Further evaluation of morphine aversion: maintenance of a taste aversion using a low, nonaversive morphine dose

Previously, in an investigation of morphine-conditioned taste aversion (CTA), we found that limited preexposure to a low, nonaversive (non-CTA-inducing) dose of morphine (2.5 mg/kg) was as effective as preexposure to a higher, CTA-inducing dose (15 mg/kg) in blocking the formation of a subsequent morphine CTA. In the present study, we examined the capacity of this low, 2.5-mg/kg morphine dose to maintain a CTA initially induced by the 15-mg/kg dose. A standard CTA procedure was used. Results indicated that rats given three initial taste-drug pairings with 15 mg/kg morphine followed on subsequent pairing days by treatment with the low, non-CTA-inducing, 2.5-mg/kg dose continued to exhibit a strong CTA over 8 pairing days. A similar pattern was observed for animals continuing to receive taste-drug pairings with the 15-mg/kg dose. Animals receiving only one taste-drug pairing with the 15-mg/kg dose, followed on subsequent pairing days by 2.5-mg/kg conditioning, failed to show such a pattern of CTA. An intermediate CTA pattern was seen with animals conditioned with 15, 10, 5, and repeated 2.5-mg/kg doses over consecutive pairing days. These data suggest that exposure to a low dose of morphine, with no apparent CTA-inducing properties, is sufficient to maintain a previously established morphine taste aversion. Potential implications for understanding the apparent discriminative complexity of morphine's motivational properties are discussed.     

Element preexposure, neophobia, and conditioned aversion to a compound flavor stimulus

Preexposure to one or two elements of a compound flavor stimulus greatly reduced a neophobic reaction to the compound but did not attenuate conditioned flavor aversion in rats. Results indicated that (1) a preexposure effect on conditioned aversion to a flavor compound is not likely to be obtained if subjects initially show a strong neophobic reaction to the elements and (2) the level of neophobia at the time of conditioning has little influence on conditioned flavor aversion.     

Effects of preexposure flavor concentration on conditioned aversion and neophobia

In Experiment 1, 128 experimentally naive, water-deprived rats (Rattus norvegicus) received pretraining access to either 0.25 or 1.5% saccharin, distilled water, or 2.0% saline, followed either by a pairing of 0.25 or 1.5% saccharin with an intraperitoneal injection of 0.15 M lithium chloride (LiCl) or by a pairing of distilled water with LiCl. Preexposure to either saccharin concentration reliably reduced conditioned aversion effects to 0.25% saccharin, relative to that for preexposure to distilled water or saline. But only preexposure to 1.5% saccharin reduced aversion effects to that concentration. In Experiment 2, 48 naive, water-deprived rats received preexposure procedures as in Experiment 1. Afterwards, the rats were tested for neophobia to 0.25 or 1.5% saccharin. Neophobia was reliably greater to the 1.5% concentration. However, preexposure to either saccharin concentration obliterated evidence for neophobia to saccharin, relative to that following preexposure to distilled water or saline.     

Reinstatement of latent inhibition following a reminder treatment in a conditioned taste aversion paradigm.

Reminder treatments have been shown to facilitate the retrieval of a variety of conditioned responses. Whether or not similar results would occur with an experimental paradigm which involves primarily memory for a stimulus, i.e., where no particular response is specified, is unclear. Accordingly, using Sprague-Dawley rats, we employed a latent inhibition paradigm with a long (10 days) retention interval between sucrose (CS) preexposure and sucrose-illness pairing (training). The results demonstrated a loss of latent inhibition following the 10-day retention interval suggesting "forgetting" of the CS preexposure. However, placing a single reminder exposure to the CS within the preexposure-to-training interval reinstated the preexposure effect. Controls indicated that in the absence of the initial preexposure the reminder per se did not produce latent inhibition. Thus, a reminder can reinstate a stimulus attribute (flavor representation) and explicit conditioned responses.     

The US preexposure phenomenon in the conditioned suppression paradigm: A role for conditioned situational stimuli

Four experiments evaluated possible associative and nonassociative accounts of the retardation in the acquisition of conditioned suppression produced by repeated prior exposure to an electric shock US. Associative interference resulting from conditioning of situational stimuli during preexposure to shock was suggested by the findings that signaling the occurrence of high-intensity shock with a discrete nontarget CS during the preexposure phase reduced the magnitude of the retardation effect compared to an unsignaled shock preexposure treatment (Experiments 1 and 4), nonreinforced presentations of putatively conditioned situational stimuli prior to conditioned suppression training reduced the magnitude of the retardation effect (Experiment 2), and the magnitude of the retardation effect was directly related to the intensity of preexposure shock (Experiment 3). Nonassociative interference was suggested by the finding that signaling the occurrence of low-intensity shock with a discrete nontarget CS during the preexposure phase did not reduce the magnitude of the retardation effect compared to an unsignaled shock preexposure treatment (Experiment 4). It was suggested that associative and nonassociative mechanisms govern the US preexposure phenomenon obtained in the conditioned suppression paradigm, and their relative contribution depends upon the intensity of shock.     

