ADDICTED

WHY DO PEOPLE GET HOOKED? MOUNTING EVIDENCE POINTS TO
A POWERFUL BRAIN CHEMICAL CALLED DOPAMINE

BY J. MADELEINE NASH

Imagine you are taking a slug of whiskey. a puff of a cigarette. A toke
of marijuana. A snort of cocaine. A shot of heroin. Put
aside whether these drugs are legal or illegal. Concentrate, for now, on
the chemistry. The moment you take that slug, that puff,
that toke, that snort, that shot, trillions of potent molecules surge
through your bloodstream and into your brain. Once there,
they set off a cascade of chemical and electrical events, a kind of
neurological chain reaction that ricochets around the skull and
rearranges the interior reality of the mind.

Given the complexity of these eventsand the inner workings of the mind
in generalit's not surprising that scientists have
struggled mightily to make sense of the mechanisms of addiction. Why do
certain substances have the power to make us feel so
good (at least at first)? Why do some people fall so easily into the
thrall of alcohol, cocaine, nicotine and other addictive
substances, while others can, literally, take them or leave them?

The answer, many scientists are convinced, may be simpler than anyone has
dared imagine. What ties all these moodaltering
drugs together, they say, is a remarkable ability to elevate levels of a
common substance in the brain called dopamine. In fact,
so overwhelming has evidence of the link between dopamine and drugs of
abuse become that the distinction (pushed primarily
by the tobacco industry and its supporters) between substances that are
addictive and those that are merely habitforming has
very nearly been swept away.

The Liggett Group, smallest of the U.S.'s Big Five cigarette makers,
broke ranks in March and conceded not only that tobacco
is addictive but also that the company has known it all along. While RJR
Nabisco and the others continue to battle in the
courtsinsisting that smokers are not hooked, just exercising free
choicetheir denials ring increasingly hollow in the face of the
growing weight of evidence. Over the past year, several scientific groups
have made the case that in dopaminerich areas of the
brain, nicotine behaves remarkably like cocaine. And late last week a
federal judge ruled for the first time that the Food and
Drug Administration has the right to regulate tobacco as a drug and
cigarettes as drugdelivery devices.

Now, a team of researchers led by psychiatrist Dr. Nora Volkow of the
Brookhaven National Laboratory in New York has
published the strongest evidence to date that the surge of dopamine in
addicts' brains is what triggers a cocaine high. In last
week's edition of the journal Nature they described how powerful
brainimaging technology can be used to track the rise of
dopamine and link it to feelings of euphoria.

Like serotonin (the brain chemical affected by such antidepressants as
Prozac), dopamine is a neurotransmittera molecule that
ferries messages from one neuron within the brain to another. Serotonin
is associated with feelings of sadness and wellbeing,
dopamine with pleasure and elation. Dopamine can be elevated by a hug, a
kiss, a word of praise or a winning poker handas
well as by the potent pleasures that come from drugs.

The idea that a single chemical could be associated with everything from
snorting cocaine and smoking tobacco to getting good
grades and enjoying sex has electrified scientists and changed the way
they look at a wide range of dependencies, chemical and
otherwise. Dopamine, they now believe, is not just a chemical that
transmits pleasure signals but may, in fact, be the master
molecule of addiction.

This is not to say dopamine is the only chemical involved or that the
deranged thought processes that mark chronic drug abuse
are due to dopamine alone. The brain is subtler than that. Drugs modulate
the activity of a variety of brain chemicals, each of
which intersects with many others. "Drugs are like sledgehammers,"
observes Dr. Eric Nestler of the Yale University School of
Medicine. "They profoundly alter many pathways."

Nevertheless, the realization that dopamine may be a common end point of
all those pathways represents a signal advance.
Provocative, controversial, unquestionably incomplete, the dopamine
hypothesis provides a basic framework for understanding
how a genetically encoded traitsuch as a tendency to produce too little
dopaminemight intersect with environmental
influences to create a serious behavioral disorder. Therapists have long
known of patients who, in addition to having
psychological problems, abuse drugs as well. Could their drug problems be
linked to some inborn quirk? Might an inability to
absorb enough dopamine, with its pleasuregiving properties, cause them
to seek gratification in drugs?

Such speculation is controversial, for it suggests that broad swaths of
the population may be genetically predisposed to drug
abuse. What is not controversial is that the social cost of drug abuse,
whatever its cause, is enormous. Cigarettes contribute to
the death toll from cancer and heart disease. Alcohol is the leading
cause of domestic violence and highway deaths. The
needles used to inject heroin and cocaine are spreading aids. Directly or
indirectly, addiction to drugs, cigarettes and alcohol is
thought to account for a third of all hospital admissions, a quarter of
all deaths and a majority of serious crimes. In the U.S.
alone the combined medical and social costs of drug abuse are believed to
exceed $240 billion.

For nearly a quartercentury the U.S. has been waging a war on drugs,
with little apparent success. As scientists learn more
about how dopamine works (and how drugs work on it), the evidence
suggests that we may be fighting the wrong battle.
Americans tend to think of drug addiction as a failure of character. But
this stereotype is beginning to give way to the
recognition that drug dependence has a clear biological basis.
"Addiction," declares Brookhaven's Volkow, "is a disorder of the
brain no different from other forms of mental illness."

