Researchers Link Effects of Withdrawal to Compulsive Drug Use And Craving

By Eric Niiler

A team of scientists at The Scripps Research Institute; the National Institutes of Health Animal Center; and the University of Tokushima Graduate School (Japan) has provided some of the first evidence that compulsive drug use stems not from obtaining a drug's pleasurable effects, but from an aversion to drug withdrawal. The finding could be used to help develop human therapies to block aspects of drug craving.

The study, led by Paul Kenny, an assistant professor at Scripps Research's campus in Jupiter, Florida, and Scott Chen, of the National Institutes of Health Animal Center, appears in the Wednesday, May 31 issue of the Journal of Neuroscience, the official journal of the Society for Neuroscience.

The research fills many gaps in our understanding of how the brain changes during drug addiction. While scientists had previously shown that drugs such as heroin stimulate the brain's pleasure centers and thereby motivate drug consumption, the role of withdrawal-associated inhibitory effects on brain pleasure centers in motivating drug intake had been more difficult to quantify.

"This is a missing piece of the puzzle that scientists have been interested in for many years," Kenny said. "Withdrawal was important anecdotally, but there had been no solid empirical data demonstrating an instrumental role of withdrawal in addiction-like behaviors."

Kenny and colleagues now provide strong evidence that withdrawal contributes to the development of compulsive drug consumption in addicts. During the study, rodents were permitted to self-administer various levels of heroin. Those receiving the highest levels showed withdrawal-like decreases in the activity of the brain's reward systems. Crucially, as this withdrawal effect got worse, their drug intake became greater.

"As levels of drug consumption increase, the withdrawal state becomes more profound," Kenny said. "Taking more of the drug alleviates withdrawal, but also makes the underlying condition worse. You set up a vicious cycle where you're taking more of the drug to relieve a progressively worsening withdrawal."

Importantly, the researchers also identified a previously unknown source of drug craving, provoked by stimuli linked to withdrawal through Pavlovian conditioning. In the study, cues in the environment—a buzzer and light—repeatedly paired with drug withdrawal by themselves came to precipitate a withdrawal-like state and to prompt drug seeking.

"Through classical conditioning, these cues alone could precipitate drug-seeking behaviors," said Kenny. "Thus, in addition to memories of the pleasurable effects of drugs, memories of aversive drug withdrawal may also drive drug craving and relapse."

This line of research has the potential to aid in the development of new therapies for addiction. "If we understand the underlying biology, we may be able to block it to eliminate craving and prevent relapse among drug addicts," Kenny said.

Other authors of the study, titled "Conditioned withdrawal drives heroin consumption and decreases brain reward sensitivity," include: Scott A. Chen, Laboratory of Clinical and Translational Studies, NIH Animal Center, Poolesville, MD; Osamu Kitamura, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan; and Athina Markou and George Koob, Molecular and Integrative Neurosciences Department, Scripps Research, La Jolla, CA.

The work was supported by the National Alliance for Research on Schizophrenia and Depression, National Institute of Drug Addiction (NIDA), and a NIDA National Research Service Award.

Send comments to: mikaono[at]scripps.edu

Paul Kenny, an assistant professor at Scripps Florida, led the new study.