Behavioral Neuroscience 1992. Vol. 106, No. 1, 106-111
Copyright 1992 by the American Psychological Association, Inc 0735-7044 /92/S3.00
Pairings of a Drug or Place Conditioned Stimulus With Lithium Chloride Produce Conditioned Sickness, Not Antisickness Bow Tong Lett
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Memorial University of Newfoundland St. John's, Newfoundland, Canada In different experiments, pairings of a drug (pentobarbital or morphine) or place as the conditioned stimulus (CS) with lithium-induced sickness as the unconditioned stimulus (US) were given to rats to produce Pavlovian conditioning. Control rats received unpaired exposures. In the test, each rat was exposed to the CS, injected with lithium, and then offered food. If such pairings produce conditioning of antisickness (i.e., a compensatory response that opposes lithium sickness), then the experimental rats should eat more than the controls. The reverse occurred. Thus, pairings of a drug or place CS with a lithium US resulted in conditioned sickness rather than antisickness.
Lett (1983) proposed that pairings of a drug conditioned stimulus (CS) such as pentobarbital with an unconditioned stimulus (US) drug such as lithium chloride (LiCl) produce compensatory conditioning (Siegel, 1983) in which the conditioned response (CR) opposes the sickness induced by the lithium. That is, the drug CS comes to elicit a conditioned antisickness response (CAR) rather than conditioned sickness. The main evidence for the CAR hypothesis was that after CS drug-Lid US pairings the administration of the CS drug with LiCl actually produced weaker conditioned taste aversion (CTA) than LiCl by itself, even though the CS drug in the absence of prior pairings with LiCl was itself capable of producing CTA. In these experiments (Lett, 1983), rats were first given pairings (Phase 1) during which the CS drug was injected 30 min before the LiCl US. In Phase 2, the rats in the experimental group were given CTA training during which access to saccharin solution was followed immediately by an injection of the CS drug and then 30 min later with LiCl. Control rats were treated in a similar fashion except that LiCl was injected without the CS drug during CTA training. Consistent with the CAR hypothesis, the experimental group subsequently showed weaker CTA than did the control group. This effect was found with a variety of drug CSs including pentobarbital, morphine, and ethanol. In similar experiments, Revusky and Harding (1986) found that a pentobarbital CS, previously paired with a LiCl US in Phase 1, will attenuate CTA induced in Phase 2 by other agents such as amphetamine or x-radiation. The reduction in CTA found in the experiments just described can also be explained in terms of blocking (Kamin, 1968,1969) as follows. During Phase 1, the drug CS was paired with the LiCl US, which made it a valid predictor of LiClinduced sickness. During CTA training in Phase 2, the pres-
ence of a CS that is a strong predictor of sickness, the drug CS, is presumed to block or interfere with the association between the saccharin taste and sickness. According to most accounts of blocking (e.g., Mackintosh, 1975; Rescorla & Wagner, 1972; Revusky, 1971), this interference is associative in nature and does not depend on any change in the motivational impact of the US. If this is so, then the presence of the CS drug during CTA training in Lett's (1983) CAR experiment could have changed the probability of an association between the taste of saccharin and LiCl-induced sickness without changing the severity of the sickness. The purpose of the present experiments was to further test the CAR hypothesis by measuring more directly whether a drug CS (Experiments 1 and 2) or a place CS (Experiment 3) previously paired with a LiCl US decreases the severity of LiCl-induced sickness. Severity of sickness was measured in terms of LiCl-induced suppression of eating (Deutsch & Gonzalez, 1978) instead of CTA.
Experiments 1 and 2 These experiments were designed to measure the effect of a pentobarbital CS (Experiment 1) or a morphine CS (Experiment 2) on the severity of LiCl-induced sickness. First, rats in the experimental group received five drug-drug pairings during which the CS drug (pentobarbital or morphine) was injected 30 min before the US drug (LiCl); those in the control group received backward pairings during which the US drug was injected before the CS drug. In the subsequent test, each rat in both groups was first injected with the CS drug and then 30 min later with LiCl; 15 min after the LiCl injection, each rat was offered powdered food, and the amount eaten was periodically measured. On the CAR hypothesis, the forward pairings of a CS drug with a LiCl US should result in compensatory conditioning. If this is so, then the CS drug should evoke an antisickness response that counteracts the suppression of eating induced by LiCl, and hence the experimental group should eat more during the test than the control group.
This research was supported by a grant from the Natural Sciences and Engineering Research Council of Canada. I thank Sam Revusky for reading an early version of this article and Anne Dawe for her skillful technical assistance. Correspondence concerning this article should be addressed to Bow Tong Lett, Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3X9.
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CONDITIONED SICKNESS
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Method Subjects. In both experiments, the subjects were male rats of the Sprague-Dawley strain that were obtained from Charles River, Canada (St. Constant, Quebec, Canada). At the start of Experiment 1, the mean weight of the rats was 179 g; in Experiment 2, the mean weight was 183 g. They were housed in a rack of metal cages. Throughout each experiment, water was continually available in the home cage. Drugs. During Phase 1 of Experiments 1 and 2, respectively, 5.0 mg of sodium pentobarbital or 2.0 mg of morphine sulfate dissolved in 0.5 ml of isotonic saline was administered to each rat as the CS drug; these amounts were the same as those used in Lett's (1983) experiments. In Phase 2, each drug was administered according to body weight; the dose of pentobarbital was 15 mg/kg, the morphine dose was 8 gm/kg, and both drugs were injected in a volume of 1 ml/kg. These doses were selected to be similar to those received by each rat at the end of Phase 1. In both experiments, the US drug was LiCl. In Phase 1, the amount injected was the same as that in previous experiments (Lett, 1983); each rat received 2.5 ml of 2% (weight to volume) LiCl solution. In Phase 2, 63.6 mg/kg of LiCl was injected in a volume of 10 ml/kg; the dose of LiCl used in the test was decreased from the earlier dose (about 250 mg/kg) to decrease the probability of a floor effect. All drugs were administered by intraperitoneal injections. Procedure. The procedures of Experiments 1 and 2 were similar in all important respects. In each experiment, the rats were divided into two groups with equated mean weights. During Phase 1, one group (group forward) received Pavlovian conditioning trials in which the CS drug (pentobarbital or morphine in Experiments 1 and 2, respectively) was injected before the US drug (LiCl), whereas the control rats (group backward) were subjected to a backward conditioning procedure in which the US drug was injected before the CS drug. On each of 5 days, which were separated by 2 or 3 days, injection of the CS drug was followed 30 min later by the US drug or vice versa. Food was continually available in the home cage. During Phase 2, the effect of the CS drug on LiCl-induced suppression of eating was tested. Powdered chow was used during the test to facilitate measurement of food intake. In Experiment 1, the rats had been maintained on chow pellets through Phase 1 and had to be habituated to powdered chow before the test. For several weeks, these rats were given access to a metal container of powdered chow from 9:30 a.m. to 7:30 p.m. each day; no other food was allowed. In Experiment 2, the rats had been maintained on powdered chow as their only food from the beginning of the experiment. During Phase 1, powdered chow was continually available in the home cage. Throughout Phase 2, it was available only from 9:30 a.m. to 7:30 p.m. each day. In both experiments, on each of several days before the test, saline was injected 15 min before each rat was given access to a preweighed container of powdered food. The container was weighed periodically, and food intake was determined by subtraction. In Experiment 1, intake was measured after 0.5, 1.0, 3.5, and 6.0 hr of food access; in Experiment 2, intake was measured after 0.5, 1.5, 3.5, and 5.5 hr. On the test day, each rat was first injected with the CS drug, then injected 30 min later with the test dose of LiCl, and then 15 min later given access to the container of powdered food. Food intake was periodically measured as before.
