The role of injection cues in the production of the morphine preexposure effect in taste aversion learning

The attenuation of an LiCl-induced conditioned taste aversion (CTA) by LiCl preexposure is mediated primarily by associative blocking via injection-related cues. Given that preexposure to morphine attenuates morphine-induced CTAs, it was of interest to determine whether injection cues also mediate this effect. Certain morphine-induced behaviors such as analgesic tolerance are controlled associatively, via injection-related cues. Accordingly, animals in the present experiments were preexposed to morphine (or vehicle) every other day for five total exposures, followed by an extinction phase, in which the subjects were given saline injections (or no treatment) for 8 (Experiment 1) or 16 (Experiment 2) consecutive days. All of the animals then received five CTA trials with morphine (or vehicle). The morphine-preexposed animals in Experiment 1 displayed an attenuation of the morphine CTA that was unaffected by extinction saline injections, suggesting that blocking by injection cues during morphine preexposure does not mediate this effect. All of the morphine-preexposed subjects in Experiment 2 displayed a weakened preexposure effect, an effect inconsistent with a selective extinction of drug-associated stimuli. The attenuating effects of morphine preexposure in aversion learning are most likely controlled by nonassociative mechanisms, like drug tolerance.     

A history of morphine-induced taste aversion learning fails to affect morphine-induced place preference conditioning in rats

Drugs of abuse have both rewarding and aversive effects, as indexed by the fact that they support place preferences and taste aversions, respectively. In the present study, we explored whether having a history with the aversive effects of morphine (via taste aversion conditioning) impacted the subsequent rewarding effects of morphine, as measured in the place preference design. In Experiment 1, rats were exposed to a taste aversion procedure in which saccharin was followed by morphine. Place preference conditioning was then initiated in which animals were injected with morphine and placed on one side of a two-chambered apparatus. Animals with a taste aversion history acquired place preferences to the same degree as controls without such a history, suggesting that morphine’s affective properties condition multiple effects, dependent on the specific stimuli present during conditioning. To determine whether these results were a reflection of processes operating in traditional associative conditioning, in a modified blocking procedure, place preference conditioning was attempted in the presence of a taste previously associated with morphine (Exp. 2). Under these conditions, animals still acquired morphine-induced place preferences comparable to those of animals without a morphine or conditioning history. These results are consistent with the position that drugs of abuse have multiple stimulus effects (positive and negative) that are differentially associated with specific stimuli (environmental and taste) that drive different behavioral responses (approach and avoidance).     

The UCS preexposure effect in taste aversion learning: Tolerance and blocking are drug specific

Following drug preexposure, rats were given taste aversion conditioning in either the preexposure environment or the home cage. For animals preexposed to LiCl, only the subjects conditioned in the preexposure environment showed the typical UCS preexposure effect, that is, an attenuated aversion, an effect consistent with a blocking interpretation of the LiCl-induced preexposure effect. On the other hand, all rats preexposed to morphine displayed attenuated aversions, independent of the preexposure and conditioning environments, an effect consistent with a pharmacological tolerance explanation of the UCS preexposure effect to morphine. The specific mechanism underlying the drug-induced attenuation appears to be drug-dependent.     

Effects of proximal unconditioned stimulus preexposure on ingestional aversions learned as a result of taste presentation following drug treatment

Taste aversions were conditioned by exposing subjects to a 1.0% saccharin solution 30 min after an injection of lithium chloride. The aversion learning was disrupted if subjects had also received an additional lithium injection some time earlier (Experiments 1–3). This interference effect of US preexposure was a decreasing function of the preexposure interval, beyond the optimal interval (105 min) for observing the phenomenon (Experiment 1), and was directly related to the dose of the preexposure injection (Experiment 2). No interference with conditioning occurred at short (e.g., 30-min) preexposure intervals (Experiment 1), probably because under these circumstances the preexposure injection itself conditioned a strong aversion (Experiment 4). At moderate (105-min) but not at short (30-min) preexposure intervals, the interference with aversions learned as a result of taste exposure following drug injection was comparable to the interference with learning in a more conventional forward conditioning procedure (Experiments 3 and 4). These findings are similar to previously documented effects of proximal CS- and US-preexposure and are consistent with recent stimulus rehearsal and opponent-process theories.     

