RESEARCH SHOWS BRAIN ON COCAINE

BOSTON (AP) -- All that could be seen of the drug addict were his gray wool
socks sticking out of an MRI machine the size of a walk-in closet. He'd
been in there about an hour when a technician pushed a big white button and
infused 40 milligrams of cocaine into his bloodstream.

Two psychiatrists watched intently, along with a heart specialist, a drug
counselor and a nurse. If all went well, they would capture amazingly clear
pictures of the drug's effects on this man's brain, a step toward mapping
addiction's grip and, ultimately, perhaps even curing it.

But at this moment, the team focused on just getting through the next half
hour without a mistake.

For a minute and a half, nothing happened. Then the man's heart picked up
speed. 90 beats per minute. Then 130. 135. His blood pressure zoomed to an
off-the-charts 194 over 116. A number came up on a computer screen: Rush 4.

"He's getting maximal rush," said Dr. Hans Breiter.

The man inside the MRI machine had just signaled how much he liked it. His
head immobilized, his ears plugged against the pulsing racket of the super
magnets, he rated his euphoria on a scale of one to four. Four meant really
good.

It was a rush in the interest of science. In this unusual experiment at
Massachusetts General Hospital, scientists were literally looking inside a
man's head to see what cocaine does.

Their souped-up MRI machine, programmed to run far faster than the kind
used to take pictures of strokes or bad knees, rattled off an image a
second of the man's brain.

It was quickly over. Within a couple of minutes, the rush fell to 2, then
1. Then came less pleasant feelings. Low 2, the man reported. Low 3. It
meant he felt jittery, out of sorts. Finally the numbers began to rise on
another scale, his inevitable hunger for more. Craving 3.

Breiter looked relieved. There had been no need to yank the man out of the
machine and jolt him with defibrillator paddles -- something they had
practiced doing in 30 seconds flat in case the cocaine triggered cardiac
arrest. Nothing had gone wrong.

Around 10 p.m., after promising he wouldn't go looking for more cocaine
that night, the addict was sent home with a lecture about the dangers of
drugs, an offer of drug rehab and his payment, a $260 credit at a supermarket.

Volunteer No. 34 received what for him was a moderate amount of cocaine44;
and left behind 200 images of what it did to his brain. At the exact
moments when he had felt so very good and then so bad, they would show just
which parts were working in high gear.

"This is, like, way beyond fried eggs," said Dr. Alan Leshner, head of the
National Institute on Drug Abuse, referring to the memorable ad campaign a
few years ago about brains on drugs.

Leshner's institute is paying for this and similar experiments around the
country. Scientists hope that by knowing exactly how cocaine gets people
high and keeps them coming back for more, they will see clues to making
medicines that can blunt these effects.

"That state of feeling good, high, euphoria, buzz, whatever you call it,
that's what we're after, and that's what users are after," said Dr. Scott
Lucas, who is doing some of the research at McLean Hospital in Belmont, Mass.

For instance, the researchers would like to know the precise circuitry of
chemicals and nerves that come to life when people feel high or are seized
with the uncontrollable urge for more drugs.

How does cocaine change the brain? What's out of whack 10 minutes after
snorting it? A month after? A year?

Until recently, the answers could only be surmised from experiments on
animals. Cocaine is perhaps the most addictive substance known. A rat will
ignore food, water and sex and take cocaine until it dies. But a rat cannot
say how it feels.

Now, the fast magnetic resonance imaging machines, called functional MRI,
along with a slower technology called PET, offer a kind of window inside
the human head during drug use.

"For the first time, using these tools, we are able to see the living,
thinking, feeling human brain at work," said Dr. Steven Hyman, head of the
National Institute of Mental Health.

Before going to the federal institute, Hyman set up the cocaine experiments
at Massachusetts General. Now they are being carried on by Breiter, a
35-year-old psychiatrist with swept-back thinning blond hair and an
exuberant manner.

A couple of weeks after the experiment on volunteer No. 34, Breiter called
up his brain scans on a computer in a reclaimed torpedo factory on Boston
Harbor. Four images appeared, each a cross-sectional slice that cut across
the man's head in a different spot.

