Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




Professor Shepard Siegel


Results of many studies have demonstrated an important contribution of Pavlovian conditioning to the phenomena of drug tolerance and withdrawal. Based on the conditioning analysis, cues paired with the drug administration conditionally elicit compensatory responses in anticipation ofthe subsequent drug-induced physiological disturbance. These conditional compensatory responses mediate tolerance development by counteracting the drug effect when the drug is administered in the presence of the drug predictive cues. Additionally, presentation of drug-predictive cues in the absence of the drug elicits the conditional responses, now unopposed by the drug effect. Such conditional responding, elicited by the usual pre-drug cues in the absence of the usual drug effect, constitutes withdrawal symptoms. Most research evaluating the role of conditioning in drug effects have examined exteroceptive, environmental cues. Recently, however, there has been interest in the interoceptive, pharmacological cues. That is, within each drug administration, early drug onset cues (DOCs) may become associated with the later, larger drug effect (and mediate tolerance and withdrawal behaviors, much like exteroceptive cues). The present experiments examined the role of DOCs in morphine tolerance and withdrawal in rats. The first series of experiments (Chapter 2) concerned the role of DOCs in tolerance to the analgesic effect of morphine. Research described in Chapter 3 evaluated whether DOC pre-exposure attenuates acquisition of conditional compensatory responses, as would be expected on the basis of a conditioning analysis of tolerance. Research described in chapter 4 evaluated the role of exteroceptive cues and DOCs in the elicitation of withdrawal symptoms, using an acoustic startle measure of withdrawaL Research described in Chapter 5 evaluated DOC-elicited behavioral withdrawal symptoms, using procedures to assess whether such withdrawal behaviors represent an associative or sensitized response. The results of these studies have implications for a range of issues in drug tolerance, withdrawal, and the treatment of addition.

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