Environmental control of morphine tolerance in the hamster

Tolerance to morphine-induced hypoactivity in hamsters was investigated under conditions designed to test a Pavlovian conditioning model of morphine tolerance. One group of animals received i.p. injections of morphine (50 mg/kg) in the test environment and saline in the home cage; a second group received saline in the test environment and morphine in the home cage; a third group received saline in both environments. A subsequent morphine challenge in the test environment gave evidence of both associative and nonassociative tolerance. Associative tolerance was detectable 1 week later during a second morphine challenge. Compensatory hyperactivity, however, was not observed during a saline challenge in the presence of morphine-associated cues. Following the acquisition of tolerance, nonreinforced exposure to morphine-associated cues produced an attenuation of morphine tolerance (i.e., extinction of tolerance). The results are interpreted as providing partial support for the Pavlovian model and are discussed in terms of alternative associative models of tolerance.     

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.     

The role of habituation of the response to LiCl in the US-preexposure effect

In two experiments, rats received preexposure consisting of six intraperitoneal injections of lithium chloride (LiCl). This treatment reduced the magnitude of the unconditioned response (UR; suppressed consumption of a novel flavor) evoked by an additional injection (Experiment 1) or by oral consumption (Experiment 2) of LiCl. In both experiments, preexposure also attenuated the acquisition of a conditioned aversion with an LiCl injection as the unconditioned stimulus (US) but had no effect on the aversion produced when the US was oral consumption of LiCl (Experiment 2). These results are consistent with the view that the reduced ability of the preexposed US to serve as a reinforcer depends on blocking by injection-related cues and is independent of habituation of the UR recorded in the present study. Possible interpretations of this dissociation are discussed.     

The effect of morphine preexposure on the acquisition of morphine-induced taste aversions: A nonassociative effect

In Experiment 1, the amount of time rats spent engaged in a range of behaviors was recorded immediately prior to and following the intraperitoneal administration of morphine sulfate (6 mg/kg) or distilled water. No behavioral differences were observed between these groups. In Experiment 2, preexposure to this low dose of morphine attenuated the subsequent acquisition of a morphine-induced taste aversion independent of the similarity of the preexposure and conditioning environments. These results with a dose of morphine that does not produce any behavioral effects, which in turn could potentially mask associative conditioning during preexposure, confirm that the attenuating effects of morphine preexposure on taste aversion learning are nonassociative.     

Acquisition and extinction of conditioned nicotine analgesic tolerance

These studies demonstrated the acquisition and extinction of conditioned tolerance to the analgesic effect of nicotine in rats. In Experiment 1, distinctive environmental cues were either paired or unpaired with nicotine. Following acquisition, the paired group was more tolerant to nicotine than the unpaired and saline groups. Conditioned tolerance was extinguished in the paired group after placebo sessions in the distinctive environment. Experiment 2 examined whether the distinctive environment functioned as a CS or as an occasion setter for injection cues. After acquisition, exposure to the distinctive environment, with or without placebo injections, resulted in extinction. This demonstrates that the distinctive environment served as a CS, not as an occasion setter for injection cues.     

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).     

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.     

The effect of drug habituation before and after taste aversion learning in rats

In Experiment I, rats received eight habituation injections of either lithium chloride (LiCl) or sodium chloride (NaCl), then two aversion training trials in which access to saccharin solution was followed by LiCl injections, and finally eight extinction trials with saccharin but no injections. The rats habituated to LiCl showed less aversion to saccharin during training and extinction. In Experiment II, rats received two aversion training trials, then eight habituation trials to either LiCl or NaCl, then eight extinction trials, four more aversion training trials, and eight more extinction trials. The rats habituated to LiCl did not differ during the first extinction period from those habituated to NaCl, but showed less aversion to saccharin during the second training and extinction periods. Consequently, habituation to LiCl reduces the learning of an aversion to saccharin but does not reduce the performance of a previously learned aversion.     

Pavlovian conditioning of fear based upon hormonal mediation of prior aversive experience

A series of three experiments was conducted to determine if epinephrine administered to animals given prior shock might support learning to new environmental cues paired with the epinephrine injection. Experiment 1, utilizing nonnaive rats, provided results snowing that such learning is possible. The effect, while dose-dependent, did not appear to be based on either epinephrine-induced place aversion or on sensitization. The results of Experiment 2 confirmed the basic finding when naive animals were utilized. Experiment 3 examined more carefully the potential contribution of generalized fear, impairment of extinction of fear, and nonspecific sensitization to the phenomenon. Since the findings did not support these alternative interpretations, it appears that epinephrine administration to previously stressed rats does indeed support new learning. The epinephrine-cue association may be mediated by either of two mechanisms: (1) higher order conditioning or (2) memory reactivation. The redintegrative function of epinephrine injections, in terms of modulating memory processing, is also discussed.     