"Tons of areas are lit," Breiter said, pointing to a scattering of purple
and yellow blotches. "But it's not at all a global response. It's very
specific."

Each bit of color showed the intensity of work being done by different
parts of the brain under the influence of cocaine. Aglow were many of the
brain's landmarks -- the hippocampus, the insula and the anterior cingulate.

MRI shows what happened during the experiment second by second. It does
this by measuring the oxygen content of the blood. Since the body needs
more oxygen when it's busy, looking at blood oxygen levels reveals which
parts of the brain are busy.

The result is a detailed picture of specific brain structures that come to
life during each stage of a session with drugs. Scientists can guess at the
ebb and flow of chemicals like dopamine that are triggering the changes.

The Massachusetts General research reveals, as expected, that cocaine
activates something called the mesolimbic dopamine system, a strip of nerve
cells that runs from deep in the center of the brain to its outer fringes.

This is the chemical pipeline linking up the body's pleasure center, the
part of the brain that makes you feel good when you bite into a perfectly
cooked steak or find a $10 bill on the street.

It's a complex piece of machinery. The Massachusetts General doctors have
counted 90 different parts of the brain that are turned on during cocaine's
rush. But as the euphoria ebbs and the craving sets in, almost all of these
fade out, leaving just a few distinct structures -- especially the amygdala
and the nucleus accumbens -- still working hard.

This was a surprise. The amygdala and the nucleus accumbens are part of the
system that gives pleasure. So why is the system involved in craving, which
is the motivation to get more pleasure? Like most interesting research,
this complicates theories as much as it clarifies them.

Indeed, making sense of craving is one of the hottest areas of this
research, because it's the craving that brings addicts back again and again.

"The picture emerging is that drugs take over structures that are involved
in normal pleasure," said Dr. Elliot Stein of the Medical College of
Wisconsin.

Cocaine44; nicotine, alcohol, amphetamine, heroin and most other drugs of
abuse exploit the same system that evolved to reward us for eating,
drinking and having sex -- in short, maintaining the species.

All of the drugs do it by increasing the supply of dopamine, a protein that
triggers the body's pleasure circuits. Cocaine's particular trick is to
block dopamine recycling. Instead of being flushed out of the system, as
ordinarily happens, dopamine spikes to astronomical levels.

Overloaded with dopamine, the brain cuts production. The addict makes up
the dopamine shortfall by snorting more cocaine.

Even recovered addicts remain at risk. Years later, the mere sight of an
old drug pal can trigger an overwhelming craving. The theory is that the
memory makes the brain release a dollop of dopamine in anticipation of a
reward.

"When they hear, smell, touch or see things that remind them of cocaine44;
they describe a state of arousal and anticipation that is very
cocaine-like," said Dr. Anna Rose Childress of the University of
Pennsylvania. "Their hearts go pitty-pat, their ears buzz and their heads
are light."

To study this, scientists put cocaine addicts into scanners, and induce
craving by showing them movies of people pretending to use crack. The
amygdala lights up on the scan, as do brain parts that involve memory and
emotion.

This kind of research strengthens the belief among scientists that drug
addiction is not just a failure of will. It is a brain disease -- a
lasting, perhaps permanent change in the brain's chemistry and physiology
that produces compulsive craving.

It also suggests the possibility of making medicines that ease people off
cocaine and keep them off. One possible approach is a receptor blocker -- a
protein that locks up a contact point that dopamine uses to trigger nerve
cells. In theory, blocking this receptor might blunt the effects of cocaine
while easing the craving.

The scientists say that only by purposely giving cocaine to volunteers can
they figure all this out. Building in all the safeguards they can think of,
they feel ethically justified in giving people a dangerous, addictive drug.

Hyman's team spent two years designing the experiment to minimize the
risks. The doctors note that only heavy, chronic users of cocaine are
recruited. The users are urged to give up the habit, even before the
experiment begins. They get detailed physical exams. A heart specialist
stands by during the cocaine injections, and only moderate doses are used.

"Frankly, even I still have my doubts about whether this is OK," Hyman
said. "But we will learn things we could never possibly learn from animals.
A rat in a cage with an IV is not the same as an addicted human."

Copyright 1998 Associated Press.