NEWSWEEK FEBRUARY 12, 200I
ADDICTION
SCIENCE: New research on how cocaine, heroin, alcohol and
amphetamines target neuronal circuits is revealing the biological
basis of addiction, tolerance, withdrawal and relapse.
By Sharon Begley
One by one, each crack addict took his turn
in the fMRI tube, its magnets pounding away with a
throbbing bass. A mirror inside was angled just so,
allowing the addict to see a screen just outside the
tube. Then the 10-minute video rolled. For two
minutes, images of monarch butterflies flitted by; the
fMRI, which detects active regions in the brain, saw
nothing untoward. Then the scene shifted. Men
ritualistically cooked crack ... an addict handed cash
to a pusher ... users smoked. It was as if a
Neurological switch had been thrown: seeing the
drug scenes not only unleashed in the addicts a surge
of craving for crack, but also triggered visible
changes in their brains as their anterior cingulate and
part of the prefrontal cortex-regions involved in
mood and learning-lit up like Times Square. Nonaddicts show no such response. The fMRI had
pinpointed physical changes in the brain that
apparently underlie cue-induced craving, showing
why walking past a bar, passing a corner crack house
or even partying with the people you used to shoot up
with can send a recovering addict racing for a hit.
"The brain regions that became active are where
memories are stored," says Dr. Scott Lukas of
McLean Hospital in Massachusetts, who led the 1998
study. "These cues turn on crack-related memories,
and addicts respond like Pavlov's dogs."
"This is your brain on drugs": it's not just an
advertising line. Through FMRI as well as PET
scans, neuroscientists are pinpointing what happens
in the brain during highs and lows, why withdrawal
can be unbearable and-in one of the most sobering
findings-how changes caused by addictive drugs
persist long after you stop using. "Imaging and other
techniques are driving home what we learned from
decades of animal experiments;' says Dr. Alan
Leshner, director of the National Institute on Drug
Abuse. "Drugs of abuse change the brain, hijack its
motivational systems and even change how its genes
function."
An addicted brain is different-physically different,
chemically different-from a normal brain. A cascade
of neurobiological changes accompanies the transition
from voluntary to compulsive drug use, but one of the
most important is this: cocaine, heroin, nicotine,
amphetamines and other addictive drugs alter the
brains pleasure circuits. Activating this circuit, also
called the reward circuit, produces a feel-good
sensation. Eating cheesecake or tacos or any other
food you love activates it. So does sex, winning a
competition, acing a test, receiving praise and other
pleasurable experiences. The pleasure circuit
communicates in the chemical language of dopamine:
this neurotransmitter zips from neuron to neuron in the
circuit like a molecular happy face, affecting the firing
of other neurons and producing feelings from mild
happiness to euphoria.
What happens to the circuit if you inject, inhale or
swallow an addictive drug? To find out, Dr. Hans
Breiter of Massachusetts General Hospital and
colleagues recruited cocaine addicts who had been
using for an average of seven to eight years and had
used on 16 of the past 30 days. After making sure none
had a heart problem or any other condition that would
put them at risk, Breiter and colleagues gave each a
"party" dose of cocaine, up to about 40 milligrams for a
150-pound man. An fMRI took snapshots of their
brains every eight seconds for 18 minutes. At first,
during the "rush” phase, the addicts described feeling
"out of control," as if they were "in a dragster" or
"being dangled 10 feet off the ground by a giant hand."
They also felt a high, a surge of energy and euphoria.
The fMRI showed why cocaine made a beeline for the
pleasure circuit, turning on brain areas called the
sublenticular extended amygdala and nucleus
aqccumbens and keeping them on.
How? "Drugs of abuse increase the concentration
of dopamine in the brain’s reward circuits," says
Nora Volkow of Brookhaven National Lab. The
drugs do that more intensely than any mere behavior,
be it eating a four-star meal or winning the lottery.
But each drug turns up this feel-good neurochemical
in a different way:
 Cocaine blocks the molecule that ordinarily mops
up dopamine sloshing around neurons. When all
the seats on this so-called transporter molecule
are occupied by cocaine, there is no room for
dopamine, which therefore hangs around and
keeps the pleasure circuit firing. The intensity of
a cocaine high, Volkow found in 1997, is directly
related to how much cocaine ties up the seats on
the transporter bus.
 Amphetamines block the transporter, too. They
also push dopamine out of the little sacs, called
NEWSWEEK FEBRUARY 12, 200I
vesicles, where neurons store it. More dopamine
means more firing of neurons in the pleasure
circuit.