Results and Discussion In both experiments, on the day preceding the test, each rat was injected with saline and offered food 15 min later in its home cage. Tables 1 and 2 show for Experiments 1 and 2, respectively, the cumulative intake of groups forward and backward after each of the four intervals of access to food on
Table 1 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.0, 3.5, and 6 Hr of Access to Food on the Pretest Day in Experiment 1 Length of access (in hours) Group
0.5
1.0
3.5
6.0
Forward Backward
5.8 ± 0.48 4.9 ± 0.45
8.7 ± 0.77 7.3 ± 0.66
11.3 ± 0.75 10.6 ± 0.66
14.7 ± 0.62 13.0 ± 0.76
the pretest day. In both experiments, the cumulative intake of the two groups was similar after each interval (p > .W,t tests). On the test day, each rat was first injected with the CS drug and 30 min later injected with the test dose of LiCl; 15 min later, food was made available. Tables 3 and 4 show the cumulative intake of each group after each period of food access in Experiments 1 and 2, respectively. Although the pattern of intake during the entire test is shown, the amount eaten during the first interval should be the most important finding in testing the CAR hypothesis. This expectation is based on the assumption that the stimulus effects produced by each drug change over time. LiCl-induced sickness, the US effect, is detectable within 5-10 min (Nachman, 1963, 1970) after lithium is injected and reaches a peak within 30 min (Boland, 1973). Because backward pairings in which the CS drug is injected 30 min after the US drug do not produce detectable conditioning (Lett, 1983; Revusky, Taukulis, Parker, & Coombes, 1979), the effects of the CS drug that comprise the effective CS must be those that precede the peak of sickness. If this is so, then the stimulus effects that occur soon after injection of the CS drug should be more likely to elicit a CR than those that occur later. Thus, the effect of the hypothesized CAR on LiCl-induced suppression of eating should be relatively strong during the first test interval and should decline in later test intervals. According to the CAR hypothesis, group forward should eat more than group backward. As can be seen, the reverse occurred; in both experiments, group forward ate less than group backward, /(29) = 2.23, p < .05 in Experiment 1; f(30) = 2.04,p < .05 in Experiment 2. Thus, pairings of a CS drug with a LiCl US resulted in conditioned sickness (Revusky, Taukulis, & Peddle, 1979) rather than antisickness. In both experiments, the cumulative intake of group forward was also reliably less than that of group backward at the end of the second test interval, but this difference disappeared by the end of the third test interval. In Experiment 1, the total
Table 2 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Pretest Day in Experiment 2 Length of access (in hours) Group
0.5
1.5
3.5
5.5
Forward Backward
6.0 ± 0.24 6.1 ± 0.26
8.3 ± 0.58 7.9 ± 0.59
9.5 ± 0.53 9.8 ± 0.47
11.6 + 0.57 12.0 ± 0.66
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Table 3 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.0, 3.5, and 6 Hr of Access to Food on the Test Day in Experiment 1
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Length of access (in hours) Group
0.5
1.0
3.5
6.0
Forward Backward
0.8 ± 0.14 1.3 ± 0.19
1.5 ± 0.27 3.2 ± 0.39
12.6 ± 0.91 10.8 ± 0.71
15.6 ± 1.02 12.8 ± 0.66
amount eaten during the 6-hr test by group forward was greater than that eaten by group backward, f (29) = 2.39, p < .05. However, the two groups did not differ in total test intake in Experiment 2 (t < 1.0). Consistent with the findings of Deutsch and Gonzalez (1978), LiCl administered in combination with a CS drug markedly suppressed eating. In Experiment 1, the rats in group forward reduced their intake during the first test interval to 15% of their intake during the same period on the pretest day (p < .001, Hest), whereas group backward showed a reduction in intake to 29% (p < .001, t test). In Experiment 2, groups forward and backward showed reductions to 15% and 30%, respectively, during the first test interval (p < .001, / test). This effect became less marked with time and was not evident by the end of the test.
