BEATING ABUSE

Glutamate May Hold A Key To Drug Addiction

Addiction has long been thought to be a form of learning.

In the past few years, molecular biologists have amassed chemical evidence
to prove it, in the process generating new ideas for combating drug use.

Some of the most striking recent studies have examined the affinity between
cocaine and glutamate, one of several chemical neurotransmitters that
govern communication between nerve cells and are involved particularly with
memory.

For example, Stanislav R. Vorel and his colleagues at the Albert Einstein
College of Medicine discovered that electrically stimulating the
hippocampus, a brain structure central to memory and rich in glutamate,
causes dependence relapse in rats formerly addicted to cocaine.

Other researchers found that glutamate activates brain cells devoted to
dopamine, a neurotransmitter associated with feelings of reward and
pleasure. Indeed, the dopamine reward circuit in the brain has been
regarded as the addiction pathway, commandeered not just by cocaine but by
all addictive drugs.

The fact that glutamate modifies dopamine action demonstrates a direct
connection between brain reward circuits and those for learning and memory.

The reward and memory systems may harbor the secrets to addiction, but they
also serve as a barrier to developing treatments. Altering either of these
fundamental brain circuits without subverting some essential function is
tricky business. "That's why there was excitement about the possibility
that the glutamate system might be involved.

But at this point, we're not there," says Francis J. White, a
pharmacologist at Finch University of Health Sciences/The Chicago Medical
School.

A discovery published in September 2001 may nudge that process along.
Researchers studying mice identified a particular glutamate receptor, known
as mGluR5, that is crucial for cocaine dependence. Mice that lack the
receptor do not become dependent no matter how much cocaine they are given.

The mGluR5 findings are significant in part because the receptor's action
appears to be selective.

The mutant mouse takes food and water just like other mice, which suggests
that lack of the receptor does not affect "natural" rewards, only interest
in cocaine.

Eliot Gardner, a senior research investigator at the National Institute on
Drug Abuse, identifies two major hurdles to basing addiction treatments on
glutamate.

The first is figuring out which glutamate receptors are involved. (Even if
mGluR5 is related to human cocaine dependence, it is not the only receptor
significant in addiction.) The second problem is glutamate's ubiquity.
"It's found all over the brain in lots of circuits subserving lots of
behavior and mental processes that one would not want to manipulate,"
Gardner says. Researchers will need to find precise delivery systems that
will target only specific brain circuits, leaving alone the dozens, or
perhaps hundreds, of other circuits that use glutamate as a neurotransmitter.

Intriguingly, the glutamate studies could strengthen that old
nonpharmaceutical standby: behavioral therapy.

One of the most promising treatments "is to have people unlearn aspects of
addiction and relearn new things to do in life," says renowned molecular
biologist and addiction specialist Eric J. Nestler of the University of
Texas Southwestern Medical Center. "An argument can be made that Alcoholics
Anonymous provides that type of alternative focus." Or pharmacotherapies
could be combined with "talking cures" to yield fewer relapses. "If we
could develop medications that could address the underlying biology, the
powerful biological forces that drive addiction, then we can make a person
more amenable to other treatments," such as behavior therapy, Nestler says.
"You really need both."

(SIDEBAR)

DRUGS FOR DRUG ABUSE

The hunt for addiction treatments grows more intense every year. The
National Institute on Drug Abuse is conducting clinical tests on more than
60 compounds for cocaine and opiate dependence alone and also a few for
methamphetamine, according to Francis Vocci, who directs NIDA's Division of
Treatment Research and Development. In addition to some compounds that act
on glutamate and dopamine, researchers are looking at other targets.

Chemicals that block the action of stress hormones are effective against
opiates, cocaine, amphetamines and alcohol, Vocci reports, which means that
a magic bullet that works against mechanisms underlying all addictive drugs
is not utterly out of the question.