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Article Summary

Drug Tolerance

New studies reveal that a learned compensatory response can trigger "drug tolerance," a physiological process central to addiction. Drug tolerance makes people need more and more drug to get the same effect, whether pain relief or a "high." Its newly discovered psychological aspect -- in which a drug-predictive cue primes the body to react "as if" the drug effect is imminent -- might be used to treat addiction more effectively. In short, if drug tolerance can be learned, there is a chance it can be unlearned, reducing or eliminating the tolerance-related cravings and other withdrawal symptoms that can lead addicts to relapse.

Drug Tolerance in Animals

The findings appear in the July issue of the Journal of Experimental Psychology: Animal Behavior Processes, which is published by the American Psychological Association (APA). This study used rats, but addiction researchers frequently generalize from rats to humans because "rats, like humans, can become dependent on addictive drugs, and display drug tolerance and drug withdrawal symptoms," says co-author Shepard Siegel, Ph.D., of McMaster University in Hamilton, Ontario.

Researchers had already shown that the drug tolerance of rats getting morphine infusions depended on the presence of environmental cues (sights or sounds paired with drugs). These external cues typically have been used because they are easily controlled by the experimenter. The new findings demonstrate there also are internal cues not controlled by the researchers -- the early bodily sensations that the drug itself surreptitiously provides.

In their July article, Siegel, with Marta Sokolowska, a graduate student at McMaster University, and Joseph A. Kim, Ph.D., of the University of California, San Francisco, explain how they built on these earlier findings to add a psychological layer to drug tolerance's already known physiological layer.

In the lab, the researchers first infused rats with morphine over several days, causing them to develop tolerance to the analgesic (pain-relieving) effect of the opiate. Following each infusion, it takes some minutes for the peak effect of a drug to occur. However, rats experience the early effects of the drug ("drug onset cues") prior to the peak effect. The researchers hypothesized that every administration constituted a learning trial that inevitably paired drug onset cues with the peak effect of the drug, thus allowing the rats to associate the early effect of the drug with the later, larger effect.

After a number of morphine infusions, the researchers gave the rats a very small dose of morphine (a "probe dose"). The probe dose was only about 10 percent of the larger dose that previously had been given repeatedly to induce tolerance. This probe dose usually is too small to have any effect, but, in rats that had prior experience with larger infusions of morphine, it replicated the drug onset cue - - a cue that previously had occurred shortly before the drug's peak effect. These rats who had received larger hits of morphine compensated, in the presence of the small dose, by becoming more sensitive to pain (a hyperalgesic response). They flicked their tails more quickly out of a warm-water bath, a common way to test rats' pain sensitivity.

The researchers concluded that the rats responded to the small dose as if the larger dose was on its way, having associated the early, weak drug effects with the later, larger drug effect -- an association formed within an administration. In other words, the rats learned that the probe dose was a drug-onset cue. As a result, the probe dose triggered a response in expectation of the later, larger effect of morphine that had previously followed this small drug effect.

"This is a new and especially important twist on a long tradition of research on the role of learning in drug tolerance," says Mark Bouton, Ph.D., of the University of Vermont, who edits the APA journal. The finding of an important internal cue from the early drug effect adds to what drug researchers know about how external cues (such as the sight of a syringe) modulate drug tolerance. Plus, while external cues may vary, internal pharmacological cues are always present.

Drug Tolerance and Cue Exposure

As a result, psychologists may now understand why certain "cue-exposure" treatments for addiction have not have worked as well as hoped, because they do not wipe out the kinds of early drug-onset cues described in this report. The findings help explain why relapse is more likely when someone is exposed to a small dose. For example, recovering alcoholics can be extremely vulnerable to just one drink because their systems respond to this learned "drug onset cue" with full-blown tolerance-induced cravings, and they go on a binge.

The current research yields a "provocative implication," says Siegel, that cue-exposure treatments could work better if they include small drug doses, to better reproduce the learned stimuli responsible for craving. "Complete therapy," he explains, "would include an uncoupling of drug cues from the drug effect through a behavioral process called extinction." That is, if an addict's response to drug-paired stimuli indeed reflects a learned compensatory response, then clinicians could conceivably weaken this response through repeated, controlled exposure to the drug-paired cues -- without administering the full drug dose. The authors cite success in this kind of treatment for alcohol abuse.

"Such a treatment may reflect a more realistic strategy for addicts who may be exposed to a variety of drug-cues," explains Kim. "Realism is key, because although we can enforce abstinence in the clinic, the real test is when the addict leaves the insulated clinic environment. "

The authors also believe that their findings may help doctors use opiates more safely when managing pain. Patients, given opiates for pain relief, have been known to overdose when, following the development of tolerance, doctors change how they administer the opiate (for example, from taken by mouth to under the skin). By understanding how learned cues influence drug tolerance within the administration of a given drug, doctors can more carefully monitor a patient's adaptation to both drug dose and delivery.

Article: "Intradministration Associations: Conditional Hyperalgesia Elicited by Morphine Cues;" Marta Sokolowska, B.Sc. and Shepard Siegel, Ph.D., McMaster University, and Joseph A. Kim, Ph.D., University of California, San Francisco; Journal of Experimental Psychology -- Animal Behavior Processes, Vol. 28, No. 3.

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