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The Suppressive Effects of LiCl, Sucrose, and Drugs of Abuse Are Modulated by Sucrose Concentration in Food-Deprived Rats
Physiology & Behavior, Vol. 67, No. 3, pp. 351–357, 1999 © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0031-9384/99/$–see front matter
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The Suppressive Effects of LiCl, Sucrose, and Drugs of Abuse Are Modulated by Sucrose Concentration in Food-Deprived Rats F. GOMEZ1 AND P. S. GRIGSON Department of Behavioral Science, Penn State College of Medicine, Hershey, PA 17033 Received 20 October 1998; Accepted 6 April 1999 GOMEZ, F. AND P. S. GRIGSON. The suppressive effects of LiCl, sucrose, and drugs of abuse are modulated by sucrose concentration in food-deprived rats. PHYSIOL BEHAV 67(3) 351–357, 1999.—Suppression of intake of a gustatory conditioned stimulus (CS) occurs when paired with either an aversive or an appetitive unconditioned stimulus (US). Toxic substances, such as lithium chloride (LiCl), induce conditioned taste aversions while rewarding stimuli, such as high a concentration of sucrose, reduce intake through a comparison process referred to as anticipatory contrast. Drugs of abuse also suppress CS intake, but it is not known whether they do so via their rewarding or aversive properties. Using 0.1, 0.3, or 0.5 M sucrose solutions as the gustatory CS, we compared the suppressive effects of LiCl (5.29 mg/kg), morphine (15 mg/kg), cocaine (10 mg/kg), and a 1.0-M sucrose solution in rats that were food deprived. The doses of the three drugs have been equated in terms of their suppressive effects in water-deprived and free-feeding rats. The results showed that in food-deprived rats the sucrose US failed to suppress intake of any of the sucrose CSs, the drugs of abuse failed to suppress intake of the 0.3 and 0.5-M concentration of sucrose, and LiCl failed to suppress intake of the 0.5-M sucrose solution. When taken together, these findings reveal that the suppressive effects of all USs (aversive, appetitive, and drugs of abuse) can be offset by the use of a caloric CS when evaluated in food-deprived rats. © 1999 Elsevier Science Inc. CTA
Conditioned taste aversion
Morphine
Cocaine
Sucrose
Anticipatory contrast
fects of drugs of abuse do not resemble those of the aversive agent LiCl. First, rats suppress intake of either a saccharin or a salt CS when paired with LiCl-induced illness, but only of a saccharin CS when paired with a matched dose of morphine or cocaine (2,17). Second, when assessed using the taste reactivity test, the suppressive effects of LiCl, but not of drugs of abuse, are associated with active rejection of the gustatory CS following taste–drug pairings (27). Third, while rats decrease both intake of, and instrumental responding for, a gustatory CS that has been paired with LiCl, they actually increase instrumental responding for, but then fail to ingest, a gustatory CS that has been paired with a drug of abuse (28,35,36). Unlike LiCl-induced CTAs, the suppressive effects of drugs of abuse often parallel those of a rewarding sucrose US. First, as is the case with the suppressive effects of cocaine and morphine, the suppressive effects of a sucrose US also depend upon the nature of the gustatory CS (2,12,17). Second, just as rats increase instrumental responding for a gustatory CS paired with a drug of abuse, but then avoid ingesting the CS,
A conditioned taste aversion (CTA) occurs when rats avoid a novel tastant, referred to as the conditioned stimulus (CS), after it has been paired with the administration of a toxin such as lithium chloride (LiCl) or x-radiation, referred to as the unconditioned stimulus or US [(14,25), see (30) for review]. The US, however, need not be aversive for the suppression of CS intake. That is, rats also suppress intake of a saccharin CS when paired with a highly preferred sucrose solution (9). This phenomenon, known as an anticipatory contrast effect, is evidence for appetitive, rather than aversive, conditioning as the rat comes to avoid the saccharin CS in anticipation of the availability of the preferred reward. Finally, intake of a gustatory CS also can be suppressed when paired with the administration of a drug of abuse such as morphine, cocaine, or amphetamine (3,4,8). It is not certain, however, whether these suppressive effects are mediated by the aversive or the appetitive properties of the drug (17), see (16,21) for review]. Evidence argues against the CTA interpretation. That is, when evaluated across a number of tasks, the suppressive ef-
1To
Food deprivation
whom requests for reprints should be addressed. E-mail: [email protected]
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rats also are faster to initiate licking a saccharin CS when paired with a sucrose US in an instrumental task, but then consume the saccharin CS more slowly (10). Third, Lewis rats, known to shown greater preference for drugs of abuse than Fischer 344 rats (23), also evidence greater cocaine- and sucrose-induced suppression of saccharin intake, while the magnitude of the LiCl-induced CTA is equivalent between the two strains (15,18,22). Finally, bilateral lesions of the gustatory thalamus prevent the suppressive effects of a sucrose US (i.e., anticipatory contrast effects) and a morphine US, but not LiCl-induced CTAs (19,29,31). The suppressive effects of rewarding and aversive USs also may be dissociated by the deprivation state of the animal or the caloric value of the gustatory CS. Sucrose-induced suppression is attenuated when using sucrose, rather than saccharin, as the gustatory CS (9,11). Relative to free-feeding rats, morphine-induced suppression also is attenuated when using a sucrose CS in water-deprived rats (20). Morphine-induced suppression of sucrose intake, however, has not yet been examined in the food deprivation state. The suppressive effects of amphetamine and chlordiazepoxide, on the other hand, are known to be attenuated by food deprivation, but these effects have only been examined when using a saccharin CS (1). Finally, unlike drugs of abuse, water deprivation does not reduce LiCl-induced CTAs when using either a saccharin or a sucrose CS (5,25). Although there is evidence that food deprivation may attenuate LiCl-induced suppression of chow intake (7), LiCl-induced CTAs have not been explicitly examined with a sucrose CS in food-deprived rats. Thus, although it is known that a sucrose US fails to suppress intake of a sucrose CS in food-deprived rats (11), neither the suppressive effects of drugs of abuse nor those of LiCl have been assessed when using a sucrose CS in fooddeprived subjects. The present study is designed to address this issue by evaluating the suppressive effects of a rewarding sucrose US, an aversive LiCl US, and drugs of abuse (morphine and cocaine) when sucrose serves as the gustatory CS in food-deprived rats. Further, given that greater CS intensity is known to facilitate the suppressive effects of each of these USs (12–14,17,24,26,32,33), a range of sucrose concentrations will serve as the gustatory stimuli. Finally, the drug doses used in this experiment have been equated in previous studies when using a saccharin CS in water-deprived rats (17). The suppressive effects of these drug doses and 1.0 M sucrose also have been equated when using a saccharin CS in free-feeding rats. The terminal percent suppression of CS intake in freefeeding rats is 98% for 5.29 mg/kg LiCl, 77% for 15 mg/kg morphine, 93% for 10 mg/kg cocaine, and 90% for 1.0 M sucrose [(34), and unpublished data]. Further, the suppressive effects of the morphine and LiCl US have been equated when using a 0.1 M sucrose CS in free-feeding rats. The percent suppression induced by 5.29 mg/kg LiCl and 15 mg/kg morphine is 88% and 82%, respectively (20).