Stimulus generalization of conditioned taste aversion in rats

Relatively little information is available regarding the intradimensional stimulus generalization of conditioned taste aversion (CTA). Experiment 1 employed a between-groups generalization test to examine the extent to which conditioned flavor aversion to one sucrose solution generalized to other concentrations of sucrose in adult rats. Evidence of a gradient of aversion was obtained. Because generalization gradients in other tasks have been found to flatten over a retention interval, Experiment 2 investigated the effects of delayed testing (2, 7, or 21 days) upon the slope of the generalization gradient. The generalization gradient flattened at the intervals, suggesting that subjects forgot the specific attributes of the conditioning concentration and avoided generalized stimuli as if they were the original CS. Experiment 3 used a long delay between taste and toxicosis to degrade the associative contingency and found no evidence that the generalization gradients found in the first two experiments could be explained in terms of enhanced neophobia due to poisoning. These findings provide further evidence (cf. A. W. Logue, 1979, Psychological Bulletin, 86, 276-296; M. Domjan, 1980, in J. S. Rosenblatt, R. A. Hinde, C. Beer, & M. Busnel (Eds.), Advances in the study of behavior, Vol. 11, New York: Academic Press) that CTA shares a number of similarities with other learning processes. Further, they illustrate that stimulus forgetting can be detected in a paradigm considered relatively immune to retention loss.     

Explicit disassociation of a conditioned stimulus and unconditioned stimulus during extinction training reduces both time to asymptotic extinction and spontaneous recovery of a conditioned taste aversion

Conditioned taste aversions (CTAs) may be acquired when an animal consumes a novel taste (CS) and then experiences the symptoms of poisoning (US). This aversion may be extinguished by repeated exposure to the CS alone. However, following a latency period in which the CS is not presented, the CTA will spontaneously recover (SR). In the current study we employed an explicitly unpaired extinction procedure (EU-EXT) to determine if it could thwart SR of a CTA. Sprague-Dawley rats acquired a strong CTA after three pairings of saccharin (SAC the CS) and Lithium Chloride (LiCl the US). CTA acquisition was followed by extinction (EXT) training consisting of either (a) CS-only exposure (CSO) or (b) exposure to saccharin and Lithium Chloride on alternate days (i.e., explicitly unpaired: EU). Both extinction procedures resulted in ?90% reacceptance of SAC, although the EU extinction procedure (EU-EXT) significantly decreased the time necessary for rats to reach this criterion (compared to CSO controls). Rats were subsequently tested for SR of the CTA upon re-exposure to SAC following a 30-day latency period of water drinking. Rats that acquired a CTA and then underwent the CSO extinction procedure exhibited a significant suppression of SAC drinking during the SR test (as compared to their SAC drinking at the end of extinction). However, animals in the EU-EXT group did not show such suppression in drinking compared to CSO controls. These data suggest that the EU-EXT procedure may be useful in reducing both time to extinction and the spontaneous recovery of fears.     

Deprivation level affects extinction of a conditioned taste aversion

Hooded rats were conditioned to avoid drinking saccharin by following exposure to saccharin with injection of cyclophosphamide, a drug that produces visceral upset. Extinction trials were then given by presenting saccharin without cyclophosamide injections with the rats under low (10 hr) or high (23 hr) fluid deprivation. The aversion extinguished in fewer trials in rats under high deprivation.     

Disrupting the conditioned stimulus preexposure effect in flavor-aversion learning: effects of interoceptive distractor manipulations

Rats exposed to a flavor prior to a conditioning trial involving that stimulus learn a significantly diminished flavor aversion relative to nonpreexposed control animals. A series of four experiments investigated the ability of the conditioned stimulus (CS) preexposure effect to be disrupted by the introduction of a distractor flavor stimulus between the preexposure and conditioning episodes. Experiment 1 demonstrated that the preexposure effect could be reduced by a distractor presented immediately following the preexposure. In Experiment 2, it was discovered that a novel distractor was more effective than a familiar distractor, even though both stimuli were sensorily equivalent. Experiment 3 further analyzed the distractor effect and demonstrated that the magnitude of disruption was more pronounced with immediate than with delayed (3 hr) distractor manipulations. Finally, Experiment 4 assessed the effects of the distractor in the absence of CS preexposure. The relation of the results from these experiments to general information theory is discussed.     

