Brain Changes Accompany Cocaine Withdrawal and Craving

Researchers have found that brain levels of a protein receptor rise, along with certain drug-seeking behaviors, after rats lose their access to cocaine. The finding may help explain why cocaine craving intensifies in the weeks and months after drug use ends. The research may also aid development of new drugs for preventing relapse.

Relapse is a significant problem for anyone struggling to curb an addiction to cocaine or other drugs. Scientists know that exposure to environmental cues—like the people, places or things associated with drug use—can trigger intense drug craving and lead to relapse. Previous research funded by NIH’s National Institute on Drug Abuse (NIDA) showed that rats have increasingly heightened responses to cocaine-related cues during the first 2 months after losing access to self-administered cocaine. In the new study, researchers identified one of the brain changes that may underlie these heightened responses.

The research team, from the Rosalind Franklin University of Medicine and Science in Chicago and NIDA’s own scientists in Baltimore, gave rats ready access to cocaine infusions when the rats pressed a lever or poked their nose into a hole. Each infusion was accompanied by a 5-second light cue. After 10 days, access to cocaine was removed but the light cues continued. As in previous studies, the researchers found that the light cues led to increased cocaine-seeking behavior over time; rats did significantly more cue-induced nose pokes 45 days after cocaine withdrawal than on their first drug-free day.

To find the brain changes that accompany withdrawal, the researchers analyzed proteins called AMPA glutamate receptors in the rats’ brains. Earlier studies suggested that these receptors play a role in cocaine craving.

In the May 25, 2008, advance online edition of Nature, the researchers reported seeing higher levels of AMPA receptors in the brain’s “pleasure center,” the nucleus accumbens, in the weeks after access to cocaine ceased. By day 45, the number of AMPA receptors had risen significantly.

“The additional AMPA receptors increase the reactivity of the nucleus accumbens to cocaine-related environmental cues, explaining the intensified cue-induced cocaine seeking that occurs after prolonged abstinence from the drug,” said lead investigator Dr. Marina E. Wolf of Rosalind Franklin University.

The researchers found that the new receptors were unusual in that they lack a component (or subunit) of the receptor called GluR2. When the rats were given a drug that selectively blocks these GluR2-lacking receptors, their cue-induced drug-seeking behaviors had dropped substantially by the 45th day after withdrawal.

These findings suggest that treatments could be developed to reduce drug craving and the risk for relapse. Medications might be designed to block GluR2-lacking AMPA receptors in the nucleus accumbens without affecting typical AMPA receptors, which are critical for normal brain functions such as learning and memory. Further research will be needed to better understand the role that these receptors may play in human cocaine addiction, craving and relapse.