Characteristics of the lithium-mediated proximal US-preexposure effect in flavor-aversion conditioning

Taste-aversion learning in rats is disrupted if the subjects are exposed to the unconditioned stimulus (US) shortly before the conditioning trial but not if this single US preexposure treatment occurs 1 day or more before conditioning. Several characteristics of this proximal US-preexposure phenomenon were explored. Experiment 1 showed that the time course of the interference with conditioning is directly related to the preexposure drug dose. Experiment 2 demonstrated that the interference effect is evident even if the test for aversion learning is conducted following a drug injection, thereby minimizing stimulus generalization decrement for the preexposed subjects. Finally, Experiment 3 showed that disruption of the contingent relationship between tastes and drug effects is probably not responsible for the proximal US-preexposure phenomenon because the interference with conditioning occurs regardless of whether or not the preexposure drug treatment is paired with a novel flavor. These findings, together with previous research, demonstrate the remarkably robust character of the proximal US-preexposure phenomenon.     

Effects of expected vs. unexpected proximal US preexposure on taste-aversion learning

Animals were first conditioned to expect lithium treatment following exposure to one taste solution (the CS+) and to expect no drug treatment following exposure to another flavor (the CS?). All subjects then received a saccharin taste-aversion conditioning trial. In Experiment 1, this conditioning trial was preceded 0, 1, 2, 4, or 6 h earlier by exposure to the CS+ flavor for independent groups. The CS+ exposure attenuated saccharin aversion learning if it occurred immediately before the saccharin conditioning trial but not if it occurred 1 h or more before conditioning. In Experiment 2, the saccharin conditioning trial was preceded 3 or 4.5 h earlier by a lithium injection. This proximal US preexposure injection was either unannounced (Li) or preceded by exposure to the CS+ (CS+Li) or the CS? (CS?Li) stimuli. The US preexposure attenuated saccharin aversion learning in all cases. However, the interference effect was less when the preexposure injection was expected (CS+Li) than when it was unexpected (CS?Li). This outcome could not be explained in terms of direct effects of the CS+ and CS? stimuli on the saccharin conditioning trial, and shows that the proximal US preexposure effect is a function of not only the drug dosage and preexposure interval, but also the anticipation of the drug pretreatment.     

The role of US novelty in retention interval effects in single-element taste-aversion learning

Retention interval effects are seen in taste-aversion learning when single-element aversions are significantly weaker 24 h after conditioning compared with tests at later intervals. This report contains three experiments which suggest that the source of the increased drinking at the 1-day interval is nonassociative interference produced by the novel conditioning episode. In Experiment 1, a parametric analysis demonstrated that aversion strength increased monotonically over a 30-h period following conditioning, and that by 48 h after conditioning it was stabilized. In Experiment 2, a single US preexposure was used to reduce the novelty of the US prior to conditioning. As a result, animals preexposed to the US had stronger taste aversions than did non-preexposed controls at a 1-day retention interval; however, no differences were seen at a 5-day interval. Experiment 3 investigated whether the counterintuitive outcome of Experiment 2 was due to the summation of environment-illness and taste-illness associations at the 1-day test. The results ruled out the summation argument; the US preexposure did not need to be presented in the conditioning context to strengthen the aversion at the 1-day interval. Collectively, these results suggest that the presentation of a surprising US can interfere with the retrieval of the taste-illness association for a short period after conditioning, and that this contributes to the retention interval effect.     