Experiment 3 Similar to the attenuation of CTA produced by a drug CS (Lett, 1983), a place CS previously paired with a drug US can also attenuate CTA. In these experiments (Batson & Best, 1979; Braveman, 1979; Willner, 1978), rats were first given pairings of a distinctive place as the CS with LiCl or some other sickness-inducing drug as the US. After several such place CS-drug US pairings, CTA training was given during which the rats drank saccharin solution and then were exposed to the place CS in combination with an administration of the sicknessinducing drug. In relation to appropriate controls, these rats later showed weakened aversions to the taste of saccharin. This finding, like that of the CAR experiments, can be analyzed in terms of compensatory conditioning (Braveman, 1979) or as a blocking effect (Batson & Best, 1979; Willner, 1978). According to an analysis in terms of compensatory conditioning, the attenuated CTA occurs because the place CS reduces the severity of the sickness by eliciting a conditioned compensatory response. In contrast, most accounts of blocking assume that the place CS reduces the likelihood of the taste-sickness association without necessarily affecting the severity of the sickness. The results of Experiments 1 and 2 indicated that the CR elicited by a drug CS previously paired with a LiCl US increases, rather than decreases, the suppression of food intake produced by LiCl. Thus, pairings of a drug CS with a LiCl US result in conditioned sickness rather than in the conditioning of a compensatory response. The purpose of Experiment 3 was to test whether pairings of a place CS with a LiCl US also produce conditioned sickness. The procedure was similar to that used in Experiments 1 and 2 except that a
place CS was substituted for the drug CS. Briefly, the rats in the experimental condition were given paired exposures to a distinctive place as the CS and LiCl as the US, whereas control rats were given equivalent exposures to the place and LiCl but separated by a long time interval. During the test, all rats were first put in the distinctive place and injected with LiCl. Then the rats were returned to the home cage and offered food. If a place CS, like a drug CS, elicits a conditioned sickness response, then it should enhance the suppression of food intake produced by LiCl. If this is so, then the experimental group should eat less than the control rats. Method Subjects. The subjects were 33 male Sprague-Dawley rats with a mean weight of 285 g. They were obtained from Charles River, Canada. As in the preceding experiments, the rats were housed in a rack of metal cages with water continually available. These rats, like those in Experiment 2, were maintained on powdered chow presented in a metal container throughout the course of the experiment. Apparatus. The CS, a distinctive place, was a transparent plastic cage (48.3 x 26.7 x 15.6 cm) with a wire-mesh floor and a wire lid. The stimulus cages were placed on steel shelving in a room adjacent to that containing the rats' home cages. No food or water was available in these cages. Each rat was assigned to a particular cage for the course of the experiment. Procedure. The rats were divided into two groups with equal mean weights. During Phase 1, one group (group paired, n = 17) received paired exposures to the CS place and the LiCl US. On five occasions each separated by 48-96 hr, each rat was placed in the stimulus cage; 20 min later, it was injected with 2.5 ml of 2% (weight to volume) LiCl solution and replaced in the stimulus cage for another 30 min after which it was returned to its home cage. On these same occasions, the second group (group unpaired, n = 16) was given equivalent, but unpaired, exposures to the stimulus cages and the LiCl injections. The rats were each placed in a stimulus cage for 50 min and then returned to the home cage; each rat was injected with the LiCl solution approximately 6 hr later. As in previous experiments, all injections were given intraperitoneally. During Phase 1, powdered chow was continually available in the home cage. In Phase 2, as in the preceding experiments, powdered food was available only from 9:30 a.m. to 7:30 p.m. On several occasions before the test, each rat was injected with isotonic saline and given access to food 15 min later. Food intake was periodically monitored from 9:30 a.m. to 3 p.m. During the test, the rats in both groups were each placed in the stimulus cage for 20 min, then injected with the same test dose of LiCl used in Experiments 1 and 2 (i.e., 63.6 mg/kg at a volume of 10 ml/kg) and replaced in the stimulus cage for another 20 min. Then each rat was returned to its home cage and immediately given access to a container of powdered food. As in Experiment 2, the food container was weighed after 0.5, 1.5, 3.5, and 5.5 hr of access.
Table 4 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Test Day in Experiment 2 Length of access (in hours) Group Forward Backward
0.5 0.9 ± 0.29 1.9 ± 0.41
1.5 3.1 ± 0.53 4.7 ± 0.46
3.5
5.5
8.6 ± 0.38 8.3 ± 0.53
11.6 ±0.59 11.3 ±0.52
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CONDITIONED SICKNESS
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Results and Discussion Table 5 shows the cumulative intake after each period of access by the two groups on the pretest day. The two groups ate similar amounts of food throughout the pretest day (p > .10, t tests). On the test day, the rats were first placed in the stimulus cages, injected with LiCl, and then offered food. Table 6 shows the cumulative intake after each interval of access in the two groups. As shown in Table 6, group paired ate less than group unpaired during the first interval, f(31) = 5.95,p < .001. This finding indicates that the place CS, like the drug CSs in Experiments 1 and 2, elicited conditioned sickness rather than antisickness. At the end of the second test interval, the cumulative intake of group paired was still reliably less than that of group unpaired, t(31) = 2.33, p < .05, but this difference was not apparent after the third or fourth interval (t < 1.0 in each case). As was found by Deutsch and Gonzalez (1978), LiCl suppressed food intake. During the first test interval, the rats in group paired reduced their food intake to 38% of their intake during the same period on the pretest day, whereas group unpaired showed a reduction to 76% (ps < .01, t test). This effect decreased with time and was gone by the third test period.
General Discussion During the test in each of the present experiments, rats were first exposed to a drug CS (pentobarbital or morphine in Experiments 1 and 2, respectively) or to a place CS (Experiment 3) followed by an injection of LiCl, and food intake was then measured. The rats that had previously received the drug or place CS paired with a LiCl US ate less during the first and second test intervals than did rats that had previously received unpaired exposures to these stimuli. That is, the CR that was elicited by the CS (regardless of whether it was a drug or a place) added to the suppressive effect of LiCl on food intake. These results indicate that pairings of a drug or place CS with a LiCl US resulted in a conditioned sickness response rather than in a conditioned compensatory response. Congruent findings have been obtained when slowing of stomach-emptying was used to measure severity of sickness. Slowing of stomach emptying is produced by drugs and other treatments with emetic effects and is thought to be an analog of vomiting in the rat, a species that cannot vomit (Hulse & Patrick, 1977). In experiments similar to the present ones (Lett, 1986), rats were first given pairings of a drug (pentobar-
Table 5 Mean Cumulative Intake (in Grams; ±SE) of Groups Paired and Unpaired After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Pretest Day in Experiment 3 Length of access (in hours) Group
0.5
1.5
3.5
5.5
Paired Unpaired
4.2 ± 0.27 4.7 ± 0.44
7.7 ± 0.42 9.0 ± 0.85
9.7 ± 0.39 10.8 ± 0.90
12.6 ± 0.51 13.3 ± 0.90
Table 6 Mean Cumulative Intake (in Grams; ±SE) of Groups Paired and Unpaired After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Test Day in Experiment 3 Group Paired Unpaired
0.5 1.5 ± 0.12 3.2 ± 0.26
Length of access (in hours) 1.5 3.5 5.3 ± 0.38 10.9 ± 0.57 6.6 ± 0.44 10.7 ± 0.66
5.5
14.1 ± 0.71 13.2 ± 0.80
