with bilateral NAc shell or core cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+) and a less-preferred 0.2% saccharin solution mixed with another flavor (CS−) during one-bottle sessions. Two-bottle tests with the two flavors mixed in saccharin solutions occurred 10min following total bilateral NAc shell or core doses of 0, 1, 25 and 50μg of NTX. The rats preferred the CS+ over CS− following vehicle (80%) and all NTX doses in the shell and core. The CS+ preference was reduced to 64% and 72% by 50μg NTX in the shell and core, although only the core effect was significant. In Experiment 2, food-restricted rats were trained to drink one flavored saccharin solution (CS+) paired with an intragastic (IG) glucose (8%) infusion and a second flavored saccharin solution (CS−) paired with an IG water infusion. In subsequent two-bottle tests, the rats displayed significant preferences for the CS+ (81–91%) that were unaltered by any NTX dose in the shell or core. CS+ intake, however, was reduced by NTX in the shell, but not the core. These data indicate that accumbal opioid antagonism slightly attenuated, but did not block the expression of sugar-conditioned flavor preferences. Therefore, while opioid drugs can have potent effects on sugar intake they appear less effective in altering sugar-conditioned flavor preferences. [Copyright &y& Elsevier]

Abstract: Systemic administration of dopamine D1-like (SCH23390) and, to a lesser degree D2-like (raclopride), receptor antagonists significantly reduce the acquisition and expression of fructose-conditioned flavor preferences (CFP) in rats. Given the role of dopamine in the amygdala (AMY) in the processing and learning of food reward, the present study examined whether dopamine D1-like or D2-like antagonists in this site altered acquisition and/or expression of a fructose-CFP. In Experiment 1, food-restricted rats with bilateral AMY cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (e.g., grape, CS+/Fs) and a less-preferred 0.2% saccharin solution mixed with another flavor (e.g., cherry, CS−/s) during one-bottle (16ml) sessions. Two-bottle tests with the two flavors mixed in saccharin solutions (CS+/s, CS−/s) occurred 10min following total bilateral AMY doses of 0, 12, 24 and 48nmol of SCH23390 or raclopride. Preference for CS+/s over CS−/s was significantly reduced relative to vehicle baseline by the 48nmol doses of SCH23390 and raclopride (from 77% to 66% and 68%), but not lower doses. In Experiment 2, rats received bilateral AMY injections (12nmol) of SCH23390 (D1 group) or raclopride (D2 group) 10min prior to one-bottle training sessions with CS+/Fs and CS−/s. Yoked Control rats received vehicle and were limited to the CS intakes of the D1 and D2 groups; untreated controls were not injected or limited to drug group intakes during training. Subsequent two-bottle tests revealed initial preferences of CS+/s over CS−/s in all groups that remained stable in untreated and Yoked Controls, but were lost over the 6 tests sessions in the D1 group, but not in the D2 group. These data indicate that dopamine D1-like and D2-like antagonists significantly attenuated the expression of the previously acquired fructose-CFP, and did not block acquisition of the fructose-CFP. D1-like antagonism during training hastened extinction of the fructose-CFP. The results are similar to those produced by dopamine D1-like and D2-like antagonist injections into the nucleus accumbens shell which suggests that flavor conditioning involves a regionally distributed brain network. [Copyright &y& Elsevier]

• Inbred mice initially prefer sucralose/saccharin to glucose or fructose solutions. • All strains switch this initial preference after experience with glucose. • Strain-specific effects are observed following fructose experience. • DBA/2 and 129P3 inbred mice also exhibit these preference patterns. • C57BL/6-129P3 F1 hybrid mice also exhibit these effects. Inbred mouse strains differ in their postoral appetite stimulating response (appetition) to fructose as demonstrated in intragastric (IG) sugar conditioning and oral sugar vs. nonnutritive conditioning experiments. For example, FVB and SWR strains show experience-induced preferences for 8% fructose over a 0.1% sucralose + 0.1% saccharin (S + S) solution, whereas C57BL/6 (B6) and BALB/c strains do not. All strains, however, learn to prefer 8% glucose to S + S after experience , which is attributed to the potent appetition actions of this sugar. The present study extended this analysis to DBA/2 (DBA) and 129P3 (129) inbred mice. In Experiment 1A, ad libitum fed DBA and 129 mice preferred S + S to fructose before and after separate experience with the two sweeteners, indicating an indifference to the postoral nutrient effects of the sugar. When food restricted (Experiment 1B), 129 mice continued to prefer S + S to fructose while DBA mice showed equal preference for the sweeteners after experience, indicating some sensitivity to fructose appetition. In Experiment 1C, both strains acquired significant preferences for glucose over S + S after experience, confirming their sensitivity to postoral glucose appetition. Experiment 2 revealed that C57BL/6 × 129P3 (B6:129) hybrid mice responded like inbred B6 mice and 129 mice in acquiring a preference for glucose but not fructose over S + S. This is of interest because sweet "taste-blind" P2 × 2 / P2 × 3 double-knockout (DKO) mice on a B6:129 genetic background prefer fructose to water in 24 h tests, which is indicative of fructose appetition. Whether differences in the genetic makeup of DKO and B6:129 hybrid mice or other factors explain the fructose appetition of the DKO mice remains to be determined. [ABSTRACT FROM AUTHOR]