Conditioned nausea in rats: Assessment by conditioned disgust reactions, rather than conditioned taste avoidance

The terms conditioned taste avoidance and conditioned taste aversion are often used interchangeably in the literature; however, considerable evidence indicates that they may represent different processes. Conditioned taste avoidance is measured by the amount that a rat drinks in a consumption test that includes both appetitive phases and consummatory phases of responding. However, conditioned taste aversion is more directly assessed using the taste reactivity (TR) test that includes only the consummatory phase of responding. Rats display a conditioned taste aversion as conditioned disgust reactions (gapes, chin rubs, and paw treads) during an intraoral infusion of a nausea-paired flavored solution. Only treatments that produce nausea produce conditioned disgust reactions, but even rewarding drugs produce conditioned taste avoidance. Furthermore, treatments that alleviate nausea prevent the establishment and the expression of conditioned disgust reactions, but they do not necessarily modify conditioned taste avoidance. Considerable evidence exists indicating that these two measures can be independent of one another. The potential of a compound to produce conditioned disgust reactions is a reflection of its nausea-inducing properties. Taste avoidance may be motivated by conditioned fear rather than conditioned nausea, but conditioned disgust is motivated by conditioned nausea. (PsycINFO Database Record (c) 2008 APA, all rights reserved).     

Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats

Considerable evidence indicates that conditioned gaping in rats reflects nausea in this species that does not vomit. A series of experiments evaluated the potential of psychoactive cannabinoid agonists, Δ-9-THC and HU-210, and non-psychoactive cannabinoids, Cannabidiol (CBD) and its dimethylheptyl homolog (CBD-dmh), to interfere with the establishment and the expression of conditioned gaping in rats. All agents attenuated both the establishment and the expression of conditioned gaping. Furthermore, the CB1 antagonist, SR-141716, reversed the suppressive effect of HU-210 on conditioned gaping. Finally, SR-141716 potentiated lithium-induced conditioned gaping, suggesting that the endogenous cannabinoid system plays a role in the control of nausea.     

Taste reactivity and consumption measures in the assessment of overshadowing: Modulation of aversive,but not ingestive,reactivity

Three dependent measures—a taste reactivity test, a two-bottle preference test, and a one-bottle extinction test—were used to investigate the conditioning effects of pairing a taste/taste compound with LiCl-induced illness in rats. Avoidance of saccharin consumption in the one-bottle test was attenuated if saccharin and denatonium were paired during illness training (overshadowing). Also, saccharin was found to be more palatable if paired with denatonium during training as reflected by aversive (but not ingestive) taste reactivity measures. It is argued that overshadowing was reflected mainly by a modulation of aversive taste reactivity behavior with little influence on ingestive taste reactivity. The results are discussed in terms of current palatability issues, and it is suggested that applying taste reactivity tests to phenomena associated with taste avoidance learning (e.g., overshadowing or potentiation) may further our understanding of the mechanisms that guide such learning.     

Amphetamine and morphine produce a conditioned taste and place preference in the house musk shrew (Suncus murinus)

Rats have been shown to avoid consuming a flavor, but prefer a location, previously paired with amphetamine or morphine. A series of 4 experiments evaluated the hedonic properties of amphetamine and morphine in the house musk shrew (Suncus murinus), an insectivore that (unlike rats) is capable of vomiting when exposed to toxins. Unlike rats, amphetamine (20 mg/kg) and morphine (20 mg/kg) produced both a conditioned sucrose (0.3 M) and saccharin (0.1%) preference in shrews (administered intraperitoneally), when measured by both a 1- and a 2-bottle test. At the same dose, both drugs also produced a place preference in shrews. These results suggest that the potential of rewarding drugs to produce taste avoidance may vary on the basis of the ability of the species to vomit.     

Taste Aversion Learning Based on Swimming and Lithium Chloride Injection in Rats: Implications From Cross-familiarization Tests and Stimulus Selectivity1

In rats, swimming causes avoidance of the taste solution consumed immediately before the swimming. Several lines of research have shown that this taste avoidance reflects Pavlovian conditioned aversion based on correlations between the taste and swimming-induced nausea. The present research compared swimming-based taste aversion learning (TAL) with conventional TAL based on nausea-inducing lithium chloride (LiCl). By exploiting cross-familiarization techniques, Experiments 1A and 1B suggested that different physiological states are induced by swimming and LiCl. This claim was supported by Experiment 2, which reports stimulus selectivity in saccharin and sucrose aversions based on swimming and LiCl.     