That new insight may be the dopamine hypothesis' most important
contribution in the fight against drugs. It completes the loop
between the mechanism of addiction and programs for treatment. And it
raises hope for more effective therapies. Abstinence, if
maintained, not only halts the physical and psychological damage wrought
by drugs but in large measure also reverses it.

Genes and social forces may conspire to turn people into addicts but do
not doom them to remain so. Consider the case of
Rafael Rios, who grew up in a housing project in New York City's
druginfested South Bronx. For 18 years, until he turned
31, Rios, whose father died of alcoholism, led a double life. He
graduated from Harvard Law School and joined a prestigious
Chicago law firm. Yet all the while he was secretly visiting a shooting
gallery once a day. His favored concoction: heroin spiked
with a jolt of cocaine. Ten years ago, Rios succeeded in kicking his
habitfor good, he hopes. He is now executive director of
A Safe Haven, a Chicagobased chain of residential facilities for
recovering addicts.

How central is dopamine's role in this familiar morality play? Scientists
are still trying to sort that out. It is no accident, they say,
that people are attracted to drugs. The major drugs of abuse, whether
depressants like heroin or stimulants like cocaine, mimic
the structure of neurotransmitters, the most mindbending chemicals
nature has ever concocted. Neurotransmitters underlie
every thought and emotion, memory and learning; they carry the signals
between all the nerve cells, or neurons, in the brain.
Among some 50 neurotransmitters discovered to date, a good half a dozen,
including dopamine, are known to play a role in
addiction.

The neurons that produce this molecular messenger are surprisingly rare.
Clustered in loose knots buried deep in the brain, they
number a few tens of thousands of nerve cells out of an estimated total
of 100 billion. But through long, wirelike projections
known as axons, these cells influence neurological activity in many
regions, including the nucleus accumbens, the primitive
structure that is one of the brain's key pleasure centers. At a purely
chemical level, every experience humans find
enjoyablewhether listening to music, embracing a lover or savoring
chocolateamounts to little more than an explosion of
dopamine in the nucleus accumbens, as exhilarating and ephemeral as a
firecracker.

Dopamine, like most biologically important molecules, must be kept within
strict bounds. Too little dopamine in certain areas of
the brain triggers the tremors and paralysis of Parkinson's disease. Too
much causes the hallucinations and bizarre thoughts of
schizophrenia. A breakthrough in addiction research came in 1975, when
psychologists Roy Wise and Robert Yokel at
Concordia University in Montreal reported on the remarkable behavior of
some drugaddicted rats. One day the animals were
placidly dispensing cocaine and amphetamines to themselves by pressing a
lever attached to their cages. The next they were
angrily banging at the lever like someone trying to summon a stalled
elevator. The reason? The scientists had injected the rats
with a drug that blocked the action of dopamine.

In the years since, evidence linking dopamine to drugs has mounted.
Amphetamines stimulate dopamineproducing cells to
pump out more of the chemical. Cocaine keeps dopamine levels high by
inhibiting the activity of a transporter molecule that
would ordinarily ferry dopamine back into the cells that produce it.
Nicotine, heroin and alcohol trigger a complex chemical
cascade that raises dopamine levels. And a still unknown chemical in
cigarette smoke, a group led by Brookhaven chemist
Joanna Fowler reported last year, may extend the activity of dopamine by
blocking a moppingup enzyme, called MAO B, that
would otherwise destroy it.

The evidence that Volkow and her colleagues present in the current issue
of Nature suggests that dopamine is directly
responsible for the exhilarating rush that reinforces the desire to take
drugs, at least in cocaine addicts. In all, 17 users
participated in the study, says Volkow, and they experienced a high whose
intensity was directly related to how extensively
cocaine tied up available binding sites on the molecules that transport
dopamine around the brain. To produce any high at all,
she and her colleagues found, cocaine had to occupy at least 47% of these
sites; the "best" results occurred when it took over
60% to 80% of the sites, effectively preventing the transporters from
latching onto dopamine and spiriting it out of circulation.

Scientists believe the dopamine system arose very early in the course of
animal evolution because it reinforces behaviors so
essential to survival. "If it were not for the fact that sex is
pleasurable," observes Charles Schuster of Wayne State University in
Detroit, "we would not engage in it." Unfortunately, some of the
activities humans are neurochemically tuned to find
agreeableeating foods rich in fat and sugar, for instancehave
backfired in modern society. Just as a surfeit of food and a
dearth of exercise have conspired to turn heart disease and diabetes into
major health problems, so the easy availability of
addictive chemicals has played a devious trick. Addicts do not crave
heroin or cocaine or alcohol or nicotine per se but want
the rush of dopamine that these drugs produce.

Dopamine, however, is more than just a feelgood molecule. It also
exercises extraordinary power over learning and memory.
Think of dopamine, suggests P. Read Montague of the Center for
Theoretical Neuroscience at Houston's Baylor College of
Medicine, as the proverbial carrot, a reward the brain doles out to
networks of neurons for making survivalenhancing choices.
And while the details of how this system works are not yet understood,
Montague and his colleagues at the Salk Institute in San
Diego, California, and M.I.T. have proposed a model that seems quite
plausible. Each time the outcome of an action is better
than expected, they predicted, dopaminereleasing neurons should increase
the rate at which they fire. When an outcome is
worse, they should decrease it. And if the outcome is as expected, the
firing rate need not change at all.

As a test of his model, