Pubdate: Tue, 14 Nov 2000
Source: New York Times (NY)
Copyright: 2000 The New York Times Company
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Author: Linda Carroll

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."
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