Swimming-induced taste aversion and its prevention by a prior history of swimming

In two experiments, the evidence showed that 20 min of forced swimming by rats caused aversion to a taste solution consumed before swimming. When one of two taste solutions (sodium saccharin or sodium chloride, counterbalanced across rats) was paired with swimming and the other was not, the rats’ intakes of these two solutions showed less consumption of the former than the latter solution. Furthermore, a post-training two-bottle choice test clearly demonstrated long-lasting avoidance of the swimming-paired solution. These results imply that forced swimming acts as an unconditioned stimulus for establishing taste aversion. Preexposure to swimming opportunities before conditioning disrupts such conditioned taste aversion induced by forced swimming.     

Effect of prior exposure to a lithium- and an amphetamine-paired flavor on the acoustic startle response in rats

The experiments reported here evaluated the hypothesis that an amphetamine-paired flavor elicits conditioned fear-arousal, whereas a lithium-paired flavor elicits conditioned nausea-disgust by examining the effect of prior flavor exposure on an acoustic startle reaction (ASR). Exposure to a lithium-paired flavor by intraoral infusion, either immediately prior to a startle session (Experiment 1) or during a startle session (Experiments 2 and 3), resulted in a blunted ASR. In contrast, intraoral infusion of an amphetamine-paired flavor resulted in a potentiated ASR. The blunted ASR produced by exposure to a lithium-paired flavor dramatically reversed to a potentiated ASR when rats were pretreated with the antiemetic drug ondansetron prior to the saccharin-lithium pairing (Experiment 3). The findings shed light on a mechanism by which rewarding drugs produce conditioned taste avoidance in rats.     

Taste avoidance caused by spontaneous wheel running: effects of duration and delay of wheel confinement

Confinement of a rat in a running wheel results in the rat's subsequent avoidance of the taste consumed before the confinement. This phenomenon has been ascribed to taste aversion conditioned by spontaneous wheel running. As a first step toward clarification of the underlying mechanism of this phenomenon, we manipulated two parameters of the taste-confinement procedure: duration of wheel confinement (Experiments 1A and 1B) and temporal intervals between the taste consumption and the wheel confinement (Experiments 2A and 2B). In general, longer confinement and shorter inter-event interval caused stronger taste avoidance. However, the results also suggested that it is possible to establish taste avoidance when wheel confinement was delayed 1-h after the taste consumption. These results correspond to those of conventional taste aversion caused by illness-inducing agents, suggesting similar mechanisms in the both preparations. Experiment 3 revealed that running in a wheel rather than wheel confinement itself is the effective factor for establishing taste avoidance.     

Instrumental Outcome Devaluation Is Attenuated by the Anti-emetic Ondansetron

In three experiments we assessed the effect of an anti-emetic, the selective S-HT antagonist ondansetron, on (1) the conditioning of a taste aversion using lithium chloride (LiCl); (2) the expression of that aversion; and (3) instrumental outcome-devaluation effects. In Experiment 1 it was found that ondansetron reduced the aversion induced by LiCl when administered prior to the LiCl injection and also attenuated the expression of that aversion when administered prior to test sessions. In Experiments 2 and 3, thirsty rats were trained, in a single session, to lever press and chain pull for sucrose and saline solutions concurrently before being injected with LiCl. They were then re-exposed to both solutions, one after injection of vehicle and the other after injection of ondansetron. In a choice extinction test on the levers and chains, animals performed more of the action whose training outcome was re-exposed under ondansetron than the other action, whether the test was conducted after an injection of vehicle or after one of ondansetron.     

