Posted on Aug. 30: Research may aid in more effective drug addiction treatments

New research by McMaster University researchers suggests 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's a chance it can be unlearned, reducing or eliminating the tolerance-related cravings and other withdrawal symptoms can lead addicts to relapse.

Research by McMaster psychology professor Shepard Siegel, graduate student Marta Sokolowska, and McMaster alumnus Joseph Kim (now a postdoctoral fellow at the University of California, San Francisco) demonstrated that there is a powerful “internal cue” process that stimulates the body to react to the effect of a drug. The research results were recently published in the Journal of Experimental Psychology: Animal Behavior Processes.

“The effect of a drug depends not only on our response to the drug, but also our response to stimuli that in the past have been
paired with the drug. We've known this for a long time in terms of external stimuli, such as where and when a drug is taken, but now it's also clear that internal stimuli also play an important role,” says Siegel. Current drug addiction treatment programs often include a component that tries to remove the effects of the external cues (so-called “cue exposure treatments”), but they ignore the importance of internal cues.

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

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 the early effects of the drug (termed “drug onset cues”) are experienced prior to
the peak effect. The researchers hypothesized that every administration constituted a learning trial. The drug onset cues were
inevitably paired with the peak effect of the drug, thus the rats associated the early effect of the drug with the later, larger effect.

After tolerance had occurred, the researchers gave the rats a small dose of morphine. This small dose usually has no 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 peak effect of the drug occurred.

These rats who had received larger hits of morphine compensated, in the presence of the small dose, by becoming more sensitive to
pain. They flicked their tails more quickly out of a warm-water bath, a common way to test rats' pain sensitivity. The rats' bodies were demonstrating compensatory behaviour in response to an
early-warning dose of the drug.

The results suggest why some “cue-exposure” treatments for addiction have not have worked as well as hoped; they do not wipe out the kinds of early drug-onset cues demonstrated in these experiments. 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.

In the example provided by Siegel: “You're a cigarette smoker and you're trying to quit. When do you crave cigarettes? It's the time of day when you usually smoke, or it's when you see other people smoking. These are external stimuli and there are treatment processes that are cue exposure treatments designed to present you with these stimuli, but not allow you to smoke. These treatments might be more effective if they included the most effective stimuli, which might be the early effects of nicotine. You would take one puff, but not be allowed to take more puffs.”