MATERIALS AND METHODS
Subjects The subjects were 100 male Sprague–Dawley rats weighing 250–400 g at the beginning of the experiment. They were housed in large individual stainless steel cages in a colony room in which the temperature (218C) and humidity were automatically regulated. Lighting was maintained on a 12/12-h light/dark cycle, and all manipulations where conducted 3 h into the light phase of the cycle. The rats received free access
to water and Harlan Teklad rodent diet except where noted otherwise. Apparatus The rats were trained in one of four identical modular operant chambers (MED Associates, Inc., St. Albans, VT) measuring 30.5 3 24.0 3 29.0 cm (length 3 width 3 height). All chambers had a clear Plexiglas top, front, and back wall. Side walls were made of aluminum. The grid floors consisted of nineteen 4.8-mm stainless steel rods spaced 1.6 cm apart (center to center). Each chamber was equipped with two retractable sipper tubes that could enter the chamber through 1.3cm diameter holes spaced 16.4 cm apart (center to center). In the advanced position, the tip of the sipper tube was aligned in the center of the hole, flush with the right end wall. A lickometer circuit was used to monitor licking. A shaded bulb, which reflected light off the ceiling, was located to the right of the cage and a white-noise speaker was on the left-end wall, opposite to the sipper tubes. Each chamber was housed in a light- and sound-attenuated cubicle that was fitted with a ventilation fan and a white-noise source that provided a background noise level of 75 dB. Control of events in the chamber and collection of the data were carried out on-line using a 33MHz computer. Programs were written in the Medstate notation language (MED Associates, Inc.). Procedure The rats were handled and weighed for 1 week. They were then food deprived to 82% of their free-feeding body weight with water freely available. Once body weight stabilized, the rats were habituated to the operant chambers for 5 min/day for 4 days. The house light and white noise were on, but the tubes were out of the reach of the animals. During the testing sessions, each animal was weighed and placed into the module with the light and white noise on. With a stroke of the key board, one tube was advanced for a 3-min period of access to either 0.1, 0.3, and 0.5 M sucrose. The tube was then retracted and, after a 5-min interval (during which time the house light and white noise remained on), the appropriate US was presented. The possible USs included: an intraperitioneal (i.p.) injection of LiCl (5.29 mg/kg), an i.p. injection of morphine (15 mg/kg), a subcutaneous (s.c.) injection of cocaine (10 mg/ kg), an i.p. or s.c. injection of saline, or a second 3-min access period to a preferred 1.0 M sucrose solution. The 1.0 M sucrose US was presented by advancing a second sipper tube. There was one CS–US pairing occurring every other day for a total of seven trials. The daily food ration was provided no less than 45 min after each rat was removed from the test chamber. For each of the five USs (saline, sucrose, morphine, cocaine, or LiCl), four animals served in the 0.1 M sucrose groups and eight in each of the 0.3 and 0.5-M sucrose groups. The saline-injected controls received either an i.p. or a s.c. injection of a matched volume. Neither the mode nor volume of the saline injection, however, affected intake by the saline controls, so the data from the two conditions were pooled prior to analysis. Drugs and Solutions The cocaine hydrochloride was injected subcutaneously in a dose of 10 mg/kg. To prevent the necrosis that typically accompanies s.c. injections of this drug (6), however, cocaine was prepared as a 1.5-mg/ml stock solution, and the volume of the injection was adjusted by body weight to obtain a 10
CALORIES, FOOD DEPRIVATION, AND CS INTAKE mg/kg dose. The dose of morphine sulfate was 15 mg/kg. Both drugs were dissolved in sterile saline immediately prior to testing. Lithium Chloride was used in a concentration of 0.009 M, and the dose injected was 5.29 mg/kg. The sucrose solutions (0.1, 0.3, 0.5, and 1.0 M) were prepared with distilled water 24 h prior to use, and were presented at room temperature. Morphine and cocaine were generously provided by NIDA. Saccharin and sucrose were purchased from Fisher Scientific (Malvera, PA) and LiCl from Sigma (St. Louis, MO).
