|Scientists Identify a Brain Mechanism Underlying
Persistent Cocaine Craving|
Finding May Lead to New Treatments to Decrease Risk of Relapse
Scientists have identified a mechanism in the brain that helps
to explain why craving for cocaine, and the risk of relapse, seems
to increase in the weeks and months after drug use is stopped.
The research was supported by the National Institute on Drug Abuse
(NIDA), part of the National Institutes of Health.
The study1 published in the May 25
issue of the journal Nature, "reveals a novel mechanism
for why cocaine craving intensifies after cessation of drug use
and suggests a new target for the development of medications to
decrease the risk of relapse in abstinent cocaine abusers," says
NIDA Director Dr. Nora Volkow.
Exposure to environmental cues (e.g., people, places, things)
previously associated with drug use can trigger drug craving, often
leading to relapse. Previous NIDA-funded research using a rat model
of drug craving and relapse (published in Nature in 20012)
has shown that the responsiveness of rats to cocaine cues progressively
increases, rather than decreases, over the first 60 days after
cessation of intravenous cocaine self-administration.
In the current study, also in rats, researchers demonstrate that
after prolonged periods of forced abstinence from cocaine self-administration,
there is an increase in the number of proteins called AMPA glutamate
receptors in a brain region known as the nucleus accumbens (a brain
area involved in motivation and reward). "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," explains lead investigator Marina E. Wolf,
Ph.D., Professor and Chair of Neuroscience at the Rosalind Franklin
University of Medicine and Science in North Chicago. "This
happens not only because there are more AMPA receptors, but also
because the new AMPA receptors are atypical — they are missing
a particular subunit, and therefore enable stronger stimulation
of the nucleus accumbens than typical AMPA receptors," adds
When the investigators blocked these atypical receptors (termed
GluR2-lacking AMPA receptors) after prolonged abstinence from cocaine,
they were able to substantially decrease intensified cue-induced
craving in the rat model. "The finding suggests," says
Wolf, "that medications could be developed to block the atypical
GluR2-lacking AMPA receptors in the nucleus accumbens, thus reducing
drug craving and the risk for relapse, without interfering with
neurotransmission at typical AMPA receptors, which are important
for normal brain functions such as learning and memory."
The research was performed in the laboratories of Wolf, Michela
Marinelli, Ph.D., and Kuei Y. Tseng, M.D., Ph.D., at Rosalind Franklin
University of Medicine and Science and Yavin Shaham, Ph.D., of
the NIDA Intramural Research Program in Baltimore, Maryland.
The National Institute on Drug Abuse is a component of the National
Institutes of Health, U.S. Department of Health and Human Services.
NIDA supports most of the world’s research on the health aspects
of drug abuse and addiction. The Institute carries out a large
variety of programs to inform policy and improve practice. Fact
sheets on the health effects of drugs of abuse and information
on NIDA research and other activities can be found on the NIDA
home page at www.drugabuse.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
1Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng
LJ, Shaham Y, Marinelli M, Wolf ME. Formation of accumbens GluR2-lacking
AMPA receptors mediates incubation of cocaine craving. Nature,
May 25, 2008
2Grimm JW, Hope BT, Wise RA, Shaham Y. Incubation
of cocaine craving after withdrawal. Nature 2001;412(6843):141-2.
On May 29, 2008 this release was updated to reflect corrections made
by the institute.