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Conditioned Sucrose Aversions Produced by Naloxone-Precipitated Withdrawal From Acutely Administered Morphine

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Abstract

The aversive properties of acute naloxone-precipitated morphine withdrawal were examined in the taste reactivity paradigm. Acute naloxone-precipitated withdrawal paired with sucrose solution established conditioned active rejection of the sucrose solution. Active rejection of sucrose was observed when naloxone was administered both 1 h and 22 h after morphine. When the stimulus properties of morphine were present during the conditioning trial, the conditioned sucrose aversion was only expressed when the rats were tested in the same drug state in which they had learned the aversion. However, when the stimulus properties of morphine were not present during conditioning, the aversion was expressed in the absence of the morphine state. The results suggest that palatability shifts can be conditioned to sucrose paired with acute morphine withdrawal.

Section snippets

Experiment 1

The first experiment was designed to evaluate the effect of naloxone precipitated withdrawal on sucrose palatability, as measured by the TR test. The design of this experiment was similar to that of previous experiments that employed taste-avoidance assessments of withdrawal [e.g. 15, 16, 20, 21, 22]. During TR conditioning trials, one group of rats was treated with morphine before sucrose exposure and administered naloxone after sucrose exposure. Thus, rats in this group had sucrose paired

Experiment 1a

Rats were injected with either 20 mg/kg of morphine or with physiological saline one hour prior to receiving an intraoral infusion of sucrose solution. Immediately following the sucrose infusion, they were injected either with 1 mg/kg of naloxone or with saline. Group designations indicate both the drug administered before the sucrose infusion (the “pre-sucrose drug”), morphine (M) or saline (S), and the drug administered following the sucrose infusion (the “post-sucrose drug”), naloxone (N) or

Subjects

Forty-two male Sprague–Dawley rats (Charles River Labs, St. Constant, Quebec) weighing 385–475 g on the first conditioning trial served as subjects. They were housed individually in wire mesh cages and maintained on ad lib food and water except as indicated.

Drugs

Naloxone HCl (Dupont) was mixed with saline at a volume of 1 mg/ml and administered intraperitoneally (IP). Morphine sulphate (British Drug House) was mixed with saline at a volume of 10 mg/ml and administered subcutaneously (SC).

TR Conditioning Trials 1–3

Fig. 1 presents the mean frequency of rejection reactions displayed by the various groups on conditioning trials 1–3 of Experiment 1A. Rats that had sucrose paired with naloxone-precipitated morphine withdrawal (group M-N) developed active rejection of a flavor with which it was associated. A 2 × 2 × 3 analysis of variance (ANOVA) of the rejection reaction scores, with the between groups factors of presucrose drug (morphine, saline) and postsucrose drug (naloxone, saline) and the within-groups

Experiment 1b

In phase 1 of Experiment 1B, rats assigned to groups M-N and M-S in Experiment 1A were now tested in the same morphine state in which they had been conditioned. On the basis of a state-dependent learning interpretation of the results of Experiment 1A, we would expect evidence of conditioned aversion to the sucrose solution that had been paired with naloxone-precipitated withdrawal. Phase 2 of Experiment 1B was designed to permit an additional evaluation of the contribution of state dependency

Phase 1—Conditioned Rejection Reactions Following Presucrose Morphine Administration

Three days after the drug-free TR and consumption test trials in Experiment 1A, rats in groups M-N and M-S were given an additional 2 min TR test trial followed immediately by a two-bottle consumption trial, with both tests taking place while the rats were in a morphine state. All rats were injected SC with 20 mg/kg morphine 60 min prior to receiving an intraoral infusion of sucrose solution for a 2-min period, and their TR reactions were videotaped. Because they were narcotized and were not

Phase 1

In this phase, all rats were administered morphine prior to the TR and consumption tests. That is, they were tested in the same drug state in which they were conditioned. In contrast to the tests in Experiment 1A (when rats were tested in a drug-free state), there was now evidence that M-N group rats displayed aversive reactions to sucrose. The mean number of aversive reactions displayed by rats in group M-N was significantly greater than that displayed by rats in group M-S (mean number of

Discussion

Acute naloxone-precipitated morphine withdrawal produced a conditioned sucrose aversion in Experiment 1, but that aversion was expressed only when the same morphine stimulus state present during conditioning was also present during testing. During the course of these conditioning trials (trials 1–3 in Experiment 1A and trials 4–6 in Experiment 1B), rats in group M-N developed conditioned rejection of sucrose solution; during each of these trials, rats in group M-N were administered morphine 60

Experiment 2

In Experiments 1A and 1B, morphine was administered 60 min prior to each of the TR conditioning trials. The results of these experiments suggested that naloxone-precipitated withdrawal from this opiate did elicit conditioned rejection reactions, but the display of these learned responses was morphine state dependent. That is, they were seen in morphine-pretreated rats, but not in saline-pretreated rats. Experiment 2 was designed to evaluate the ability of naloxone-precipitated withdrawal from

Method

The subjects were 27 male Sprague–Dawley rats weighing between 274–364 g on the first conditioning trial. They were treated in a manner similar to those of Experiment 1 except as indicated.

On each of three TR conditioning trials (separated by 72 h), rats were injected SC with 20 mg/kg of morphine. The next day (22 h later), they received an intraoral infusion of 17% sucrose solution in the TR chamber. Immediately following the sucrose infusion, rats were injected SC with either 1 mg/kg of

Results and discussion

Naloxone-precipitated withdrawal produced a taste aversion even when naloxone was administered 22 h after 20 mg/kg of morphine. Fig. 3 presents the mean frequency of rejection reactions displayed by each group during conditioning trials 1–3 in Experiment 2. A 2 × 2 × 3 mixed factors ANOVA of the rejection reaction scores, with the between-groups factors of presucrose drug (morphine or saline) and postsucrose drug (naloxone or saline) and the within-groups factor of conditioning trial, revealed

General discussion

Withdrawal from acutely administered morphine produced conditioned rejection of sucrose solution. The results of these experiments indicate that acute naloxone-precipitated withdrawal produces an aversive effect that is capable of becoming associated with a flavor. The results also have implications for state-dependent learning of withdrawal-elicited aversions.

Although conditioned changes in the palatability of sucrose were established across conditioning trials in Experiment 1A when morphine

Acknowledgements

This research was supported by research grants from the Natural Sciences and Engineering Research Council of Canada to Linda Parker (NSERC-OGP 92057) and Shepard Siegel (NSERC-OGP 298), Robert McDonald (currently continuing graduate studies at McMaster University) held an NSERC undergraduate student award while conducting these experiments. Appreciation is expressed to Marion Corrick for assistance in scoring data tapes.

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