Pubdate: Mon, 01 Jan 2001
Source: Scientific American (US)
Copyright: 2001 Scientific American, Inc
Contact:  http://www.sciam.com/
Details: http://www.mapinc.org/media/404
Author: Tabitha M. Powledge
Note: Tabitha M. Powledge is a science writer who specializes in biology.

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.
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