Palatability shifts in taste and flavour preference conditioning

Changes in palatability of tastes and flavours as a result of flavour preference conditioning were examined. In Experiment 1, when tastes were paired with glucose in a reverse-order differential conditioning paradigm, rats acquired conditioned preferences for CS + and displayed more hedonic responses to CS + than to CS - in a postconditioning taste reactivity test. In Experiment 2, rats that received oral infusions of flavours as CSs during a reverse-order conditioning procedure expressed both palatability shifts and conditioned preferences for CS + . Rats that received a forward conditioning procedure acquired a preference for CS + , but the palatability of CS + was unchanged. In Experiment 3, hungry rats drank mixtures of a flavour CS and a calorific or sweet tasting reinforcer in a long-exposure conditioning paradigm. When tested hungry, rats preferred CS + whether they had acquired flavour-calorie or flavour-taste associations. However, CS + became more palatable only for rats that acquired flavour-calorie associations. These results suggest that acquisition of flavour preferences, as measured by 2-bottle tests, may not always be accompanied by enhanced palatability.     

Alcohol-induced conditioned aversion: genotypie specificity in mice (Mus musculus).

Acetaldehyde poisoning from ethanol ingestion may lead to aversion to ethanol among DBA mice but not among C57s, since the former are relatively deficient in aldehyde dehydrogenase activity. The present study paired ingestion of saccharin with a single intraperitoneal injection of one of four concentrations of ethanol for DBA/2J and C57BL/6J mice. Subjects were then given a two-bottle saccharin versus water preference test for 10 days. Substitution of saccharin for the taste of ethanol resulted in avoidance of saccharin with all concentrations of ethanol by DBAs but not by C57s, consistent with the conditioned taste aversion paradigm as a model for genetically mediated ethanol avoidance.     

Modification of the punishing effects of psychoactive drugs in rats by previous drug experience.

In Experiment 1, it was shown that chronic prior exposure to amphetamine attenuated the conditioned avoidance of saccharin that was produced by both amphetamine and morphine during gustatory conditioning trials; the relationship between morphine and amphetamine was somewhat anomalous because of their pharmacological dissimilarity. The relationship was also asymmetrical, since in Experiment 2, chronic prior exposure to morphine failed to mitigate avoidance conditioning by amphetamine but was effective in attenuating conditioning by morphine itself. In a third experiment, it was found that prior treatment with chlordiazepoxide attenuated saccharin avoidance conditioned by chlordiazepoxide but not by amphetamine or morphine. The findings were related to Parker, Failor, and Weidman's hypothesis, based on findings with morphine, concerning the development of conditioned preferences for substances associated with the repletion of artificially induced biological needs. It was suggested that the findings were best interpreted as a reflection of drug tolerance rather than conditioned preference.     

The influence of flavor preexposure and test interval on conditioned taste aversions in the rat

The effects of flavor preexposure and test interval on conditioned taste aversions were examined in four experiments. In the first three experiments, prior experience with a flavor different from that used as a conditioned-stimulus (CS) produced attenuated aversions when testing occurred after a 1-day interval but not after a 21-day interval. Preexposure to the same stimulus used as a CS produced attenuated aversions at both 1- and 21-day intervals. In Experiment 4, a delay interval between flavor preexposure and conditioning eliminated the attenuating effect of preexposure, but only when different stimuli were used for preexposure and conditioning. These data could not be easily accounted for by contemporary interpretations of preexposure as an event that interferes with subsequent acquisition of a conditioned aversion. An alternative retrieval interference hypothesis was outlined.     

Effect of exposure to lithium-paired or amphetamine-paired saccharin solution on open arm avoidance in an elevated plus maze

Recent evidence suggests that drug-induced conditioned taste avoidance may be mediated by conditioned fear (e.g., Parker, 2003). The experiments reported here evaluated the effect of exposure to a drug-paired flavor on open arm exploration in an elevated plus maze (EPM), a measure of fear. When rats were tested on a familiar (trial 2) EPM, but not on a novel (trial 1) EPM, prior exposure to a lithium-paired saccharin solution enhanced open arm activity relative to saline-paired saccharin. On the other hand, when rats were exposed to lithium-paired saccharin during plus maze exposure, they displayed suppressed open arm activity relative to unpaired controls when tested in a familiar maze. The pattern of results was specific to the conditional affective properties of the taste, because exposure to unconditional sickness produced by administration of lithium, and unconditionally unpalatable quinine solution did not produce this pattern. These results were interpreted in terms of the opponent process model of motivation; that is, exposure to a lithium-paired flavor elicits conditioned fear which is immediately followed by conditioned relief when the exposure is terminated. On the other hand, exposure to an amphetamine-paired flavor either before or during EPM testing enhanced open arm exploration. Since the strength of taste avoidance did not differ among amphetamine and lithium conditioned rats, these results provide further evidence that the nature of a saccharin-lithium association differs from that of a saccharin-amphetamine association.     