An empirical analysis of the super-latent inhibition effect

In three conditioned taste aversion experiments, we examined the roles of several variables in producing super-latent inhibition (LI). This effect, greater LI after a long interval than after a short interval between the conditioning and the test stages (De la Casa & Lubow, 2000), was shown to increase with the number of stimulus preexposures (0, 2, or 4; Experiment 1) and with the length of the delay interval (1, 7, 14, or 21 days; Experiment 2). Furthermore, super-LI was obtained when the delay interval was introduced between the conditioning and the test stages (Experiments 1 and 2), but not when it was introduced between the preexposure and the conditioning stages (Experiment 3). The results are discussed in relation to interference explanations of LI.     

Effects of compound or element preexposure on compound flavor aversion conditioning

Two experiments with rat subjects examined conditioning of an aversion to a compound flavor stimulus after preexposing the compound, its constituent elements, or no explicit flavor stimulus. Experiment 1 used a short-term procedure in which preexposure and conditioning treatments occurred on the same day; Experiment 2 used a long-term procedure in which more extensive preexposure was administered several days before conditioning. In both experiments, preexposure of the elements slowed conditioning to the compound more than did preexposure of the compound itself. These effects were apparently not mediated by changes in pseudoconditioned or neophobic responses. The results were related to Lubow’s conditioned attention theory of stimulus preexposure effects.     

Second-order conditioning detects unexpressed morphine-induced salt aversion

Morphine failed to condition a salt taste aversion at a dose (15 mg/kg) sufficient to produce a robust aversion to a saccharin taste. Indeed, three different concentrations of salt (1%, 1.5%, and 2%) paired with the same morphine dose yielded no direct evidence for conditioned aversion. Yet, when a novel saccharin taste was paired in compound with the previously conditioned salt conditioned stimulus, we found evidence for a conditioning to the saccharin cue alone in three separate experiments. Control groups eliminated alternative accounts such as neophobia and differential exposure to morphine. Combined, these findings indicate that morphine conditioned a salt aversion. Although this aversion was not directly expressed, a second-order conditioning procedure was able to provide a more sensitive index of conditioning.     

A within-event analysis of taste-potentiated odor and contextual aversions

A series of experiments was conducted to examine the phenomenon of potentiation. Experiment 1 demonstrated potentiation of odor aversions by taste when morphine served as the unconditioned stimulus (US). Experiment 2 provided evidence that the observed potentiation was due to a within-event association between odor and taste stimuli, rather than reflecting an enhanced odor-morphine association. In Experiment 3, morphine supported place conditioning to contextual cues and aversive conditioning to a taste cue, but potentiation of place conditioning by a taste cue was not obtained. Apparently the absence of potentiation was due to the dual nature of the morphine US, as potentiation of a contextual aversion by taste was obtained in Experiment 4 when a strictly aversive US (lithium) was used. These data suggest that potentiation depends on (1) an initially weak association between the to-be-potentiated conditioned stimulus (CS) element and the US, and (2) the elicitation of qualitatively similar responses by the individual elements of the CS compound. Collectively, these results support an explanation of potentiation based on within-event learning.     

Effect of extended training on generalization of latent inhibition: an instance of perceptual learning

Four experiments examined generalization of latent inhibition (LI) as a function of the length of preexposure in a conditioned taste aversion procedure with rats. Experiment 1 showed that one or four nonreinforced presentations of a flavor compound (BX) retarded subsequent conditioning to another compound (AX). However, after eight presentations of BX, conditioning to AX occurred at the same rate as with no preexposure. These results indicate that generalization of LI decreased as the length of preexposure to BX increased. Experiment 2 replicated this effect of reducing generalization, as well as demonstrating that LI actually increased as the length of preexposure to AX increased. Experiment 3 extended the generality of the effect to a procedure in which both BX and AX were preexposed. Experiment 4 demonstrated a similar reducing-generalization effect when generalization of LI from BX to X was assessed. All of these data are consistent with the notion that prolonged preexposure to BX enhances its discriminability. Different learning mechanisms that might be responsible for this perceptual learning effect are discussed.     

