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Drug Addiction, Learning Share Common Brain Protein

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Duke Health News 919-660-1306

DURHAM, N.C. -- Howard Hughes Medical Institute
investigators at Duke University Medical Center have linked a
gene previously shown to play a role in learning and memory to
the early manifestations of drug addiction in the brain.
Although scientists had previously speculated that similar
brain processes underlie aspects of learning and addiction, the
current study in mice is the first to identify a direct
molecular link between the two.

The findings suggest new genetic approaches for assessing an
individual's susceptibility to drug addiction. They also
illuminate the complex series of molecular events that underlie
addiction, the researchers said, and ultimately may lead to new
therapeutic methods to interfere with that process, thereby
curbing the cravings common to addiction.

The Duke-based study, which examined genes involved in the
brain's response to cocaine, appears in the Feb. 19, 2004,
issue of Neuron. The work was supported by
the National Institutes of Health, the Zaffaroni Foundation and
the Wellcome Trust.

"There has been the idea that brain changes in response to
psychostimulants may be similar to those critical for learning
and memory," said Marc G. Caron, Ph.D., an HHMI investigator at
Duke. "Now, for the first time, we have found a molecule that
links drug-induced plasticity in one part of the brain to a
mechanism that underlies learning and memory in another brain
region." Caron is also interim director of the Center for
Models of Human Disease, part of Duke's Institute for Genome
Sciences and Policy, and James B. Duke professor of cell
biology.

Previous work by other researchers revealed that exposure to
cocaine triggers changes in a brain region called the striatum
-- a reward center that also plays a fundamental role in
movement and emotional responses. Cocaine leads to a sharp
increase in communication among nerve cells in the striatum
that use dopamine as their chemical messenger. This brain
chemical surge is responsible for the feeling of pleasure, or
high, that leads drug users to crave more.

"Drugs essentially hijack the brain's natural reward
system," thereby leading to addiction, explained Wei-Dong Yao,
Ph.D., an HHMI fellow at Duke and first author of the new
study.

The study sought to identify genes involved in the brain's
heightened response after drug use. The researchers compared
the activity of more than 36,000 genes in the striatum of mice
that had "super-sensitivity" to cocaine due to a genetic defect
or prior cocaine exposure, with the gene activity in the same
brain region of normal mice. The genetic screen revealed six
genes with consistently increased or decreased activity in
super-sensitive versus normal mice, the team reported.

The protein encoded by one of the genes -- known as
postsynaptic density-95 or PSD-95 -- dropped by half in the
brains of super-sensitive mice, the researchers found. The
protein had never before been linked to addiction, Caron said,
but had been shown by Seth Grant, a member of the research team
at the Wellcome Trust Sanger Institute, to play a role in
learning. Mice lacking PSD-95 take longer than normal mice to
learn their way around a maze. In other words, mice with normal
amounts of PSD-95 appear less likely to become addicted and
more likely to learn.

Two of the other five genes had earlier been suggested to
play a role in addiction. The function of the remaining three
genes is not known, Caron said, and will be the focus of
further investigation.

Among the mice more responsive to the effects of cocaine,
the decline in PSD-95 occurred only in the striatum, while
levels of the protein in other brain regions remained
unaffected. In normal mice, the protein shift occurred after
three injections of cocaine and lasted for more than two
months.

The researchers also measured the activity of nerve cells in
brain slices from the different groups of mice. Neurons in the
brains of super-sensitive mice exhibited a greater response to
electrical stimulation than did the nerve cells of control
mice. Neurons from mice lacking a functional copy of PSD-95
showed a similar increase in activity, the team reported.

Mice deficient in PSD-95 also became more hyperactive than
normal mice following cocaine injection, further linking the
protein to the drug's brain effects. However, the deficient
mice failed to gain further sensitivity upon repeated cocaine
exposure, as mice typically do.

"Drug abuse is a complex disorder and will therefore be
influenced by multiple genes," Caron noted. "PSD-95 represents
one cog in the wheel."

The brain protein likely plays a role in addiction to other
drugs -- including nicotine, alcohol, morphine and heroine --
because they all exert effects through dopamine, Caron added.
Natural variation in brain levels of PSD-95 might lead to
differences in individual susceptibility to drugs of abuse, he
suggested. The gene might therefore represent a useful marker
for measuring such differences.

The researchers will next examine the effects of PSD-95 on
the addictive behavior of mice, Caron said. For example, they
will test whether PSD-95-deficient mice self-administer greater
amounts of cocaine than do normal mice.

Other study investigators at Duke include Raul Gainetdinov,
M.D., Tatyana Sotnikova, Ph.D., Michel Cyr, Ph.D., Jean-Martin
Beaulieu, Ph.D. and Gonzalo Torres, Ph.D. Margaret Arbuckle,
Ph.D., of the University of Edinburgh also contributed to the
research.

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