Conditioning Method Dramatically Alters the Role of Amygdala in Taste Aversion Learning

Although an important role for the amygdala in taste aversion learning has been suggested by work in a number of laboratories, results have been inconsistent and interpretations varied. The present series of studies reevaluated the role of the amygdala in taste aversion learning by examining the extent to which conditioning methods, testing methods and lesioning methods, influence whether amygdala lesions dramatically affect conditioned taste aversion (CTA) learning. Results indicated that when animals are conditioned with an intraoral (I/O) taste presentation, lesions of amygdala eliminate evidence of conditioning whether animals are tested intraorally or with a two-bottle solution presentation. Dramatic effects of amygdala lesions on CTA learning were seen whether lesions were made electrolytically or using an excitotoxin. In contrast, when animals were conditioned using bottle presentation of the taste, electrolytic lesions attenuated CTAs but did not eliminate them, and excitotoxic lesions had no effect. These results are consistent with the hypothesis that neural structures critical for CTA learning may differ depending on the extent to which the method of conditioned stimulus delivery incorporates a response component.     

Taste sensitivity in infrahuman species: Use of a genetic model to test the validity of alternative measures

In a genetic analysis of PTC taste sensitivity of mice, Ss were presented tap water and a PTC solution in a two-choice situation. A preference index was used as a measure of taste sensitivity, assuming that ability to taste would lead to avoidance, i.e., negative preference. This assumption, however, lead to the rejection of seven Ss who preferred the test solution. Due to the undesirability of deleting Ss, the data were reanalyzed, using an alternative index of taste sensitivity that required no assumption concerning the hedonic quality of the test solution. Information regarding the inheritance of taste sensitivity to PTC provided the validating criterion for this measure.     

The addition of saccharin to taste cues affects taste preference conditioning in thirsty rats

Previous failures to condition preferences for the unacceptable taste cues sucrose octaacetate (SOA) and citric acid (CA) using a reverse-order, differential conditioning procedure (Forestell & LoLordo, 2000) may have been the result of low consumption of the taste cues in training or of their relatively low acceptability to rats that are thirsty and hungry. In the present study, rats that were thirsty but not hungry readily consumed the SOA and CA conditioned stimulus solutions in training. In test, stronger preferences were displayed for CS+ if the taste cues had been mixed in water (i.e., for the previously unacceptable taste cues) than if they had been made more acceptable by the addition of saccharin in training and test. In Experiment 2, again with rats that were thirsty but not hungry, stronger preferences for CS+ were observed when taste cues were presented in water in the test than when they were presented in saccharin. Addition of saccharin to the taste cues in test eliminated the preference for CS+.     

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.     

Further evidence for the summation of latent inhibition and overshadowing in rats’ conditioned taste aversion

Repeated exposures to a target taste (X) attenuated subsequent development of rats’ conditioned aversion to X (latent inhibition effect). Presentation of another taste (A) after X in conditioning (serial X-A compound conditioning) also attenuated conditioned X aversion compared with conditioning without A (overshadowing). Furthermore, the latent inhibition and overshadowing effects summed to show the least conditioned aversion in the rats given both the target preexposures and the serial X-A compound conditioning treatment. These results question the validity of the comparator hypothesis as an explanation for Pavlovian conditioning of rats’ conditioned taste aversion.     

Cannabinoid Agonists and Antagonists Modulate Lithium-induced Conditioned Gaping in Rats

Considerable evidence indicates that conditioned gaping in rats reflects nausea in this species that does not vomit. A series of experiments evaluated the potential of psychoactive cannabinoid agonists, delta-9-THC and HU-210, and non-psychoactive cannabinoids, Cannabidiol (CBD) and its dimethylheptyl homolog (CBD-dmh), to interfere with the establishment and the expression of conditioned gaping in rats. All agents attenuated both the establishment and the expression of conditioned gaping. Furthermore, the CB1 antagonist, SR-141716, reversed the suppressive effect of HU-210 on conditioned gaping. Finally, SR-141716 potentiated lithium-induced conditioned gaping, suggesting that the endogenous cannabinoid system plays a role in the control of nausea.