353 pressed by LiCl, morphine, and cocaine relative to intake by the saline-injected controls (see Fig. 1). Rats receiving the 1.0 M sucrose US, on the other hand, tended to increase intake of 0.1 M sucrose relative to the saline-injected controls (see Fig. 1d). A post hoc assessment of a significant US 3 trials interaction, F(24, 84) 5 4.28, p , 0.001, showed that LiCl, morphine, and cocaine reduced intake of the 0.1 M sucrose CS on trials 6 and 7 relative to the saline-injected controls (ps , 0.05), and on trial 7, relative to trial 1 intake (ps , 0.05). The elevation observed with the 1.0 M sucrose US did not attain statistical significance.
RESULTS
The data for the three CS conditions were analyzed separately using repeated-measures analyses of variance (ANOVA). When appropriate, post hoc comparisons were made using the Newman–Keuls test with a set at 0.05. Low Concentration When using the lowest concentration of sucrose (0.1 M) as the gustatory CS, intake was slightly, but significantly, sup-
Medium Concentration When using a higher 0.3 M sucrose solution as the gustatory CS, the suppressive effects of morphine, cocaine, and sucrose were absent even following as many as seven CS–US pairings. Treatment with the same dose of the illness-inducing agent, LiCl, however, readily suppressed intake relative to the saline-injected controls (see Fig. 2a–d). This conclusion was supported by post hoc tests of a signif-
FIG. 1. Mean (6SEM) licks/3 min of 0.1 M sucrose across seven pairings with saline, LiCl (5.29 mg/kg, i.p.), morphine sulfate (15 mg/kg, i.p.), cocaine hydrochloride (10 mg/kg, s.c.), or 3 min access to 1.0 M sucrose (reflected in a, b, c, and d, respectively). *p , .05; # p, .01.
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FIG. 2. Mean (6SEM) lick/3 min of 0.3 M sucrose across seven pairings with saline, LiCl (5.29 mg/kg, i.p.), morphine sulfate (15 mg/kg, i.p.), cocaine hydrochloride (10 mg/kg, s.c.), or 3 min access to 1.0 M sucrose (reflected in a, b, c, and d, respectively). #p , .01.
icant US 3 trials interaction, F(24, 204) 5 2.55, p , 0.001, which indicated that the LiCl US suppressed intake compared to the saline-injected controls on trials 3–7 (ps , 0.01). Relative to trial 1 intake, treatment with morphine, cocaine, and sucrose augmented intake beginning on trials 4, 3, and 4, respectively (ps , 0.05). Intake by the LiCl-treated subjects, in comparison did not change significantly from trial 1 to trial 7 (ps . 0.05). High Concentration. Finally, use of the highest concentration of sucrose (0.5 M) offset the suppressive effects of all USs, including those of the aversive illness-inducing agent, LiCl (see Fig. 3a–d). Thus, neither the main effect of US, F(4, 35) 5 1.29, p . 0.05, nor the US 3 trials interaction, F , 1, was statistically significant. The main effect of trials, however, was significant, F(6, 210) 5 92.49, p , 0.0001, and post hoc analysis indicated that intake during trials 2–7 was greater than intake during trial 1 overall, ps , 0.05. DISCUSSION
Together, the data show that the suppressive effects of a range of USs can be attenuated when using a sucrose CS in
food-deprived rats. The suppressive effects of the 1.0 M sucrose solution (i.e., anticipatory contrast effects) were absent when evaluated with the low, medium, or the high sucrose CS. As stated, this finding is consistent with that of Flaherty et al. (11), where food-deprived rats failed to suppress intake of a sucrose CS when having to wait 5 min for access to the preferred sucrose reward. Furthermore, these contrast-reducing effects are known to relate to the caloric content of the gustatory CS because a sucrose US will suppress intake in food-deprived rats when using a non–caloric saccharin CS or in free-feeding subjects when using a caloric sucrose CS (9– 11). Thus, it appears that food-deprived rats will not forgo a caloric sucrose CS when having to wait for access to a preferred, higher concentration sucrose. Like the suppressive effects of sucrose, the suppressive effects of both the 15 mg/kg dose of morphine and the 10 mg/kg dose of cocaine were absent, but only when using the medium (0.3 M) or the high (0.5 M) concentration of sucrose as the gustatory CS. Once again, the failure to suppress intake of the 0.3 M and the 0.5 M sucrose CSs appears to relate to the caloric value of the gustatory CS. That is, the same dose of mor-
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FIG. 3. Mean (6SEM) licks/3 min of 0.5 M sucrose across seven pairings with saline, LiCl (5.29 mg/kg, i.p.), morphine sulfate (15 mg/kg, i.p.), cocaine hydrochloride (10 mg/kg, s.c.), or 3 min access to 1.0 M sucrose (reflected in a, b, c, and d, respectively).