bital or morphine) or place CS with a LiCl US. Later, the effect of the CS on LiCl-induced slowing of stomach emptying was tested. In each case, the CS enhanced, rather than attenuated, the slowing of stomach emptying induced by LiCl. Thus, these findings, like those of the present experiments, indicate that the drug or place CS elicited conditioned sickness. Less consistent results have been obtained when fluid intake was measured. Domjan, Gillan, and Gemberling (1980) found that an odor CS previously paired with a LiCl US depressed fluid intake. Revusky, Taukulis, and Peddle (1979) found that a pentobarbital CS previously paired with a LiCl US depressed fluid intake but that a morphine or chlordiazepoxide CS similarly paired with a LiCl US had no reliable effect on fluid intake. In contrast, Braveman (1979) found that rats given pairings of a place CS with a LiCl US drank more fluid in the CS place than did the control rats. Most of the evidence reviewed above contradicts the notion of a CAR. However, there is evidence that some form of compensatory conditioning may be produced by pairing a CS with a LiCl US. Domjan and his associates (Domjan & Gillan, 1977; Domjan, Gillan, & Gemberling, 1980) showed that a CS previously paired with a LiCl US evokes a conditioned aftereffect that is compensatory to the suppression of drinking produced by lithium. In one of their experiments, the odor of mentholatum was the CS that was paired with the LiCl US. During the test, fluid intake was measured in different groups of rats in the presence of the odor CS or some time after exposure to the odor CS had ended. As mentioned earlier, the immediate presence of the odor CS depressed fluid intake; however, in a test given after exposure to the odor CS had terminated, fluid intake was reliably elevated. That is, the odor CS appeared to initiate two CRs: one that resembled the unconditioned effect of LiCl and a second that was compensatory to it. The first CR was evident only in the immediate presence of the CS, whereas the compensatory effect became observable after removal of the CS. A similar conditioned aftereffect that resulted in elevated drinking was obtained when the CS paired with LiCl was a taste or place stimulus (Domjan & Gillan, 1977). The conditioned aftereffect also elevated LiCl-induced suppression of drinking (Domjan et al., 1980). The present experiments provide little support for such a conditioned compensatory aftereffect on eating. Only Experiment 1 yielded any supporting evidence. In the test, as described earlier, each rat was exposed to the pentobarbital CS before being exposed to LiCl and then given access to food for 6 hr. For each of the first two test intervals, group forward, which had previously received the pentobarbital CS paired
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with the LiCl US, had a lower cumulative intake than group backward (the control group), which had previously received unpaired exposures to the pentobarbital CS and the LiCl US. Later, the reverse occurred so that group forward had a reliably higher cumulative intake at the end of the test than did the controls. Thus, it could be argued that the presence of the pentobarbital CS enhanced LiCI-induced suppression of eating; but after the pentobarbital CS had dissipated, a conditioned compensatory aftereffect elevated food intake. However, no similar elevation of food intake occurred when morphine was the CS (Experiment 2). Furthermore, the results of Experiment 3 strongly contradicted the notion of a compensatory aftereffect on eating. In the test phase of Experiment 3, rats were put in the CS place, injected with LiCl, and then returned to the home cage before the feeding test began. In other words, the effect of the CS place was measured only after exposure to it had terminated. As reported earlier, the aftereffect of the relatively brief exposure to the place CS was to enhance, rather than to counteract, LiCI-induced suppression of eating. No support for a conditioned compensatory aftereffect on stomach emptying (Lett, 1986) was found. If anything, the aftereffect of a place CS was to enhance, rather than oppose, LiCI-induced slowing of stomach emptying. During the test phase of Experiment 4 (Lett, 1986), one group of rats received a brief exposure to the place CS. Each rat in this group was put in the CS place, injected 15 min later with LiCl, and then 8 min later returned to the home cage where it remained for 3.18 hr before the measurement of stomach emptying. A second group was treated the same way except that its members spent the entire period in the CS place. Whether exposure to the CS place was short or long, it enhanced LiCI-induced slowing of stomach emptying to the same extent. Thus, the conditioned compensatory aftereffect appears to be specific to drinking and is unlikely to be the hypothesized CAR (Lett, 1983). The original impetus for Lett's (1983) hypothesis of a CAR was the avfail effect (Cunningham & Linakis, 1980; Revusky, Coombes, & Pohl, 1982; Revusky, Taukulis, Parker, & Coombes, 1979). To produce the avfail effect, rats in the experimental condition were first given repeated pairings of a drug CS (e.g., pentobarbital) with LiCl as the US, whereas control rats received unpaired exposures to these drugs. Later, the rats were given CTA training during which saccharin solution was followed by the pentobarbital. Initially, Revusky, Taukulis, Parker, and Coombes (1979) expected the experimental group to show enhanced saccharin aversions in relation to the control group because they expected that the pentobarbital CS would come to elicit a conditioned sickness response that would summate with the mild sickness produced by pentobarbital as an unconditioned effect. Instead, the opposite result was found. As implied by the term avfail, the experimental rats failed to show CTA, whereas the control group showed, as expected, mild CTA. To explain avfail, Lett (1983) hypothesized that the pentobarbital-LiCl pairings produced a CAR. During CTA training, the pentobarbital evoked the CAR that alleviated the mild sickness produced by the pentobarbital as an unconditioned effect and thereby eliminated CTA. The review of the evidence just given provided no evidence for the hypothesized CAR. Thus, it is concluded that Lett's
(1983) finding of attenuated CTA when LiCl is signaled by a drug or place CS must be due to blocking (i.e., Kamin, 1968, 1969). Furthermore, the blocking analysis can be extended to explain avfail as follows. In Phase 1, the pentobarbital-LiCl pairings resulted in the conditioning of the pentobarbital CS to intense sickness. During CTA training in Phase 2, the pentobarbital CS blocked the conditioning of saccharin to mild sickness induced by pentobarbital just as a tone CS previously conditioned to an intense shock in Phase 1 would be expected to interfere with the conditioning of a light CS to a mild shock in Phase 2 (Rescorla & Wagner, 1972).
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CONDITIONED SICKNESS Rescorla, R. A., & Wagner, A. R. (1972). A theory of Pavlovian conditioning: Variations in the effectiveness of reinforcement and nonreinforcement. In A. H. Black & W. F. Prokasy (Eds.), Classical conditioning: II. Current research and theory (pp. 64-99). New York: Appleton-Century-Crofts. Revusky, S. (1971). The role of interference in association over a delay. In W. K. Honig & P. H. R. James (Eds.), Animal memory (pp. 155-213). New York: Academic Press. Revusky, S., Coombes, S., & Pohl, R. W. (1982). Pharmacological generality of the Avfail effect. Behavioral and Neural Biology, 34, 240-260. Revusky, S., & Harding, R. K. (1986). Pairing pentobarbital with one toxin causes it to attenuate taste aversions produced by a different toxin: Implications for conditioned antisickness theory. Behavioral Neuroscience, 100, 685-694. Revusky, S., Taukulis, H. K., Parker, L. A., & Coombes, S. (1979). Chemical aversion therapy: Rat data suggest it may be counterther-
apeutic to pair an addictive drug state with illness. Behaviour Research and Therapy, 17, 177-188. Revusky, S., Taukulis, H. K., & Peddle, C. (1979). Learned associations between drug states: Attempted analysis in Pavlovian terms. Physiological Psychology, 7, 352-363. Siegel, S. (1983). Classical conditioning, drug tolerance, and drug dependence. In Y. Israel, F. B. Glaser, H. Kalant, R. E. Popham, W. Schmidt, & R. G. Smart (Eds.), Research advances in alcohol and drug problems (Vol. 7, pp. 207-246). New York: Plenum Press. Willner, J. A. (1978). Blocking of a taste aversion by prior pairing of exteroceptive stimuli with illness. Learning and Motivation, 9, 125140.