 Heroin stimulates dopamine-containing neurons
to fire, releasing the neurochemical into the
nucleus accum-bens, a key re 'on in the pleasure
circuit. Nicotine does the same. Heroin also
excites the same neurons that our brain's natural
opioids do, but much more powerfully.
 Alcohol opens the neurotransmitter floodgates.
It releases dopamine, serotonin (which governs
our sense of well-being) and the brain's own
opioids. It also disturbs levels of glutamate,
which incites neurons to fire and helps account
for the initial alcoholic high, as well as GABA,
which dampens neuronal firing and eventually
makes (most) drinkers sleepy.
After igniting these acute effects, an ad-dictive
drug isn’t nearly through with the brain. Chronic use
produces enduring changes. The most important: it
reduces the number of dopamine receptors. Receptors
are simply little molecular baseball gloves that sit on
neurons, grab passing neuro-transmitters like fly balls
and reel them in. Animal evidence suggests that the
more you take an addictive drug, the more dopamine
receptors you wipe out, as the brain attempts to quiet
down an overly noisy pleasure circuit. Having fewer
dopamine receptors means fewer of those passing
dopamines get caught, and the pleasure circuit calms
down. But now the law of unintended consequences
kicks in. With fewer dopamine receptors, a hit that
used to produce pleasure doesn’t. This is the
molecular basis for tolerance. Drugs don't have the
effect they originally did. To get the original high,
the addict has to up his dose.
But there's worse. The dearth of dopamine
receptors means that experiences that used to bring
pleasure become impotent. A good meal, a good
chat, a good massage-none ignite that frisson of
happiness they once did. The only escape from
chronic dysphoria, irritability, anxiety and even depression, the user believes, is to take more drug.
Initial use, in other words, may be about feeling
good. But addiction is about avoiding abject,
unremitting distress and despair.
The agony of withdrawal is also a direct result of
drugs' resetting the brain’s dopamine system.
Withdrawal and abstinence deprive the brain of the
only source of dopamine that produces any sense of
joy. Without it, life seems not worth living. When a
junkie stops supplying his brain with heroin, for
instance, he becomes hypersensitive to pain,
chronically nauseated and subject to uncontrollable
tremors. "This is why addiction is a brain disease'
says NIDA’s Leshner. "It may start with the
voluntary act of taking drugs, but once you’ve got it,
you can’t just tell the addict 'Stop' 'any more than you
can tell the smoker 'Don't have emphysema.' Starting
may be volitional. Stopping isn’t.”
Although the biological basis of tolerance,
addiction and withdrawal is yielding some of its
secrets, relapse is harder to explain. Why does an
addict who has abstained for weeks, months or longer
suddenly reach for the needle or the bottle?
According to lab-animal studies, abstinence allows
dopamine receptors to eventually return to normal, so
after some period of withdrawal agony the brain
should stop craving the drug. Yet addiction is
practically the dictionary definition of a relapsing
disease. One clue might lie in Scott Lukas's fMRI
findings about cue-induced craving. The memories
of drug abuse are so enduring and so powerful that
even seeing a bare arm beneath a rolled-up sleeve
reawakens them. And just as Pavlov's dog learned to
salivate when he heard a bell that meant "chow time,"
so an addict begins to crave his drug when he sees,
hears or smells a reminder of past use. Relapse might
also reflect enduring genetic changes. Drugs can act
as DNA switches, turning genes on or off. In lab
animals, for instance, bingeing on cocaine turns down
the activity of a gene that makes a dopamine
receptor, finds Dr. Mary Jeanne Kreek of Rockefeller
University. If that gene remains chronically inactive,
it could lay the basis for relapse as an addict tries to
compensate for a crippled pleasure circuit.
Genes may also explain, at least in part, why some
people are at greater risk of drug addiction than
others. It turns out that the same dqpamine system
that drugs activate can also be turned on by novel
experiences, finds Dr. Michael Bardo of the
University of Kentucky. That suggests that people
driven to experience the Next New Thing may be
trying to appease the same primal pleasure as drug
abusers - and that if they don’t by, say, bungee
jumping, they may try to do so with drugs. In fact,
people who compulsively seek novelty also tend to
abuse drugs more than people who are content with
the same-old same-old. And novelty-seeking seems
to have a genetic basis. That suggests that "there is a
heritable component to addiction;' says Kreek. But
genes can also reduce the risk of addiction. Many
Asians carry variants of genes that control the
metabolism of alcohol. As a result, they suffer
intense reactions-flushing, nausea, palpitations - from
liquor. That could serve as a built-in defense against
alcoholism, since people tend to avoid things that
make them throw up. If only avoiding addiction were
as easy for everyone else.
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