Positive and negative patterning after CS preexposure in flavor aversion conditioning

Three experiments examined rats’ ability to discriminate a compound conditioned stimulus (CS) from the individual elements of that compound in a flavor aversion conditioning paradigm. In Experiment 1, presentations of a compound of sucrose and saline solutions were followed by lithium chloride injections, but presentations of those elements individually were nonrein-forced (positive patterning). Conversely, in Experiments 2 and 3, presentations of the individual elements were followed by lithium chloride injection, but compound presentations were non-reinforced (negative patterning). The discriminations were acquired in all three experiments. In addition, all three experiments investigated the effects of preexposure of the discriminative stimuli on subsequent acquisition of the patterned discriminations. In positive patterning, preexposure had no measurable effect on the acquisition of responding (suppression) to the reinforced compound stimulus, but slowed the loss of suppression to the nonreinforced elements. In negative patterning, preexposure slowed the acquisition of suppression to the reinforced elements but had little effect on the loss of suppression to the nonreinforced compound.     

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.     

An extinction cue reduces spontaneous recovery of a conditioned taste aversion

The effect of an auditory cue presented during extinction on spontaneous recovery of a conditioned taste aversion was investigated in three experiments. Experiment 1 demonstrated that the presence of the cue during extinction did not influence saccharin consumption during that phase, and that an aversion to saccharin in the absence of the cue was stronger at 18 days than at 1 day after extinction, representing spontaneous recovery rather than a renewal effect. Experiment 2 showed that a cue presented during extinction and testing reduced spontaneous recovery. Experiment 3 replicated that effect and showed that it depended on the cue’s correlation with extinction and not on an unconditioned effect; cues that had been presented during or prior to conditioning did not reduce spontaneous recovery when presented during testing. The cue’s potential to reduce spontaneous recovery through conditioned inhibition or configural cue learning is discussed, as is the possibility that the cue retrieves a saccharin extinction memory in a manner consistent with Bouton’s (1993) account of spontaneous recovery.     

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.     

Impact of brief or extended extinction of a taste aversion on inhibitory associations: Evidence from summation,retardation, and preference tests

In five conditioned taste aversion experiments with rats, summation, retardation, and preference tests were used to assess the effects of extinguishing a conditioned saccharin aversion for three or nine trials. In Experiment 1, a summation test showed that saccharin aversion extinguished over nine trials reduced the aversion to a merely conditioned flavor (vinegar), whereas three saccharin extinction trials did not subsequently influence the vinegar aversion. Experiment 2 clarified that result, with unpaired controls equated on flavor exposure prior to testing; the results with those controls suggested that the flavor extinguished for nine trials produced generalization decrement during testing. In Experiment 3, the saccharin aversion reconditioned slowly after nine extinction trials, but not after three. Those results suggested the development of latent inhibition after more than three extinction trials. Preference tests comparing saccharin consumption with a concurrently available fluid (water in Experiment 4, saline in Experiment 5) showed that the preference for saccharin was greater after nine extinction trials than after three. However, saccharin preference after nine extinction trials was not greater, as compared with that for either latent inhibition controls (Experiments 4 and 5) or a control given equated exposures to saccharin and trained to drink saline at a high rate prior to testing (Experiment 5). Concerns about whether conditioned inhibition has been demonstrated in any flavor aversion procedure are discussed. Our findings help explain both successes and failures in demonstrating postextinction conditioned response recovery effects reported in the conditioned taste aversion literature, and they can be explained using a memory interference account.     

Recovery from blocking achieved by extinguishing the blocking CS

Extinction-induced attenuation of single-phase and two-phase blocking was examined with rats in a conditioned lick-suppression task. In Experiment 1, which compared the effectiveness of single- and two-phase blocking, it was found that single-phase blocking was facilitated by the initiation of training with an A-US trial rather than an AX-US trial. Single-phase (but not two-phase) blocking was attenuated as a result of 200 extinction trials with the blocking stimulus (Experiment 2). Experiment 3 revealed recovery from two-phase blocking after 800 extinction trials with the blocking stimulus. Recovery from both types of blocking was specific to the blocked CS trained in compound with the extinguished stimulus (Experiment 4). This is the first article to report that the blocking deficit can be reversed by extinguishing the blocking stimulus. These results are discussed in light of acquisition models (i.e., retrospective revaluation) and expression models (i.e., the comparator hypothesis).     