A context-specific detrimental effect of UCS preexposure on place conditioning with morphine

The effect of morphine preexposure on place conditioning with morphine was investigated. In the first experiment, five injections of 10 mg/kg morphine were administered to rats prior to place conditioning or taste-aversion training with morphine. Although this number of preexposures retarded taste-aversion learning, there was no effect on place conditioning. In subsequent experiments we investigated the role of context blocking in UCS preexposure in place conditioning. In one experiment, preexposure to five morphine injections prior to place conditioning resulted in a reduced place preference, compared with preexposure and place conditioning in different contexts. However, the overall detrimental effect of morphine preexposure was questionable, because the rats that were preexposed were only marginally different from those that were not preexposed. In a final experiment we examined the effect of a context change from preexposure to place conditioning with 15 preexposures and demonstrated a detrimental effect of preexposure on place conditioning that was context specific. These results support a role of classical conditioning in place-preference conditioning with morphine.     

Effect of taste preexposure on taste and odor aversions

Thirsty Sprague-Dawley rats drank flavored water in a wind tunnel prior to lithium-induced toxicosis. Flavors were presented for 5 min; 30 min later a toxin, lithium chloride, was injected. After the rats had recovered, subsequent aversions to the taste and the odor were assessed separately. In Experiment 1, extensive preexposure to the taste component of the flavor attenuated neophobia to the flavor and the subsequent taste aversion. However, the subsequent odor aversion was unaffected. Experiment 2 partially replicated the results of Experiment 1 and showed that, in a situation in which only taste-potentiated odor aversions are usually found, nonpotentiated aversions were evident. Experiment 3 found that, in addition to attenuating taste aversions, taste preexposure enhances the capacity of rats to learn nonpotentiated odor aversions. The results are interpreted with a neural-based model of conditioned flavor aversions.     

Variations in the retention of taste aversions: Evidence for retrieval competition

In six experiments, we examined taste and compound taste/taste aversions at different retention intervals. In Experiment 1, saccharin aversions were significantly weaker 1 day after conditioning than 21 days after conditioning. This effect was determined not to be caused by the aftereffects of illness or differential hydration. With the use of a saccharin/denatonium compound, Experiment 2 demonstrated overshadowing of a denatonium aversion at 21- and 1-day retention intervals, Experiment 4 showed a potentiated saccharin aversion only at the 21-day retention interval, and both Experiments 2 and 4 revealed that the aversion of the taste-only controls was stronger at the later retention interval. Experiments 3 and 5 demonstrated that the differences at the two retention intervals were not caused by unconditioned changes in taste preference. Finally, Experiment 6 showed that extinction of the conditioning environment prior to testing results in stronger saccharin aversions than occur in nonextinguished controls. Collectively, these experiments suggest that testing within a 24-h period after conditioning will result in significantly weaker taste aversions. Also, these results support a retrieval-competition explanation that may account for the weakened aversions at the 1-day testing interval of both groups conditioned to single elements and those conditioned to compounds.     

Pentobarbital-induced place aversion learning

Pentobarbital is self-administered by rats but has also been reported to produce a conditioned place aversion. Since the self-administration and place preference paradigms both are considered to assess drug reward, we further examined the hedonic properties of pentobarbital, using place conditioning. In Experiment 1, a dose of 15 mg/kg (intraperitoneal) of pentobarbital produced a conditioned place aversion after 4 conditioning trials of various durations (5, 15, 30, or 60 min). Since rats are typically drug experienced in the self-administration paradigm, in Experiments 2 and 3, we examined the effect of drug history on pentobarbital-induced place conditioning. Although preexposure to pentobarbital attenuated the place aversion, it never resulted in a place preference. As has been reported with alcohol, pentobarbital is hedonically aversive in rats, when novel.     

