ANN ARBOR---For recovering alcoholics and ex-smokers, as well as former users of illicit drugs, the mundane trappings of their addictions---ice cubes, ashtrays, straws, needles---exert a strong, long-lasting power to trigger relapse. A new University of Michigan study, published in the current (October 2001) issue of the Journal of Neuroscience, provides experimental evidence supporting a neurological explanation for why cues as innocent as the sound of ice cubes tinkling in a glass can cause "recovered" addicts to experience dangerous drug cravings.

"Drug use is known to 'sensitize' certain neural systems within the brain, causing changes that are relatively permanent," says U-M psychologist Kent C. Berridge, co-author of the study with U-M psychologist Cindy L. Wyvell. "This study shows that the brain is vulnerable to cues that trigger irrational 'wanting,' even after a long period of remaining drug-free, once sensitized by prior drug use or exposure."

The research was supported by the National Science Foundation and by the National Institute on Drug Abuse.

For the study, Wyvell and Berridge designed an experiment with rats that eliminated several alternative explanations, such as withdrawal symptoms, learned habits or drug pleasure, for the increase in compulsive drug-seeking that is commonly triggered in human addicts by encounters with drug cues.

First, in order to avoid withdrawal symptoms, they trained the rats to press a lever to get a reward of sugar pellets, not an addictive drug. They also taught the rats to associate a 30-second tone with getting sugar pellets, without needing to press the lever. Then they sensitized one group of rats by administering a series of amphetamine injections, while injecting controls with a saline solution. Next, the researchers waited 10 to 14 days to make sure both groups were drug-free, then resumed the experiment. While the rats pressed the lever in hope of getting the sugar reward, they were presented intermittently with the sound cue, to assess the cue's ability to trigger excessive pursuit of reward.

"In the sensitized rats, the cue triggered excessive 'wanting,'" says Berridge. "Whenever a sugar cue (a sound) occurred, rats pressed in a frenzy on a lever that had previously earned them a sugar reward." In fact, the researchers found that sensitized rats pressed the lever 200 percent more than rats in the control group, an increase equivalent to the behavior produced in other rats by injecting amphetamine directly into their brains. This showed that sensitization of the brain and direct drug activation of the brain's dopamine reward-craving system amplified equally the ability of reward cues to trigger excessive "wanting."

"Much more remains to be done before we understand how this process works in humans, with drug rewards such as cocaine and heroin, and to a lesser extent, alcohol or nicotine," says Berridge. "But this study is an important step, because it provides the first pure demonstration that neural sensitization causes a specific process---irrational cue-triggered 'wanting' for reward---that is a plausible psychological mechanism for relapse. These results from animals based on a natural sugar reward this may be a useful step toward understanding brain mechanisms of cue-triggered relapse in human drug addiction."

---University of Michigan

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