Falling off the wagon

Why do so many former addicts relapse after long periods of abstinence?
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Image credit: Steve Buissinne (CC0)

More than 85% of people who give up an addictive drug begin using it again within a year. Relapse rates have changed little over the past five decades. Situations, places and objects associated with drug-taking can trigger relapse long after a person’s last exposure to a drug.

We can study relapse by training animals to self-administer drugs such as cocaine. For example, rats can learn to press a lever to receive an infusion of a drug paired with a cue (a conditioned stimulus), such as a tone or a light. After training, the rats continue to press the lever to seek the drug, even if this behavior no longer delivers it. In addition, their lever pressing in response to cues increases with time for several months after their last drug exposure. This phenomenon, known as incubation of drug craving, mirrors the increase in cravings reported by abstinent drug users.

In drug users, cues such as the crack pipe or syringe used to take the drug can later contribute to drug relapse during abstinence. Most studies modeling this phenomenon have focused on how the rats respond to a conditioned stimulus that signaled the delivery of a drug during training. However, a second type of signal, known as the discriminative stimulus, can also influence relapse. Discriminative stimuli are sets of cues that signal whether drugs are about to become available or not; for example, the presence of people selling drugs on a street corner as opposed to the presence of police.

Madangopal et al. now show that discriminative stimuli – in the absence of conditioned stimuli – can also control the incubation of drug craving. Rats learned to press a lever in response to a light signaling the availability of cocaine (the positive discriminative stimulus), and to avoid responding to a different light indicating that cocaine was unavailable (the negative discriminative stimulus). When tested during abstinence, the rats only increased their lever pressing to the first light over time, i.e., they showed an incubation of drug craving controlled by the positive discriminative stimulus. Lever pressing peaked after 60 days of abstinence and persisted for up to 300 days (almost half the rats' lifespan). By contrast, the same discriminative stimuli did not trigger increased lever pressing when used to signal the availability of a palatable food.

Discriminative stimuli are thus powerful and persistent triggers of craving for addictive drugs. They signal the availability of a drug prior to both drug-taking and relapse, making them a critical target for intervention strategies. Understanding the mechanisms by which discriminative stimuli promote drug craving could lead to new treatments to prevent relapse.