Interval between preexposure and test determines the magnitude of latent inhibition: Implications for an interference account

The effect of a retention interval on latent inhibition was studied in three experiments by using rats and the conditioned taste-aversion procedure. In Experiment 1, we demonstrated an apparent loss of latent inhibition (i.e., a strengthening of the aversion) in preexposed subjects that experienced a retention interval of 12 days between conditioning and the test. In Experiment 2, we found no effect of this retention interval on the habituation of neophobia produced by the phase of exposure to the flavor. In Experiment 3, we showed that interposing a retention interval between preexposure and conditioning produced effects exactly comparable to those seen in Experiment 1. The implications of these results for rival theories of latent inhibition, as an acquisition deficit or as a case of interference at retrieval, are discussed.     

CS–US interval determines the transition from overshadowing to potentiation with flavor compounds

The present series of five flavor aversion experiments with rat subjects examined compound conditioning at varying CS-US intervals. Using a taste-taste design, Experiments 1A and 1B demonstrated overshadowing at a 0-min CS-US interval and potentiation at a 120-min CS-US interval, and these effects occurred with both tastes of the compound. Experiment 2 showed that the aversion to a single element is reduced when the CS-US interval is increased to 120 min, but the aversion for a compound taste is not. Experiments 3A and 3B explored odor + taste compound conditioning; the results demonstrated odor potentiation across the trace interval and a transition from taste overshadowing to taste potentiation. Collectively, the data show that the change from overshadowing to potentiation was not due to changes in the aversions produced by compound conditioning but, instead, was due to a more rapid loss of conditionability across a trace interval prior to the US in single-element conditioning. These experiments suggest that following compound conditioning, the aversion to each element represents generalization decrement from the configured compound, but the designation of overshadowing or potentiation actually depends on the status of conditioning in the single-element control.     

Habituation to illness: Effects of prior experience with the US on the formation of learned taste aversions in rats

Experiment 1 investigated the effects of US habituation on the acquisition and extinction of learned taste aversions in rats. Subjects receiving five noncontingent LiCl intubations prior to conditioning failed to develop a conditioned taste aversion, while control subjects experiencing a single saccharin/LiCl pairing displayed a pronounced taste aversion which weakened during subsequent poisonings. Experiment 2 examined whether habituation, defined as a waning of responses to repeated presentation of an illness stimulus, was a possible mechanism for explaining the results of Experiment 1. Subjects showed a decrease in motor activity following an initial LiCl intubation, but less attenuation of activity with successive intubations.     

Nonreinforced flavor exposure attenuates the effects of conditioned taste aversion on both flavor consumption and cue palatability

Nonreinforced exposure to a cue tends to attenuate subsequent conditioning with that cue—an effect referred to as latent inhibition (LI). In the two experiments reported here, we examined LI effects in the context of conditioned taste aversion by examining both the amount of consumption and the microstructure of the consummatory behavior (in terms of the mean size of lick clusters). The latter measure can be taken to reflect affective responses to, or the palatability of, the solution being consumed. In both experiments, exposure to a to-be-conditioned flavor prior to pairing the flavor with nausea produced by lithium chloride attenuated both the reduction in consumption and the reduction in lick cluster sizes typically produced by taste aversion learning. In addition, we observed a tendency (especially in the lick cluster measure) for nonreinforced exposure to reduce neophobic responses to the test flavors. Taken together, these results reinforce the suggestion from previous experiments using taste reactivity methods that LI attenuates the effects of taste aversion on both consumption and cue palatability. The present results also support the suggestion that the failure in previous studies to see concurrent LI effects on consumption and palatability was due to a context specificity produced by the oral taste infusion methods required for taste reactivity analyses. Finally, the fact that the pattern of extinction of conditioned changes in consumption and in lick cluster sizes was not affected by preexposure to the cue flavors suggests that LI influenced the quantity but not the quality of conditioned taste aversion.