Acquisition and extinction of context-specific morphine withdrawal

Abstract

The acquisition, retention, and extinction of context-specific morphine withdrawal in rats were investigated in two experiments. In Experiment 1, context-specific withdrawal was observed after a placebo injection following 11 sessions in which the context was paired with either a 10-mg/kg or a 75-mg/kg dose of morphine. Contextual withdrawal was retained during 10 days of drug abstinence in both dose conditions. In Experiment 2, context-specific withdrawal (rearing) was retained after 21 days of morphine abstinence. In addition, conditioned rearing was extinguished by exposure to the drug context with or without a placebo injection. II\iection cues did not contribute to conditioned withdrawal.Chronic administration of morphine and other opiates produces both tolerance and dependence. Tolerance is defined as a decrease in drug effectiveness that occurs after repeated administration, and dependence is identified by the appearance of withdrawal symptoms after the drug is abruptly discontinued. A large body of research has shown that tolerance to many of the effects of morphine (e.g., analgesia, hyperthermia, sedation) is at least partly mediated by environmental or contextual cues paired with the drug (for a review, see Goudie & Demellweek, 1986).Siegel (1975, 1989) proposed a classical conditioning model of drug tolerance in which contextual cues present during drug administration serve as a conditioned stimulus (CS) and the drug acts as the unconditioned stimulus (US). After repeated pairings of these cues and the drug, the cues elicit compensatory, drug-opposite responses. These compensatory conditioned responses (CRs) serve a homeostatic function and reduce the drug's effects, which results in tolerance.Siegel 's model (l975, 1989) also incorporates drug dependence. In the absence of drug administration, the environmental cues still elicit the compensatory CRs, which are withdrawal signs. Tolerance and dependence, according to this model, result from the same underlying process. Although contextual control of tolerance to opiates is well documented (see Goudie & Demellweek, 1986; Siegel, 1989), its mediation by compensatory CRs is con-troversiaL Siegel and others have found cue-elicited compensatory hyperalgesia (

Applying laboratory research: Drug anticipation and the treatment of drug addiction.

“…It has been known for a long time that the effects of a drug are importantly modulated by responses elicited by drug-paired cues. The finding has been reported by clinicians (e.g., Macnish, 1859), epidemiologists (e.g., Frykholm, 1979), and laboratory scientists (e.g., Deffner-Rappold, Azorlosa, & Baker, 1996). It features in narrative reports of addicts (e.g., Biernacki, 1986) and in novels describing opiate effects (see Siegel, 1983).…”

Intra-Administration Associations and Withdrawal Symptoms: Morphine-Elicited Morphine Withdrawal.

“…Although there was no difference between groups in the frequency of rearing, it should be noted that there is some controversy concerning the efficacy of rearing as a measure of morphine withdrawal. There are studies of associative contributions to morphine withdrawal that have used this rearing measure (e.g., Azorlosa, Hartley, & Deffner-Rappold, 1994; Deffner-Rappold, Azorlosa, & Baker, 1996; Kelsey, Aranow, & Matthews, 1990); however McDonald and Siegel (1998) provided evidence suggesting that rearing in morphine-experienced rats is a manifestation of novelty-elicited exploration rather than morphine withdrawal (but see Azorlosa & Simmons, 1999).…”

“…Such findings are relevant for interpreting some apparently conflicting findings in the literature. Although there are many reports that withdrawal symptoms are especially pronounced in the presence of drug-paired environmental cues (e.g., Azorlosa et al., 1994; Deffner-Rappold et al, 1996; Kelsey et al, 1990), there are some reports to the contrary; that is, it has been suggested that morphine withdrawal symptoms are not more pronounced in the drug-paired environment than in an alternative environment (Sobrero & Bouton, 1989; Zellner, Dacanay, & Riley, 1984). Such findings typically have been interpreted as evidence contrary to an associative analysis of withdrawal symptoms: “These results [transenvironmental withdrawal symptoms] lead us to suggest that withdrawal responses are not compensatory conditioned responses elicited by drug-associated cues” (Zellner et al, 1984, p. 179).…”

Learning and homeostasis: Drug addiction and the McCollough effect.

“…There is much experimental (both human and nonhuman animal) and epidemiological evidence that so-called withdrawal symptoms, seen long after the last exposure to a drug, are especially pronounced in the presence of drug related cues (e.g., Deffner-Rappold, Azorlosa, & Baker, 1996; Kelsey, Aranow, & Matthews, 1990; Ternes, 1977); that is, “it is the anticipation of the drug, rather than the drug itself, that is responsible for these symptoms. .…”