Received January 28,1991 Revision received June 28, 1991 Accepted July 21, 1991
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Pairings of a Drug or Place Conditioned Stimulus With Lithium Chloride Produce Conditioned Sickness, Not Antisickness Bow Tong Lett
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Memorial University of Newfoundland St. John's, Newfoundland, Canada In different experiments, pairings of a drug (pentobarbital or morphine) or place as the conditioned stimulus (CS) with lithium-induced sickness as the unconditioned stimulus (US) were given to rats to produce Pavlovian conditioning. Control rats received unpaired exposures. In the test, each rat was exposed to the CS, injected with lithium, and then offered food. If such pairings produce conditioning of antisickness (i.e., a compensatory response that opposes lithium sickness), then the experimental rats should eat more than the controls. The reverse occurred. Thus, pairings of a drug or place CS with a lithium US resulted in conditioned sickness rather than antisickness.
Lett (1983) proposed that pairings of a drug conditioned stimulus (CS) such as pentobarbital with an unconditioned stimulus (US) drug such as lithium chloride (LiCl) produce compensatory conditioning (Siegel, 1983) in which the conditioned response (CR) opposes the sickness induced by the lithium. That is, the drug CS comes to elicit a conditioned antisickness response (CAR) rather than conditioned sickness. The main evidence for the CAR hypothesis was that after CS drug-Lid US pairings the administration of the CS drug with LiCl actually produced weaker conditioned taste aversion (CTA) than LiCl by itself, even though the CS drug in the absence of prior pairings with LiCl was itself capable of producing CTA. In these experiments (Lett, 1983), rats were first given pairings (Phase 1) during which the CS drug was injected 30 min before the LiCl US. In Phase 2, the rats in the experimental group were given CTA training during which access to saccharin solution was followed immediately by an injection of the CS drug and then 30 min later with LiCl. Control rats were treated in a similar fashion except that LiCl was injected without the CS drug during CTA training. Consistent with the CAR hypothesis, the experimental group subsequently showed weaker CTA than did the control group. This effect was found with a variety of drug CSs including pentobarbital, morphine, and ethanol. In similar experiments, Revusky and Harding (1986) found that a pentobarbital CS, previously paired with a LiCl US in Phase 1, will attenuate CTA induced in Phase 2 by other agents such as amphetamine or x-radiation. The reduction in CTA found in the experiments just described can also be explained in terms of blocking (Kamin, 1968,1969) as follows. During Phase 1, the drug CS was paired with the LiCl US, which made it a valid predictor of LiClinduced sickness. During CTA training in Phase 2, the pres-
ence of a CS that is a strong predictor of sickness, the drug CS, is presumed to block or interfere with the association between the saccharin taste and sickness. According to most accounts of blocking (e.g., Mackintosh, 1975; Rescorla & Wagner, 1972; Revusky, 1971), this interference is associative in nature and does not depend on any change in the motivational impact of the US. If this is so, then the presence of the CS drug during CTA training in Lett's (1983) CAR experiment could have changed the probability of an association between the taste of saccharin and LiCl-induced sickness without changing the severity of the sickness. The purpose of the present experiments was to further test the CAR hypothesis by measuring more directly whether a drug CS (Experiments 1 and 2) or a place CS (Experiment 3) previously paired with a LiCl US decreases the severity of LiCl-induced sickness. Severity of sickness was measured in terms of LiCl-induced suppression of eating (Deutsch & Gonzalez, 1978) instead of CTA.
Experiments 1 and 2 These experiments were designed to measure the effect of a pentobarbital CS (Experiment 1) or a morphine CS (Experiment 2) on the severity of LiCl-induced sickness. First, rats in the experimental group received five drug-drug pairings during which the CS drug (pentobarbital or morphine) was injected 30 min before the US drug (LiCl); those in the control group received backward pairings during which the US drug was injected before the CS drug. In the subsequent test, each rat in both groups was first injected with the CS drug and then 30 min later with LiCl; 15 min after the LiCl injection, each rat was offered powdered food, and the amount eaten was periodically measured. On the CAR hypothesis, the forward pairings of a CS drug with a LiCl US should result in compensatory conditioning. If this is so, then the CS drug should evoke an antisickness response that counteracts the suppression of eating induced by LiCl, and hence the experimental group should eat more during the test than the control group.
This research was supported by a grant from the Natural Sciences and Engineering Research Council of Canada. I thank Sam Revusky for reading an early version of this article and Anne Dawe for her skillful technical assistance. Correspondence concerning this article should be addressed to Bow Tong Lett, Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3X9.