Disruption of conditioned taste aversion: evidence that ECS weakens the gustatory engram

Two experiments are reported concerning the neural substrate of conditioned taste aversion (CTA) and the amnesic mechanisms involved when such learning is disrupted by electroconvulsive shock (ECS). Subjects were adult male rats. In the first experiment it is demonstrated that an aversion established to a 2.5% sucrose solution can simulate the learning loss reported in earlier studies which was caused by interpolating ECS between tasting and illness when the aversion was established using a 10% sucrose cue. It is concluded that if ECS acts to disrupt the memory of the taste cue, it possibly reduces it to only about one-quarter of its original strength, a substantial deficit not readily apparent simply from the degree of aversion displayed. In the second experiment, CTAs were established using either a 2.5% sucrose cue or a 10% cue with ECS interpolated during the taste-illness interval. Animals in the two groups were subsequently confronted with a range of sucrose stimuli and their respective aversions were compared. Near identical responses were observed under all conditions tested. These findings are consistent with the theory that ECS disrupts CTA by weakening the gustatory engram.     

Aversive properties of the negative stimulus in a successive discrimination

Experiment I sought to determine if the stimulus correlated with extinction in a successive discrimination was an aversive stimulus. An escape response provided an index of aversive control. Two groups of pigeons were exposed to a multiple variable-interval 30-sec extinction schedule. For the experimental group, a single peck on a second key produced a timeout during which all lights in the chamber were dark. For the control group, pecks on the second key had no contingency. The rate of responding on the timeout key during extinction for the experimental group was higher than that of the control group during all sessions of discrimination training except the first. In Exp. II, green was correlated with variable interval 30-sec and red was correlated with variable-interval 5-min. Timeouts were obtained from variable-interval 5-min. There were more timeouts from extinction in Exp. I than from variable-interval 5-min in Exp. II. Experiment III showed that not presenting the positive stimulus reduced the number of timeouts from the negative stimulus for the two birds from Exp. I that had the highest rate of timeouts from extinction, but had little effect on the two birds that had the lowest rate of timeouts. These results suggest that in a multiple schedule, the stimulus correlated with extinction, or the lower response rate, functions as a conditioned aversive stimulus. Explanations of the timeout response in terms of extinction produced variability, displaced aggression, and stimulus change, were considered but found inadequate.     

Interference with ingestional aversion learning produced by preexposure to the unconditioned stimulus: Associative and nonassociative aspects

Preconditioning exposure to a lithium chloride unconditioned stimulus (US) interferes with the subsequent conditioning of a taste aversion. Multiple US preexposures produce a long-lasting or durable interference with aversion learning, whereas a single US exposure produces a transient interference effect. The present experiments demonstrate that the durable US preexposure effect is substantially reduced if the method of drug treatment (infusion versus injection of the drug into the peritoneal cavity) or the spatial cues present during drug treatment (home cage versus a distinctive environment) are changed between the preexposure and taste conditioning phases of the experiment. In contrast, these manipulations do not attenuate the proximal/transient US preexposure effect. These findings indicate that different mechanisms are responsible for the two US preexposure effects. The results are consistent with previous suggestions that the durable effects of lithium preexposure are due to associative interference produced by the exteroceptive stimuli that accompany drug administrations and indicate that the proximal/transient US preexposure effect is mediated by nonassociative mechanisms.     

Potentiation of a conditioned taste aversion in preweanling and adult rats

Preweanling (18 days old) and adult rats were made ill with LiCl either 2 min or 1 hr after tasting controlled amounts of either one of two single flavors (saccharin or NaCl) or a compound mixture of the two. Conditioning was assessed with a single test 4 days later relative to explicitly unpaired control conditions. Generally, potentiation of the aversions to either flavor occurred for animals conditioned to the compound. The potentiation effect was decreased or eliminated by nonreinforced exposure to the alternative flavor of the compound. These effects tended to be stronger for the younger rats. Specifically, adult animals did not express potentiation of the saccharin aversion whereas preweanlings expressed potentiated salt aversions. Nonreinforced exposure to the alternative element eliminated the potentiation effect. Conditions conducive to potentiation are discussed in light of investigators who have not observed this effect in similar studies with compound stimuli.     

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.     

CAMKII inhibition in the parabrachial nuclei elicits conditioned taste aversion in rats

The conditioned taste aversion (CTA) paradigm was used to assess the role of Ca(2+)/calmodulin-dependent protein kinase (CAMKII) in associative learning. KN62, a specific inhibitor of CAMKII, was injected into the parabrachial nuclei (PBN) either immediately after saccharin drinking (CS) or after saccharin drinking and i.p. injection of LiCl (US). Injection of KN62 into the PBN after saccharin drinking elicited clear CTA (Exp. 1). This effect was dosage-dependent and site-specific (Exp. 2). The results are discussed in relation with an earlier report showing that CTA acquisition is disrupted by injection of Ca(2+)/phospholipid-dependent protein kinase (PKC) inhibitor chelerythrine into the PBN during CS-US interval. It is suggested that the principal serine/threonine kinases play different roles in CTA learning: whereas PKC activity is necessary for the gustatory short-term memory formation, CAMKII acts similarly to the US itself-an unexpected role of CAMKII in associative learning.