phine and cocaine that had mixed effects in the present manuscript readily suppressed intake of a noncaloric saccharin CS in water-deprived rats (17) or in free-feeding rats (34), and the same dose of morphine effectively suppressed intake of a 0.1 or a 0.5-M sucrose CS when assessed in free-feeding subjects (20). Unlike the suppressive effects of the sucrose US, however, both morphine and cocaine significantly suppressed intake of the 0.1 M sucrose CS in food-deprived rats. This difference may reflect differences in US intensity and/or paradigmatic differences. As stated, although these USs exerted relatively equivalent effects in free-feeding rats when using a saccharin CS, the suppressive effects of the 1.0 M sucrose US may not be equivalent to those of the 15 mg/kg dose of morphine or the 10 mg/kg dose of cocaine when assessed in food-deprived rats using a sucrose CS. Consequently, the intensity of the drugs of abuse may have been greater than that of the 1.0 M sucrose solution under these conditions, leading to suppression of intake of the low concentration of sucrose by the
more powerful drugs of abuse, but not by the 1.0 M sucrose solution. Alternatively, differential suppression may have more to do with obvious paradigmatic differences than with more subtle differences in US intensity. In particular, while both sucrose and drugs of abuse are rewarding, only the sucrose US supplies the much needed caloric load. In the anticipatory contrast paradigm, presentation of the caloric CS and US follows so closely in time that it probably is not possible for the rat to determine whether the bulk of the caloric load is provided by the first or the second stimulus. As a consequence, the failure to suppress intake of the 0.1 M sucrose CS following pairings with the 1.0 M sucrose US may not be due to weaker US intensity (relative to the drugs of abuse and LiCl), but to an inflated perception of the caloric load imparted by the 0.1 M sucrose CS. This simple hypothesis is easily tested. Either way (i.e., whether due to the calories or intensity of the US), the results clearly show that hungry rats will not forgo access to a caloric sucrose CS when having to
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wait for access to either a preferred sucrose solution or to a drug of abuse. In contrast to the suppressive effects of sucrose and drugs of abuse (1,11), the data from previous reports suggest that the suppressive effects of LiCl are not easily attenuated by the deprivation state of the animal, the caloric concentration of the gustatory CS, or by the intensity of the CS. First, as discussed above, Bell et al. (1) recently reported that LiCl-induced CTAs are not attenuated by food deprivation when using a more standard dose of LiCl and a noncaloric saccharin solution as the CS. Second, Nachman and Ashe (25) and Dacanay et al. (5) have obtained similar LiCl-induced CTAs across a range of US doses when using either a saccharin or a sucrose CS in water-deprived rats. In fact, Nachman and Ashe (25) found that a 6.36 mg/kg dose of LiCl (a dose that closely approximates our dose) significantly reduced intake of a 0.44 M sucrose CS when the rats were water deprived. Finally, the magnitude of LiCl-induced CTAs is reportedly augmented, not reduced, as the concentration (i.e., intensity or salience) of the CS is increased in water-deprived rats (14,25,26,32,33). The data from the present manuscript call for an extension of these earlier conclusions. That is, the suppressive effects of the low dose of LiCl, like those of sucrose, morphine, and cocaine, also were attenuated when using a sucrose solution as the gustatory CS in food-deprived rats. This effect does not appear to track differences in CS intensity because, as stated, the magnitude of LiCl-induced CTAs is reportedly increased as the concentration (i.e., salience) of a saccharin CS is increased (14,25,26,32,33). Indeed, as was the case with the other USs, the data appear to relate more to the caloric nature of the gustatory CS. Consistent with this interpretation, the suppressive effects of 5.29-mg/kg LiCl were reduced as the caloric value of the CS increased to 0.5-M sucrose. This same dose of LiCl, however, will suppress intake of a 0.5 M sucrose CS if the animals are tested in a free-feeding or a water-deprived state (20). It also will suppress the intake of a noncaloric saccharin CS when tested under free-feeding, food-deprived, or water-deprived conditions (17,34). Finally, a similar dose of LiCl reportedly suppressed intake of a .44 M sucrose CS when the rats were deprived of water (25). Although sensitive to the caloric value of the sucrose CS, the suppressive effects of LiCl were more resilient in food-deprived rats than were the suppressive effects of either sucrose or the drugs of abuse. Data suggest, however, that this finding does not reflect US intensity differences, per se, but an inter-
action between the nature of the USs, the caloric value of the CS, and the deprivation state of the animal. As stated, the suppressive effects of same doses of LiCl, morphine, and cocaine are similar when using a saccharin CS in water-deprived rats (17), when using a saccharin CS in free-feeding rats (34) and, for morphine and LiCl, when using a sucrose CS in freefeeding rats (20). Further, when tested using a saccharin CS in free-feeding rats, the suppressive effects of the 1.0 M sucrose CS also closely approximated those of the selected doses of the drugs of abuse and LiCl (unpublished data). Thus, while the suppressive effects of these doses of sucrose, morphine, cocaine, and LiCl are similar when using a saccharin CS or free-feeding rats, they clearly differed in the present study when using a caloric sucrose solution as the gustatory CS and food-deprived rats. In conclusion, while all USs exert similar suppressive effects when using a saccharin CS in free-feeding rats (34), the suppressive effect of a 1.0 M sucrose US were absent when using 0.1, 0.3, or 0.5 M sucrose as the CS. The suppressive effects of 15 mg/kg morphine and 10 mg/kg cocaine were absent when using 0.3 or 0.5 M sucrose as the CS; and the suppressive effect of 5.29 mg/kg LiCl was absent when using the 0.5 M concentration of sucrose as the gustatory CS in food-deprived rats. This pattern of results indicates that 1) the suppressive effects of each of the USs tested (sucrose, morphine, cocaine, and LiCl) can be attenuated when using a sucrose CS in fooddeprived rats. 2) The attenuating effects are mediated by the caloric value of the gustatory CS. 3) The attenuating effects differ across USs and these differences likely relate to the nature of the US, rather than to US intensity, per se, because the same doses/concentrations of the USs exert suppressive effects that are similar to one another when evaluated in the absence of metabolic need. Finally, while this manipulation (i.e., use of a caloric CS and food deprivation) does not fully dissociate the suppressive effects of the aversive and appetitive USs, the data clearly demonstrate that even this simple and, sometimes robust, dependent measure (i.e., the suppression of CS intake) can be differentially influenced by the nature of the CS, the nature of the US, and by the deprivation state of the animal. ACKNOWLEDGEMENTS
This research was supported by the U.S. Public Health Service Grants DA 09815 and DC 02016. We thank the National Institute on Drug Abuse for generously providing the morphine sulfate and cocaine hydrochloride.
