THE BRAIN: THE ORIGINS OF DEPENDENCE

New Research On How Cocaine, Heroin, Alcohol And Amphetamines Target
Neuronal Circuits Is Revealing The Biological Basis Of Addiction,
Tolerance, Withdrawal And Relapse

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
brain's 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 accumbens 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 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 accumbens, a key region 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 addictive 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 neurotransmitters 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 dopamine 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 system as drug
abusers-and that if they don't do it 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.