GENETIC STUDIES PROMISE A PATH TO BETTER TREATMENT OF ADDICTIONS

In a quiet, dark room at the University of Pennsylvania, Edward
Coleman, 30, lies back and watches a videotape of addicts like him
smoking crack while a PET scanner records each neurochemical nuance
of his brain.

Normally, the images would spark an irresistible craving for the
drug. His heart would start to race; his ears would begin to buzz;
and a spot deep inside his brain would flash brightly on the scan.
But today it is different. Before starting the videotape, Dr. Anna
Rose Childress gave Mr. Coleman a medication that may someday help
him, and others, combat the craving that lures so many back to their
addictions.

After the video Mr. Coleman admits the images evoked an urge to use
cocaine, but not such a strong one. And the PET scan backs him up:
his amygdala - the small almond-shaped brain structure that helps
humans and animals remember all the details associated with
pleasurable events - flickers only weakly.

"Edward can still remember what the cocaine high is like, but while
taking baclofen in the right dose range, he doesn't feel pulled to go
out and find it," said Dr. Childress, a research associate professor
in the department of psychiatry at the Treatment Research Center of
the University of Pennsylvania. "For a patient wishing to stop
cocaine, this could provide a desperately needed tool."

As the war on drugs has marched into the scientist's lab, researchers
have devised a paradigm that may help explain why some people get
hooked after a single "taste" of an illegal drug while others can use
it for years and quit when they choose. Once thought of as
weak-willed people who lacked the moral strength to just say no to
drugs, addicts are now viewed as victims of genes that make them
susceptible to the powerful pull of mind-altering substances.

Scientists in research centers around the country are studying how
drugs affect the brain. They tweak various neurotransmitters,
searching for ways to alter both an addict's genetic wiring and the
rewiring of the brain that drugs initiate. Some researchers seek ways
to rev up the "stop" circuitry of the forebrain - the part that
considers consequences =F3 while others look for ways to tune down the
"go" circuitry of the limbic system - a part of the brain involved in
processing emotion.

While researchers emphasize that environmental factors are also
crucial, many population studies have pointed to the importance of
genetics. For example, studies of twins have found that identical
twins are more likely than fraternal twins to share a tendency to
become addicted. But the predilection may be even more specific. Dr.
Ming Tsuang, a a professor of psychiatry at Harvard Medical School,
has found that people inherit not only a general susceptibility to
substance abuse but also a vulnerability to particular drugs.

"Our group is interested in finding the actual gene that is specific
for heroin addiction," Dr. Tsuang says. "If we can find the gene and
learn what the gene's products are, we may be able to prevent people
from abusing heroin."

When it comes to a general genetic susceptibility, the leading
suspect is a defect in the dopamine system, experts say. In the past
decade or so, researchers have discovered that although drugs affect
a variety of neurotransmitters, virtually all of them increase the
levels of dopamine in the brain's mesolimbic region, which is
involved in pleasure, reward and motivation.

Research has also shown that compared with those who do not use
drugs, addicts tend to be deficient in a certain type of dopamine
receptor, dubbed DR2. That receptor leads to feelings of pleasure
when stimulated by dopamine. Some scientists have assumed that this
deficiency was simply the result of the brain's reaction to a
drug-induced overload of dopamine by cutting back on the number of
receptors available to pick up the neurotransmitter.

And an experiment that followed with monkeys that were allowed to
self-administer cocaine for a year showed that this was at least
partly true. The five addicted monkeys ended up with a 15 percent to
20 percent decrease in dopamine receptors, says Dr. Michael Nader, an
associate professor of physiology and pharmacology at the Wake Forest
University's medical school in Winston-Salem, N.C. Nine months after
the monkeys were deprived of cocaine, three had returned to normal,
but two had not.

Still, several recent studies have suggested that some people may be
born with a defect in the gene that doles out dopamine receptors.
Those born with the defect end up with fewer DR2s and as a
consequence experience life with less intensity and joy, said Dr.
Ernest P. Noble, a professor of psychiatry and biobehavioral sciences
and the director of the Alcohol Research Center at the University of
California at Los Angeles.

"These people often say they don't feel the normal rewards and
pleasures in life," Dr. Noble said. "For example, a man will describe
the experience of going to the beach with a girlfriend to view a
beautiful sunset and say, `I hardly felt anything.' Or he will
describe how he went to a concert where his buddies all feel
exhilarated, but not him."

These patients often report that the first time they really felt
normal was after their first drink or dose of an illegal drug, Dr.
Noble said.