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The Suppressive Effects of LiCl, Sucrose, and Drugs of Abuse Are Modulated by Sucrose Concentration in Food-Deprived Rats F. GOMEZ1 AND P. S. GRIGSON Department of Behavioral Science, Penn State College of Medicine, Hershey, PA 17033 Received 20 October 1998; Accepted 6 April 1999 GOMEZ, F. AND P. S. GRIGSON. The suppressive effects of LiCl, sucrose, and drugs of abuse are modulated by sucrose concentration in food-deprived rats. PHYSIOL BEHAV 67(3) 351–357, 1999.—Suppression of intake of a gustatory conditioned stimulus (CS) occurs when paired with either an aversive or an appetitive unconditioned stimulus (US). Toxic substances, such as lithium chloride (LiCl), induce conditioned taste aversions while rewarding stimuli, such as high a concentration of sucrose, reduce intake through a comparison process referred to as anticipatory contrast. Drugs of abuse also suppress CS intake, but it is not known whether they do so via their rewarding or aversive properties. Using 0.1, 0.3, or 0.5 M sucrose solutions as the gustatory CS, we compared the suppressive effects of LiCl (5.29 mg/kg), morphine (15 mg/kg), cocaine (10 mg/kg), and a 1.0-M sucrose solution in rats that were food deprived. The doses of the three drugs have been equated in terms of their suppressive effects in water-deprived and free-feeding rats. The results showed that in food-deprived rats the sucrose US failed to suppress intake of any of the sucrose CSs, the drugs of abuse failed to suppress intake of the 0.3 and 0.5-M concentration of sucrose, and LiCl failed to suppress intake of the 0.5-M sucrose solution. When taken together, these findings reveal that the suppressive effects of all USs (aversive, appetitive, and drugs of abuse) can be offset by the use of a caloric CS when evaluated in food-deprived rats. © 1999 Elsevier Science Inc. CTA
Conditioned taste aversion
Morphine
Cocaine
Sucrose
Anticipatory contrast
fects of drugs of abuse do not resemble those of the aversive agent LiCl. First, rats suppress intake of either a saccharin or a salt CS when paired with LiCl-induced illness, but only of a saccharin CS when paired with a matched dose of morphine or cocaine (2,17). Second, when assessed using the taste reactivity test, the suppressive effects of LiCl, but not of drugs of abuse, are associated with active rejection of the gustatory CS following taste–drug pairings (27). Third, while rats decrease both intake of, and instrumental responding for, a gustatory CS that has been paired with LiCl, they actually increase instrumental responding for, but then fail to ingest, a gustatory CS that has been paired with a drug of abuse (28,35,36). Unlike LiCl-induced CTAs, the suppressive effects of drugs of abuse often parallel those of a rewarding sucrose US. First, as is the case with the suppressive effects of cocaine and morphine, the suppressive effects of a sucrose US also depend upon the nature of the gustatory CS (2,12,17). Second, just as rats increase instrumental responding for a gustatory CS paired with a drug of abuse, but then avoid ingesting the CS,
A conditioned taste aversion (CTA) occurs when rats avoid a novel tastant, referred to as the conditioned stimulus (CS), after it has been paired with the administration of a toxin such as lithium chloride (LiCl) or x-radiation, referred to as the unconditioned stimulus or US [(14,25), see (30) for review]. The US, however, need not be aversive for the suppression of CS intake. That is, rats also suppress intake of a saccharin CS when paired with a highly preferred sucrose solution (9). This phenomenon, known as an anticipatory contrast effect, is evidence for appetitive, rather than aversive, conditioning as the rat comes to avoid the saccharin CS in anticipation of the availability of the preferred reward. Finally, intake of a gustatory CS also can be suppressed when paired with the administration of a drug of abuse such as morphine, cocaine, or amphetamine (3,4,8). It is not certain, however, whether these suppressive effects are mediated by the aversive or the appetitive properties of the drug (17), see (16,21) for review]. Evidence argues against the CTA interpretation. That is, when evaluated across a number of tasks, the suppressive ef-
1To
Food deprivation
whom requests for reprints should be addressed. E-mail: [email protected]
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rats also are faster to initiate licking a saccharin CS when paired with a sucrose US in an instrumental task, but then consume the saccharin CS more slowly (10). Third, Lewis rats, known to shown greater preference for drugs of abuse than Fischer 344 rats (23), also evidence greater cocaine- and sucrose-induced suppression of saccharin intake, while the magnitude of the LiCl-induced CTA is equivalent between the two strains (15,18,22). Finally, bilateral lesions of the gustatory thalamus prevent the suppressive effects of a sucrose US (i.e., anticipatory contrast effects) and a morphine US, but not LiCl-induced CTAs (19,29,31). The suppressive effects of rewarding and aversive USs also may be dissociated by the deprivation state of the animal or the caloric value of the gustatory CS. Sucrose-induced suppression is attenuated when using sucrose, rather than saccharin, as the gustatory CS (9,11). Relative to free-feeding rats, morphine-induced suppression also is attenuated when using a sucrose CS in water-deprived rats (20). Morphine-induced suppression of sucrose intake, however, has not yet been examined in the food deprivation state. The suppressive effects of amphetamine and chlordiazepoxide, on the other hand, are known to be attenuated by food deprivation, but these effects have only been examined when using a saccharin CS (1). Finally, unlike drugs of abuse, water deprivation does not reduce LiCl-induced CTAs when using either a saccharin or a sucrose CS (5,25). Although there is evidence that food deprivation may attenuate LiCl-induced suppression of chow intake (7), LiCl-induced CTAs have not been explicitly examined with a sucrose CS in food-deprived rats. Thus, although it is known that a sucrose US fails to suppress intake of a sucrose CS in food-deprived rats (11), neither the suppressive effects of drugs of abuse nor those of LiCl have been assessed when using a sucrose CS in fooddeprived subjects. The present study is designed to address this issue by evaluating the suppressive effects of a rewarding sucrose US, an aversive LiCl US, and drugs of abuse (morphine and cocaine) when sucrose serves as the gustatory CS in food-deprived rats. Further, given that greater CS intensity is known to facilitate the suppressive effects of each of these USs (12–14,17,24,26,32,33), a range of sucrose concentrations will serve as the gustatory stimuli. Finally, the drug doses used in this experiment have been equated in previous studies when using a saccharin CS in water-deprived rats (17). The suppressive effects of these drug doses and 1.0 M sucrose also have been equated when using a saccharin CS in free-feeding rats. The terminal percent suppression of CS intake in freefeeding rats is 98% for 5.29 mg/kg LiCl, 77% for 15 mg/kg morphine, 93% for 10 mg/kg cocaine, and 90% for 1.0 M sucrose [(34), and unpublished data]. Further, the suppressive effects of the morphine and LiCl US have been equated when using a 0.1 M sucrose CS in free-feeding rats. The percent suppression induced by 5.29 mg/kg LiCl and 15 mg/kg morphine is 88% and 82%, respectively (20).