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CONDITIONED SICKNESS
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Method Subjects. In both experiments, the subjects were male rats of the Sprague-Dawley strain that were obtained from Charles River, Canada (St. Constant, Quebec, Canada). At the start of Experiment 1, the mean weight of the rats was 179 g; in Experiment 2, the mean weight was 183 g. They were housed in a rack of metal cages. Throughout each experiment, water was continually available in the home cage. Drugs. During Phase 1 of Experiments 1 and 2, respectively, 5.0 mg of sodium pentobarbital or 2.0 mg of morphine sulfate dissolved in 0.5 ml of isotonic saline was administered to each rat as the CS drug; these amounts were the same as those used in Lett's (1983) experiments. In Phase 2, each drug was administered according to body weight; the dose of pentobarbital was 15 mg/kg, the morphine dose was 8 gm/kg, and both drugs were injected in a volume of 1 ml/kg. These doses were selected to be similar to those received by each rat at the end of Phase 1. In both experiments, the US drug was LiCl. In Phase 1, the amount injected was the same as that in previous experiments (Lett, 1983); each rat received 2.5 ml of 2% (weight to volume) LiCl solution. In Phase 2, 63.6 mg/kg of LiCl was injected in a volume of 10 ml/kg; the dose of LiCl used in the test was decreased from the earlier dose (about 250 mg/kg) to decrease the probability of a floor effect. All drugs were administered by intraperitoneal injections. Procedure. The procedures of Experiments 1 and 2 were similar in all important respects. In each experiment, the rats were divided into two groups with equated mean weights. During Phase 1, one group (group forward) received Pavlovian conditioning trials in which the CS drug (pentobarbital or morphine in Experiments 1 and 2, respectively) was injected before the US drug (LiCl), whereas the control rats (group backward) were subjected to a backward conditioning procedure in which the US drug was injected before the CS drug. On each of 5 days, which were separated by 2 or 3 days, injection of the CS drug was followed 30 min later by the US drug or vice versa. Food was continually available in the home cage. During Phase 2, the effect of the CS drug on LiCl-induced suppression of eating was tested. Powdered chow was used during the test to facilitate measurement of food intake. In Experiment 1, the rats had been maintained on chow pellets through Phase 1 and had to be habituated to powdered chow before the test. For several weeks, these rats were given access to a metal container of powdered chow from 9:30 a.m. to 7:30 p.m. each day; no other food was allowed. In Experiment 2, the rats had been maintained on powdered chow as their only food from the beginning of the experiment. During Phase 1, powdered chow was continually available in the home cage. Throughout Phase 2, it was available only from 9:30 a.m. to 7:30 p.m. each day. In both experiments, on each of several days before the test, saline was injected 15 min before each rat was given access to a preweighed container of powdered food. The container was weighed periodically, and food intake was determined by subtraction. In Experiment 1, intake was measured after 0.5, 1.0, 3.5, and 6.0 hr of food access; in Experiment 2, intake was measured after 0.5, 1.5, 3.5, and 5.5 hr. On the test day, each rat was first injected with the CS drug, then injected 30 min later with the test dose of LiCl, and then 15 min later given access to the container of powdered food. Food intake was periodically measured as before.
Results and Discussion In both experiments, on the day preceding the test, each rat was injected with saline and offered food 15 min later in its home cage. Tables 1 and 2 show for Experiments 1 and 2, respectively, the cumulative intake of groups forward and backward after each of the four intervals of access to food on
Table 1 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.0, 3.5, and 6 Hr of Access to Food on the Pretest Day in Experiment 1 Length of access (in hours) Group
0.5
1.0
3.5
6.0
Forward Backward
5.8 ± 0.48 4.9 ± 0.45
8.7 ± 0.77 7.3 ± 0.66
11.3 ± 0.75 10.6 ± 0.66
14.7 ± 0.62 13.0 ± 0.76
the pretest day. In both experiments, the cumulative intake of the two groups was similar after each interval (p > .W,t tests). On the test day, each rat was first injected with the CS drug and 30 min later injected with the test dose of LiCl; 15 min later, food was made available. Tables 3 and 4 show the cumulative intake of each group after each period of food access in Experiments 1 and 2, respectively. Although the pattern of intake during the entire test is shown, the amount eaten during the first interval should be the most important finding in testing the CAR hypothesis. This expectation is based on the assumption that the stimulus effects produced by each drug change over time. LiCl-induced sickness, the US effect, is detectable within 5-10 min (Nachman, 1963, 1970) after lithium is injected and reaches a peak within 30 min (Boland, 1973). Because backward pairings in which the CS drug is injected 30 min after the US drug do not produce detectable conditioning (Lett, 1983; Revusky, Taukulis, Parker, & Coombes, 1979), the effects of the CS drug that comprise the effective CS must be those that precede the peak of sickness. If this is so, then the stimulus effects that occur soon after injection of the CS drug should be more likely to elicit a CR than those that occur later. Thus, the effect of the hypothesized CAR on LiCl-induced suppression of eating should be relatively strong during the first test interval and should decline in later test intervals. According to the CAR hypothesis, group forward should eat more than group backward. As can be seen, the reverse occurred; in both experiments, group forward ate less than group backward, /(29) = 2.23, p < .05 in Experiment 1; f(30) = 2.04,p < .05 in Experiment 2. Thus, pairings of a CS drug with a LiCl US resulted in conditioned sickness (Revusky, Taukulis, & Peddle, 1979) rather than antisickness. In both experiments, the cumulative intake of group forward was also reliably less than that of group backward at the end of the second test interval, but this difference disappeared by the end of the third test interval. In Experiment 1, the total
Table 2 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Pretest Day in Experiment 2 Length of access (in hours) Group
0.5
1.5
3.5
5.5
Forward Backward
6.0 ± 0.24 6.1 ± 0.26
8.3 ± 0.58 7.9 ± 0.59
9.5 ± 0.53 9.8 ± 0.47
11.6 + 0.57 12.0 ± 0.66
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Table 3 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.0, 3.5, and 6 Hr of Access to Food on the Test Day in Experiment 1
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Length of access (in hours) Group
0.5
1.0
3.5
6.0
Forward Backward
0.8 ± 0.14 1.3 ± 0.19
1.5 ± 0.27 3.2 ± 0.39
12.6 ± 0.91 10.8 ± 0.71
15.6 ± 1.02 12.8 ± 0.66
amount eaten during the 6-hr test by group forward was greater than that eaten by group backward, f (29) = 2.39, p < .05. However, the two groups did not differ in total test intake in Experiment 2 (t < 1.0). Consistent with the findings of Deutsch and Gonzalez (1978), LiCl administered in combination with a CS drug markedly suppressed eating. In Experiment 1, the rats in group forward reduced their intake during the first test interval to 15% of their intake during the same period on the pretest day (p < .001, Hest), whereas group backward showed a reduction in intake to 29% (p < .001, t test). In Experiment 2, groups forward and backward showed reductions to 15% and 30%, respectively, during the first test interval (p < .001, / test). This effect became less marked with time and was not evident by the end of the test.