Acquisition and retention of conditioned aversions to context and taste in laboratory mice

We compared the rate of acquisition and strength of retention of conditioned context aversion (CCA) with conditioned taste aversion (CTA) using pigmented, genetically heterogeneous mice (derived from Large and Small strains). Extending previous findings, in Experiment 1, mice accustomed to drinking from large glass bottles in the colony room learned to avoid graduated tubes after a single conditioning trial when drinking from these novel tubes was paired with injections of LiCl. The results also showed that CCA could be developed even when there was a 30-minute delay between conditioned stimulus and unconditioned stimulus. Retention of the aversion lasted for 4 weeks in both Immediate and Delay groups. Studies of conditioned saccharin aversion were conducted in Experiment 2. CTA acquisition was very similar to that observed in CCA and duration of aversion retention was similar in the CCA and CTA Delay groups, although at least 2 weeks longer in the Immediate group. Thus, CCA acquisition and retention characteristics are closer to those seen for CTA than has previously been reported. In Experiment 3, we examined whether albino mice (which are known to have weaker visual abilities compared to pigmented mice) would develop CCA comparable to those of pigmented mice. The development of conditioned aversion and its duration of retention was similar in albinos and pigmented mice. Nonspecific aversion emerged as an important contributor to strength of aversion during retention trials in both CCA and CTA paradigms with pigmented (but not albino) mice and deserves additional scrutiny in this field of inquiry.     

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.     

Toxiphobia conditioning with exteroceptive cues

The types of conditioned properties acquired by novel (i.e., nonpreexposed) or familiar (i.e., preexposed) exteroceptive cues that were paired with toxicosis, in the absence of a flavor CS, were evaluated in four experiments. In Experiment 1, the conditioned properties of novel exteroceptive cues served to block the acquisition of an aversion to a flavor CS during flavor conditioning and to suppress the ingestion response during flavor testing; animals failed to suppress their ingestion of either the flavor CS or a neutral flavor when tested in the absence of the exteroceptive CS, but suppressed their ingestion of both the flavor CS and the neutral flavor when tested in the presence of the exteroceptive CS. In Experiment 2, preexposed exteroceptive cues that had been paired with toxicosis failed to provide evidence of such conditioned properties. Experiment 3 demonstrated that preexposed contextual cues that were reinforced in compound with novel exteroceptive cues failed to acquire the conditioned properties acquired by nonpreexposed contextual cues under the same conditions of reinforcement. Finally, in Experiment 4, the conditioned properties of the novel exteroceptive cues served to evoke a conditioned gastrointestinal response that gradually extinguished as a function of repeated nonreinforced exposures to the exteroceptive cues, and, in the absence of such extinction, the conditioned properties served to block the acquisition of a flavor aversion.     

A mixed design reveals that glucose moieties facilitate extinction of a conditioned taste aversion in rats

Separate groups of water-deprived rats had four trials with 15-min access to 0.0073 M saccharin, 0.3 M alanine, 0.3 M glucose, 0.1 M maltose, 0.3 M fructose, 0.06 M sucrose, or 0.03 M Polycose. Trials 1–3 were followed by injections of either 0.15 M LiCl (1.33 ml/100 g b.w., i.p.) or saline; Trial 4 (Test) was CS only. Extinction included either 48-h access to water alone or to the appropriate CS, both followed by a 24-h, two-bottle choice of CS and water. This 3-day cycle was repeated five to six times. All rats acquired comparable conditioned taste aversions (CTAs), but extinction rates varied with the test and the taste CS. No CTA extinguished during the two-bottle choices following 2 water days. During one-bottle CS exposure, all CTAs extinguished, but the aversion continued longer in the probe two-bottle tests. Intake of glucose moieties recovered rapidly, often in two cycles; the other CSs took four to six cycles. Thus, CTA extinction varies with the nature of the taste CS.     

Injected flavor as a CS in the conditioned aversion preparation

Three experiments were conducted to determine the effectiveness of intravenous (IV) flavor injections in the formation of conditioned taste aversions and in the attenuation of neophobia. In Experiment 1, two groups of rats were permitted to drink either a .1% saccharin solution or tap water followed immediately by IV injections of lithium chloride (LiCl), and two more groups were given IV injections of a 2% saccharin solution followed immediately by IV injections of either LiCl or distilled water. Injected flavor did not serve as an effective CS for the conditioning of an aversion to .1% saccharin. The second experiment employed a two-bottle procedure to detect attenuation of neophobia using the injected-flavor technique. It was found that, whether saccharin had been injected intravenously (2%), injected intraperitoneally (2% IP), or orally consumed (.1%), neophobia for .5% saccharin was attenuated equally relative to controls. CS-US intervals were manipulated in the final experiment such that IP injections of 2% saccharin solution were followed 0–480 min later by IP injections of LiCl. In this case, it was shown that injected flavor (2% saccharin) could act as an effective CS if the US was delayed (optimally about 120 min) and when the test solution was .1% saccharin. The delay gradient found in Experiment 3 was interpreted as a generalization gradient where optimum conditioning was displayed at the point where the concentration of saccharin circulating in the animal at the time of illness onset most closely matched the concentration of the test solution.