MATERIALS AND METHODS
Subjects The subjects were 100 male Sprague–Dawley rats weighing 250–400 g at the beginning of the experiment. They were housed in large individual stainless steel cages in a colony room in which the temperature (218C) and humidity were automatically regulated. Lighting was maintained on a 12/12-h light/dark cycle, and all manipulations where conducted 3 h into the light phase of the cycle. The rats received free access
to water and Harlan Teklad rodent diet except where noted otherwise. Apparatus The rats were trained in one of four identical modular operant chambers (MED Associates, Inc., St. Albans, VT) measuring 30.5 3 24.0 3 29.0 cm (length 3 width 3 height). All chambers had a clear Plexiglas top, front, and back wall. Side walls were made of aluminum. The grid floors consisted of nineteen 4.8-mm stainless steel rods spaced 1.6 cm apart (center to center). Each chamber was equipped with two retractable sipper tubes that could enter the chamber through 1.3cm diameter holes spaced 16.4 cm apart (center to center). In the advanced position, the tip of the sipper tube was aligned in the center of the hole, flush with the right end wall. A lickometer circuit was used to monitor licking. A shaded bulb, which reflected light off the ceiling, was located to the right of the cage and a white-noise speaker was on the left-end wall, opposite to the sipper tubes. Each chamber was housed in a light- and sound-attenuated cubicle that was fitted with a ventilation fan and a white-noise source that provided a background noise level of 75 dB. Control of events in the chamber and collection of the data were carried out on-line using a 33MHz computer. Programs were written in the Medstate notation language (MED Associates, Inc.). Procedure The rats were handled and weighed for 1 week. They were then food deprived to 82% of their free-feeding body weight with water freely available. Once body weight stabilized, the rats were habituated to the operant chambers for 5 min/day for 4 days. The house light and white noise were on, but the tubes were out of the reach of the animals. During the testing sessions, each animal was weighed and placed into the module with the light and white noise on. With a stroke of the key board, one tube was advanced for a 3-min period of access to either 0.1, 0.3, and 0.5 M sucrose. The tube was then retracted and, after a 5-min interval (during which time the house light and white noise remained on), the appropriate US was presented. The possible USs included: an intraperitioneal (i.p.) injection of LiCl (5.29 mg/kg), an i.p. injection of morphine (15 mg/kg), a subcutaneous (s.c.) injection of cocaine (10 mg/ kg), an i.p. or s.c. injection of saline, or a second 3-min access period to a preferred 1.0 M sucrose solution. The 1.0 M sucrose US was presented by advancing a second sipper tube. There was one CS–US pairing occurring every other day for a total of seven trials. The daily food ration was provided no less than 45 min after each rat was removed from the test chamber. For each of the five USs (saline, sucrose, morphine, cocaine, or LiCl), four animals served in the 0.1 M sucrose groups and eight in each of the 0.3 and 0.5-M sucrose groups. The saline-injected controls received either an i.p. or a s.c. injection of a matched volume. Neither the mode nor volume of the saline injection, however, affected intake by the saline controls, so the data from the two conditions were pooled prior to analysis. Drugs and Solutions The cocaine hydrochloride was injected subcutaneously in a dose of 10 mg/kg. To prevent the necrosis that typically accompanies s.c. injections of this drug (6), however, cocaine was prepared as a 1.5-mg/ml stock solution, and the volume of the injection was adjusted by body weight to obtain a 10
CALORIES, FOOD DEPRIVATION, AND CS INTAKE mg/kg dose. The dose of morphine sulfate was 15 mg/kg. Both drugs were dissolved in sterile saline immediately prior to testing. Lithium Chloride was used in a concentration of 0.009 M, and the dose injected was 5.29 mg/kg. The sucrose solutions (0.1, 0.3, 0.5, and 1.0 M) were prepared with distilled water 24 h prior to use, and were presented at room temperature. Morphine and cocaine were generously provided by NIDA. Saccharin and sucrose were purchased from Fisher Scientific (Malvera, PA) and LiCl from Sigma (St. Louis, MO).