Experiment 3 Similar to the attenuation of CTA produced by a drug CS (Lett, 1983), a place CS previously paired with a drug US can also attenuate CTA. In these experiments (Batson & Best, 1979; Braveman, 1979; Willner, 1978), rats were first given pairings of a distinctive place as the CS with LiCl or some other sickness-inducing drug as the US. After several such place CS-drug US pairings, CTA training was given during which the rats drank saccharin solution and then were exposed to the place CS in combination with an administration of the sicknessinducing drug. In relation to appropriate controls, these rats later showed weakened aversions to the taste of saccharin. This finding, like that of the CAR experiments, can be analyzed in terms of compensatory conditioning (Braveman, 1979) or as a blocking effect (Batson & Best, 1979; Willner, 1978). According to an analysis in terms of compensatory conditioning, the attenuated CTA occurs because the place CS reduces the severity of the sickness by eliciting a conditioned compensatory response. In contrast, most accounts of blocking assume that the place CS reduces the likelihood of the taste-sickness association without necessarily affecting the severity of the sickness. The results of Experiments 1 and 2 indicated that the CR elicited by a drug CS previously paired with a LiCl US increases, rather than decreases, the suppression of food intake produced by LiCl. Thus, pairings of a drug CS with a LiCl US result in conditioned sickness rather than in the conditioning of a compensatory response. The purpose of Experiment 3 was to test whether pairings of a place CS with a LiCl US also produce conditioned sickness. The procedure was similar to that used in Experiments 1 and 2 except that a
place CS was substituted for the drug CS. Briefly, the rats in the experimental condition were given paired exposures to a distinctive place as the CS and LiCl as the US, whereas control rats were given equivalent exposures to the place and LiCl but separated by a long time interval. During the test, all rats were first put in the distinctive place and injected with LiCl. Then the rats were returned to the home cage and offered food. If a place CS, like a drug CS, elicits a conditioned sickness response, then it should enhance the suppression of food intake produced by LiCl. If this is so, then the experimental group should eat less than the control rats. Method Subjects. The subjects were 33 male Sprague-Dawley rats with a mean weight of 285 g. They were obtained from Charles River, Canada. As in the preceding experiments, the rats were housed in a rack of metal cages with water continually available. These rats, like those in Experiment 2, were maintained on powdered chow presented in a metal container throughout the course of the experiment. Apparatus. The CS, a distinctive place, was a transparent plastic cage (48.3 x 26.7 x 15.6 cm) with a wire-mesh floor and a wire lid. The stimulus cages were placed on steel shelving in a room adjacent to that containing the rats' home cages. No food or water was available in these cages. Each rat was assigned to a particular cage for the course of the experiment. Procedure. The rats were divided into two groups with equal mean weights. During Phase 1, one group (group paired, n = 17) received paired exposures to the CS place and the LiCl US. On five occasions each separated by 48-96 hr, each rat was placed in the stimulus cage; 20 min later, it was injected with 2.5 ml of 2% (weight to volume) LiCl solution and replaced in the stimulus cage for another 30 min after which it was returned to its home cage. On these same occasions, the second group (group unpaired, n = 16) was given equivalent, but unpaired, exposures to the stimulus cages and the LiCl injections. The rats were each placed in a stimulus cage for 50 min and then returned to the home cage; each rat was injected with the LiCl solution approximately 6 hr later. As in previous experiments, all injections were given intraperitoneally. During Phase 1, powdered chow was continually available in the home cage. In Phase 2, as in the preceding experiments, powdered food was available only from 9:30 a.m. to 7:30 p.m. On several occasions before the test, each rat was injected with isotonic saline and given access to food 15 min later. Food intake was periodically monitored from 9:30 a.m. to 3 p.m. During the test, the rats in both groups were each placed in the stimulus cage for 20 min, then injected with the same test dose of LiCl used in Experiments 1 and 2 (i.e., 63.6 mg/kg at a volume of 10 ml/kg) and replaced in the stimulus cage for another 20 min. Then each rat was returned to its home cage and immediately given access to a container of powdered food. As in Experiment 2, the food container was weighed after 0.5, 1.5, 3.5, and 5.5 hr of access.
Table 4 Mean Cumulative Intake (in Grams; ±SE) of Groups Forward and Backward After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Test Day in Experiment 2 Length of access (in hours) Group Forward Backward
0.5 0.9 ± 0.29 1.9 ± 0.41
1.5 3.1 ± 0.53 4.7 ± 0.46
3.5
5.5
8.6 ± 0.38 8.3 ± 0.53
11.6 ±0.59 11.3 ±0.52
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CONDITIONED SICKNESS
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Results and Discussion Table 5 shows the cumulative intake after each period of access by the two groups on the pretest day. The two groups ate similar amounts of food throughout the pretest day (p > .10, t tests). On the test day, the rats were first placed in the stimulus cages, injected with LiCl, and then offered food. Table 6 shows the cumulative intake after each interval of access in the two groups. As shown in Table 6, group paired ate less than group unpaired during the first interval, f(31) = 5.95,p < .001. This finding indicates that the place CS, like the drug CSs in Experiments 1 and 2, elicited conditioned sickness rather than antisickness. At the end of the second test interval, the cumulative intake of group paired was still reliably less than that of group unpaired, t(31) = 2.33, p < .05, but this difference was not apparent after the third or fourth interval (t < 1.0 in each case). As was found by Deutsch and Gonzalez (1978), LiCl suppressed food intake. During the first test interval, the rats in group paired reduced their food intake to 38% of their intake during the same period on the pretest day, whereas group unpaired showed a reduction to 76% (ps < .01, t test). This effect decreased with time and was gone by the third test period.