After determining that severe alcoholism was associated with a
mutation of the gene that doles out DR2s, Dr. Noble and his
colleagues tried treating alcoholics with bromocriptine, a medicine
that boosts the amount of dopamine available to the brain. The
medication quieted craving and ultimately helped alcoholics fight
their addiction, Dr. Noble said.

In another experiment designed to discover whether the "taste" for
drugs might be related to inherited brain chemistry, researchers at
Brookhaven National Laboratory tested a group of people who had no
experience with illegal drugs. After using a PET scanner to determine
how many dopamine receptors each person had, the researchers injected
each with a small amount of the stimulant Ritalin.

"And, lo and behold, the people with low levels of dopamine receptors
in their brains were the ones who liked the way the Ritalin made them
feel," said Dr. Nora Volkow, associate laboratory director for life
science at Brookhaven National Laborator. "Those who had high
concentrations of receptors in their brains said the Ritalin made
them feel very unpleasant. They felt like they were losing control.
One almost had a panic attack."

In a follow-up experiment designed to test whether an increase in
dopamine receptors could prevent drug abuse, Dr. Panayotis Thanos, a
scientist at Brookhaven, used gene therapy to boost the number of
dopamine receptors in rats that had developed a taste for alcohol.
The result: the rats quit drinking, Dr. Volkow said.

In New York, researchers are looking at a different dopamine receptor
- - DR1. Scientists suspect that DR1, which gives a sensation of
satiety when stimulated by dopamine, is a sort of check to DR2, said
Dr. Marc Laruelle, an associate professor of psychiatry and radiology
at the Columbia College of Physicians and Surgeons. In an attempt to
discover whether DR1 levels can make a difference in an addict's
ability to postpone gratification, Dr. Laruelle and his colleagues
are giving volunteer addicts small doses of cocaine and then offering
them the choice of a $5 dose of the drug or a $10 bill.

"We want to see if they go for the money or the cocaine," Dr.
Laruelle said. "The hope is that the ratio of DR1 to DR2 will be
predictive. And then, perhaps, we will be able to identify addicts
with very low levels of DR1 and give them a drug to stimulate DR1
more effectively."

Perhaps as important as the issue of genetic susceptibility is the
effect drugs have on the wiring of the brain. Drugs lure people back
because they tap into a very primal system in the human brain. In
essence, drugs of abuse hijack the brain circuitry that has evolved
to help people find their way back to food sources or a sexual
partners to reproduce, Dr. Childress said. Once people experience a
pleasurable - or terrible - moment, the amygdala helps the brain
remember how it got that feeling and how to get it or avoid it in the
future.

"Monkeys with amygdalar damage stare expressionless at a banana
across a Plexiglas screen," Dr. Childress said. "Normally this would
drive them into a frenzy of excited anticipation. People with severe
amygdalar damage quite literally have difficulty staying alive. They
will cross the street in front of oncoming cars, as the normal
signals for fear have been undone."

And when we see cues to positive experiences - a picture of a syringe
or a mound of white powder, in the case of the addict - the brain
releases a small spurt of dopamine that reminds us of the pleasurable
experience, Dr. Childress explained.

"This increase in dopamine feels similar to a small dose of the drug
itself," she added. Some even feel they can taste the drug in the
back of their throats.

=46or many recovering addicts, that little "taste" of the drug is often
too strong a temptation to ignore, Dr. Childress said.

A possible therapy is to find a drug to tone down the dopamine system
and give the thinking part of the brain a better chance at
remembering the consequences of drug use.

Baclofen is one candidate. An older medication, used for years to
treat muscle spasms, baclofen latches onto the GABA receptor, which
acts as a set of brakes to the dopamine system. It appears to quiet
craving and to blunt the high associated with drugs of abuse.

In a pilot study, Dr. Childress found that baclofen can soothe
craving. She was about to start a study of the long-term effects of
the medication to determine, among other things, whether it would
continue to quiet the desire for drugs when she discovered Mr.
Coleman.

Mr. Coleman, a paraplegic, had been taking baclofen for spasms in his
legs for years. On his own, Mr. Coleman had discovered the powers of
baclofen. He had experimented with different doses and discovered
that it would block his high if he took the baclofen too close to the
time he took cocaine. He learned that the medication could reduce his
craving when cocaine was unavailable. He also figured out that it
quieted his craving for alcohol and cigarettes.

"In a way," Dr. Childress ssid, "he's done my experiment for me."