353 pressed by LiCl, morphine, and cocaine relative to intake by the saline-injected controls (see Fig. 1). Rats receiving the 1.0 M sucrose US, on the other hand, tended to increase intake of 0.1 M sucrose relative to the saline-injected controls (see Fig. 1d). A post hoc assessment of a significant US 3 trials interaction, F(24, 84) 5 4.28, p , 0.001, showed that LiCl, morphine, and cocaine reduced intake of the 0.1 M sucrose CS on trials 6 and 7 relative to the saline-injected controls (ps , 0.05), and on trial 7, relative to trial 1 intake (ps , 0.05). The elevation observed with the 1.0 M sucrose US did not attain statistical significance.
RESULTS
The data for the three CS conditions were analyzed separately using repeated-measures analyses of variance (ANOVA). When appropriate, post hoc comparisons were made using the Newman–Keuls test with a set at 0.05. Low Concentration When using the lowest concentration of sucrose (0.1 M) as the gustatory CS, intake was slightly, but significantly, sup-
Medium Concentration When using a higher 0.3 M sucrose solution as the gustatory CS, the suppressive effects of morphine, cocaine, and sucrose were absent even following as many as seven CS–US pairings. Treatment with the same dose of the illness-inducing agent, LiCl, however, readily suppressed intake relative to the saline-injected controls (see Fig. 2a–d). This conclusion was supported by post hoc tests of a signif-
FIG. 1. Mean (6SEM) licks/3 min of 0.1 M sucrose across seven pairings with saline, LiCl (5.29 mg/kg, i.p.), morphine sulfate (15 mg/kg, i.p.), cocaine hydrochloride (10 mg/kg, s.c.), or 3 min access to 1.0 M sucrose (reflected in a, b, c, and d, respectively). *p , .05; # p, .01.
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FIG. 2. Mean (6SEM) lick/3 min of 0.3 M sucrose across seven pairings with saline, LiCl (5.29 mg/kg, i.p.), morphine sulfate (15 mg/kg, i.p.), cocaine hydrochloride (10 mg/kg, s.c.), or 3 min access to 1.0 M sucrose (reflected in a, b, c, and d, respectively). #p , .01.
icant US 3 trials interaction, F(24, 204) 5 2.55, p , 0.001, which indicated that the LiCl US suppressed intake compared to the saline-injected controls on trials 3–7 (ps , 0.01). Relative to trial 1 intake, treatment with morphine, cocaine, and sucrose augmented intake beginning on trials 4, 3, and 4, respectively (ps , 0.05). Intake by the LiCl-treated subjects, in comparison did not change significantly from trial 1 to trial 7 (ps . 0.05). High Concentration. Finally, use of the highest concentration of sucrose (0.5 M) offset the suppressive effects of all USs, including those of the aversive illness-inducing agent, LiCl (see Fig. 3a–d). Thus, neither the main effect of US, F(4, 35) 5 1.29, p . 0.05, nor the US 3 trials interaction, F , 1, was statistically significant. The main effect of trials, however, was significant, F(6, 210) 5 92.49, p , 0.0001, and post hoc analysis indicated that intake during trials 2–7 was greater than intake during trial 1 overall, ps , 0.05. DISCUSSION
Together, the data show that the suppressive effects of a range of USs can be attenuated when using a sucrose CS in
food-deprived rats. The suppressive effects of the 1.0 M sucrose solution (i.e., anticipatory contrast effects) were absent when evaluated with the low, medium, or the high sucrose CS. As stated, this finding is consistent with that of Flaherty et al. (11), where food-deprived rats failed to suppress intake of a sucrose CS when having to wait 5 min for access to the preferred sucrose reward. Furthermore, these contrast-reducing effects are known to relate to the caloric content of the gustatory CS because a sucrose US will suppress intake in food-deprived rats when using a non–caloric saccharin CS or in free-feeding subjects when using a caloric sucrose CS (9– 11). Thus, it appears that food-deprived rats will not forgo a caloric sucrose CS when having to wait for access to a preferred, higher concentration sucrose. Like the suppressive effects of sucrose, the suppressive effects of both the 15 mg/kg dose of morphine and the 10 mg/kg dose of cocaine were absent, but only when using the medium (0.3 M) or the high (0.5 M) concentration of sucrose as the gustatory CS. Once again, the failure to suppress intake of the 0.3 M and the 0.5 M sucrose CSs appears to relate to the caloric value of the gustatory CS. That is, the same dose of mor-
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355
FIG. 3. Mean (6SEM) licks/3 min of 0.5 M sucrose across seven pairings with saline, LiCl (5.29 mg/kg, i.p.), morphine sulfate (15 mg/kg, i.p.), cocaine hydrochloride (10 mg/kg, s.c.), or 3 min access to 1.0 M sucrose (reflected in a, b, c, and d, respectively).