General Discussion During the test in each of the present experiments, rats were first exposed to a drug CS (pentobarbital or morphine in Experiments 1 and 2, respectively) or to a place CS (Experiment 3) followed by an injection of LiCl, and food intake was then measured. The rats that had previously received the drug or place CS paired with a LiCl US ate less during the first and second test intervals than did rats that had previously received unpaired exposures to these stimuli. That is, the CR that was elicited by the CS (regardless of whether it was a drug or a place) added to the suppressive effect of LiCl on food intake. These results indicate that pairings of a drug or place CS with a LiCl US resulted in a conditioned sickness response rather than in a conditioned compensatory response. Congruent findings have been obtained when slowing of stomach-emptying was used to measure severity of sickness. Slowing of stomach emptying is produced by drugs and other treatments with emetic effects and is thought to be an analog of vomiting in the rat, a species that cannot vomit (Hulse & Patrick, 1977). In experiments similar to the present ones (Lett, 1986), rats were first given pairings of a drug (pentobar-
Table 5 Mean Cumulative Intake (in Grams; ±SE) of Groups Paired and Unpaired After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Pretest Day in Experiment 3 Length of access (in hours) Group
0.5
1.5
3.5
5.5
Paired Unpaired
4.2 ± 0.27 4.7 ± 0.44
7.7 ± 0.42 9.0 ± 0.85
9.7 ± 0.39 10.8 ± 0.90
12.6 ± 0.51 13.3 ± 0.90
Table 6 Mean Cumulative Intake (in Grams; ±SE) of Groups Paired and Unpaired After 0.5, 1.5, 3.5, and 5.5 Hr of Access to Food on the Test Day in Experiment 3 Group Paired Unpaired
0.5 1.5 ± 0.12 3.2 ± 0.26
Length of access (in hours) 1.5 3.5 5.3 ± 0.38 10.9 ± 0.57 6.6 ± 0.44 10.7 ± 0.66
5.5
14.1 ± 0.71 13.2 ± 0.80
bital or morphine) or place CS with a LiCl US. Later, the effect of the CS on LiCl-induced slowing of stomach emptying was tested. In each case, the CS enhanced, rather than attenuated, the slowing of stomach emptying induced by LiCl. Thus, these findings, like those of the present experiments, indicate that the drug or place CS elicited conditioned sickness. Less consistent results have been obtained when fluid intake was measured. Domjan, Gillan, and Gemberling (1980) found that an odor CS previously paired with a LiCl US depressed fluid intake. Revusky, Taukulis, and Peddle (1979) found that a pentobarbital CS previously paired with a LiCl US depressed fluid intake but that a morphine or chlordiazepoxide CS similarly paired with a LiCl US had no reliable effect on fluid intake. In contrast, Braveman (1979) found that rats given pairings of a place CS with a LiCl US drank more fluid in the CS place than did the control rats. Most of the evidence reviewed above contradicts the notion of a CAR. However, there is evidence that some form of compensatory conditioning may be produced by pairing a CS with a LiCl US. Domjan and his associates (Domjan & Gillan, 1977; Domjan, Gillan, & Gemberling, 1980) showed that a CS previously paired with a LiCl US evokes a conditioned aftereffect that is compensatory to the suppression of drinking produced by lithium. In one of their experiments, the odor of mentholatum was the CS that was paired with the LiCl US. During the test, fluid intake was measured in different groups of rats in the presence of the odor CS or some time after exposure to the odor CS had ended. As mentioned earlier, the immediate presence of the odor CS depressed fluid intake; however, in a test given after exposure to the odor CS had terminated, fluid intake was reliably elevated. That is, the odor CS appeared to initiate two CRs: one that resembled the unconditioned effect of LiCl and a second that was compensatory to it. The first CR was evident only in the immediate presence of the CS, whereas the compensatory effect became observable after removal of the CS. A similar conditioned aftereffect that resulted in elevated drinking was obtained when the CS paired with LiCl was a taste or place stimulus (Domjan & Gillan, 1977). The conditioned aftereffect also elevated LiCl-induced suppression of drinking (Domjan et al., 1980). The present experiments provide little support for such a conditioned compensatory aftereffect on eating. Only Experiment 1 yielded any supporting evidence. In the test, as described earlier, each rat was exposed to the pentobarbital CS before being exposed to LiCl and then given access to food for 6 hr. For each of the first two test intervals, group forward, which had previously received the pentobarbital CS paired
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with the LiCl US, had a lower cumulative intake than group backward (the control group), which had previously received unpaired exposures to the pentobarbital CS and the LiCl US. Later, the reverse occurred so that group forward had a reliably higher cumulative intake at the end of the test than did the controls. Thus, it could be argued that the presence of the pentobarbital CS enhanced LiCI-induced suppression of eating; but after the pentobarbital CS had dissipated, a conditioned compensatory aftereffect elevated food intake. However, no similar elevation of food intake occurred when morphine was the CS (Experiment 2). Furthermore, the results of Experiment 3 strongly contradicted the notion of a compensatory aftereffect on eating. In the test phase of Experiment 3, rats were put in the CS place, injected with LiCl, and then returned to the home cage before the feeding test began. In other words, the effect of the CS place was measured only after exposure to it had terminated. As reported earlier, the aftereffect of the relatively brief exposure to the place CS was to enhance, rather than to counteract, LiCI-induced suppression of eating. No support for a conditioned compensatory aftereffect on stomach emptying (Lett, 1986) was found. If anything, the aftereffect of a place CS was to enhance, rather than oppose, LiCI-induced slowing of stomach emptying. During the test phase of Experiment 4 (Lett, 1986), one group of rats received a brief exposure to the place CS. Each rat in this group was put in the CS place, injected 15 min later with LiCl, and then 8 min later returned to the home cage where it remained for 3.18 hr before the measurement of stomach emptying. A second group was treated the same way except that its members spent the entire period in the CS place. Whether exposure to the CS place was short or long, it enhanced LiCI-induced slowing of stomach emptying to the same extent. Thus, the conditioned compensatory aftereffect appears to be specific to drinking and is unlikely to be the hypothesized CAR (Lett, 1983). The original impetus for Lett's (1983) hypothesis of a CAR was the avfail effect (Cunningham & Linakis, 1980; Revusky, Coombes, & Pohl, 1982; Revusky, Taukulis, Parker, & Coombes, 1979). To produce the avfail effect, rats in the experimental condition were first given repeated pairings of a drug CS (e.g., pentobarbital) with LiCl as the US, whereas control rats received unpaired exposures to these drugs. Later, the rats were given CTA training during which saccharin solution was followed by the pentobarbital. Initially, Revusky, Taukulis, Parker, and Coombes (1979) expected the experimental group to show enhanced saccharin aversions in relation to the control group because they expected that the pentobarbital CS would come to elicit a conditioned sickness response that would summate with the mild sickness produced by pentobarbital as an unconditioned effect. Instead, the opposite result was found. As implied by the term avfail, the experimental rats failed to show CTA, whereas the control group showed, as expected, mild CTA. To explain avfail, Lett (1983) hypothesized that the pentobarbital-LiCl pairings produced a CAR. During CTA training, the pentobarbital evoked the CAR that alleviated the mild sickness produced by the pentobarbital as an unconditioned effect and thereby eliminated CTA. The review of the evidence just given provided no evidence for the hypothesized CAR. Thus, it is concluded that Lett's
(1983) finding of attenuated CTA when LiCl is signaled by a drug or place CS must be due to blocking (i.e., Kamin, 1968, 1969). Furthermore, the blocking analysis can be extended to explain avfail as follows. In Phase 1, the pentobarbital-LiCl pairings resulted in the conditioning of the pentobarbital CS to intense sickness. During CTA training in Phase 2, the pentobarbital CS blocked the conditioning of saccharin to mild sickness induced by pentobarbital just as a tone CS previously conditioned to an intense shock in Phase 1 would be expected to interfere with the conditioning of a light CS to a mild shock in Phase 2 (Rescorla & Wagner, 1972).
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Received January 28,1991 Revision received June 28, 1991 Accepted July 21, 1991
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