Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




University Professor Shepard Siegel


The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRS) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. Although there are many studies evaluating the molecular mechanisms underlying opiate drug tolerance, there are few experiments examining the role of Pavlovian conditioning in modulating the intracellular mechanisms that are hypothesized to mediate opiate tolerance. The results reported in Chapter 2 suggest that external predrug cues signalling morphine, and not simply chronic administration of morphine, are crucial in inducing morphine tolerance, striatal c-Fos, and AP-1 DNA binding. Besides external cues, internal cues also are important in mediating opiate tolerance and striatal c-Fos. The yoked-control experiments of Chapter 3 demonstrate that interoceptive cues inherent in self-administration are important for striatal c-Fos expression. Self-administering heroin (SA-H) animals exhibit less ataxia and more striatal c-Fos expression than their yoked partners (Y-H). The role of c-Fos is to activate other genes. The CCK2 receptor gene may be modulated by c-Fos and has been implicated in associative opiate tolerance. The in situ hybridization experiments reported in Chapter 4 were designed to investigate, in several brain areas, the RNA encoding the CCK2 receptor in SA-H, Y-H, and yoked-saline (Y-S) rats. Although no differences were found between the groups in the brain areas examined, the cDNA array experiments in Chapter 5 showed that the CCK2 receptor is up-regulated in the nucleus accumbens (NAcc ) of the SA-H rat compared to the Y-H rat. Furthermore, several other genes were also differentially expressed between SA-H and Y-H groups. The results of these experiments have helped narrow down those genes that may be involved in the associative opiate tolerance. Further investigation with more sophisticated gene screening techniques (e.g., gene chips) may elucidate the molecular mechanisms underlying the learned aspects of opiate tolerance.

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