phine and cocaine that had mixed effects in the present manuscript readily suppressed intake of a noncaloric saccharin CS in water-deprived rats (17) or in free-feeding rats (34), and the same dose of morphine effectively suppressed intake of a 0.1 or a 0.5-M sucrose CS when assessed in free-feeding subjects (20). Unlike the suppressive effects of the sucrose US, however, both morphine and cocaine significantly suppressed intake of the 0.1 M sucrose CS in food-deprived rats. This difference may reflect differences in US intensity and/or paradigmatic differences. As stated, although these USs exerted relatively equivalent effects in free-feeding rats when using a saccharin CS, the suppressive effects of the 1.0 M sucrose US may not be equivalent to those of the 15 mg/kg dose of morphine or the 10 mg/kg dose of cocaine when assessed in food-deprived rats using a sucrose CS. Consequently, the intensity of the drugs of abuse may have been greater than that of the 1.0 M sucrose solution under these conditions, leading to suppression of intake of the low concentration of sucrose by the
more powerful drugs of abuse, but not by the 1.0 M sucrose solution. Alternatively, differential suppression may have more to do with obvious paradigmatic differences than with more subtle differences in US intensity. In particular, while both sucrose and drugs of abuse are rewarding, only the sucrose US supplies the much needed caloric load. In the anticipatory contrast paradigm, presentation of the caloric CS and US follows so closely in time that it probably is not possible for the rat to determine whether the bulk of the caloric load is provided by the first or the second stimulus. As a consequence, the failure to suppress intake of the 0.1 M sucrose CS following pairings with the 1.0 M sucrose US may not be due to weaker US intensity (relative to the drugs of abuse and LiCl), but to an inflated perception of the caloric load imparted by the 0.1 M sucrose CS. This simple hypothesis is easily tested. Either way (i.e., whether due to the calories or intensity of the US), the results clearly show that hungry rats will not forgo access to a caloric sucrose CS when having to
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wait for access to either a preferred sucrose solution or to a drug of abuse. In contrast to the suppressive effects of sucrose and drugs of abuse (1,11), the data from previous reports suggest that the suppressive effects of LiCl are not easily attenuated by the deprivation state of the animal, the caloric concentration of the gustatory CS, or by the intensity of the CS. First, as discussed above, Bell et al. (1) recently reported that LiCl-induced CTAs are not attenuated by food deprivation when using a more standard dose of LiCl and a noncaloric saccharin solution as the CS. Second, Nachman and Ashe (25) and Dacanay et al. (5) have obtained similar LiCl-induced CTAs across a range of US doses when using either a saccharin or a sucrose CS in water-deprived rats. In fact, Nachman and Ashe (25) found that a 6.36 mg/kg dose of LiCl (a dose that closely approximates our dose) significantly reduced intake of a 0.44 M sucrose CS when the rats were water deprived. Finally, the magnitude of LiCl-induced CTAs is reportedly augmented, not reduced, as the concentration (i.e., intensity or salience) of the CS is increased in water-deprived rats (14,25,26,32,33). The data from the present manuscript call for an extension of these earlier conclusions. That is, the suppressive effects of the low dose of LiCl, like those of sucrose, morphine, and cocaine, also were attenuated when using a sucrose solution as the gustatory CS in food-deprived rats. This effect does not appear to track differences in CS intensity because, as stated, the magnitude of LiCl-induced CTAs is reportedly increased as the concentration (i.e., salience) of a saccharin CS is increased (14,25,26,32,33). Indeed, as was the case with the other USs, the data appear to relate more to the caloric nature of the gustatory CS. Consistent with this interpretation, the suppressive effects of 5.29-mg/kg LiCl were reduced as the caloric value of the CS increased to 0.5-M sucrose. This same dose of LiCl, however, will suppress intake of a 0.5 M sucrose CS if the animals are tested in a free-feeding or a water-deprived state (20). It also will suppress the intake of a noncaloric saccharin CS when tested under free-feeding, food-deprived, or water-deprived conditions (17,34). Finally, a similar dose of LiCl reportedly suppressed intake of a .44 M sucrose CS when the rats were deprived of water (25). Although sensitive to the caloric value of the sucrose CS, the suppressive effects of LiCl were more resilient in food-deprived rats than were the suppressive effects of either sucrose or the drugs of abuse. Data suggest, however, that this finding does not reflect US intensity differences, per se, but an inter-
action between the nature of the USs, the caloric value of the CS, and the deprivation state of the animal. As stated, the suppressive effects of same doses of LiCl, morphine, and cocaine are similar when using a saccharin CS in water-deprived rats (17), when using a saccharin CS in free-feeding rats (34) and, for morphine and LiCl, when using a sucrose CS in freefeeding rats (20). Further, when tested using a saccharin CS in free-feeding rats, the suppressive effects of the 1.0 M sucrose CS also closely approximated those of the selected doses of the drugs of abuse and LiCl (unpublished data). Thus, while the suppressive effects of these doses of sucrose, morphine, cocaine, and LiCl are similar when using a saccharin CS or free-feeding rats, they clearly differed in the present study when using a caloric sucrose solution as the gustatory CS and food-deprived rats. In conclusion, while all USs exert similar suppressive effects when using a saccharin CS in free-feeding rats (34), the suppressive effect of a 1.0 M sucrose US were absent when using 0.1, 0.3, or 0.5 M sucrose as the CS. The suppressive effects of 15 mg/kg morphine and 10 mg/kg cocaine were absent when using 0.3 or 0.5 M sucrose as the CS; and the suppressive effect of 5.29 mg/kg LiCl was absent when using the 0.5 M concentration of sucrose as the gustatory CS in food-deprived rats. This pattern of results indicates that 1) the suppressive effects of each of the USs tested (sucrose, morphine, cocaine, and LiCl) can be attenuated when using a sucrose CS in fooddeprived rats. 2) The attenuating effects are mediated by the caloric value of the gustatory CS. 3) The attenuating effects differ across USs and these differences likely relate to the nature of the US, rather than to US intensity, per se, because the same doses/concentrations of the USs exert suppressive effects that are similar to one another when evaluated in the absence of metabolic need. Finally, while this manipulation (i.e., use of a caloric CS and food deprivation) does not fully dissociate the suppressive effects of the aversive and appetitive USs, the data clearly demonstrate that even this simple and, sometimes robust, dependent measure (i.e., the suppression of CS intake) can be differentially influenced by the nature of the CS, the nature of the US, and by the deprivation state of the animal. ACKNOWLEDGEMENTS
This research was supported by the U.S. Public Health Service Grants DA 09815 and DC 02016. We thank the National Institute on Drug Abuse for generously providing the morphine sulfate and cocaine hydrochloride.
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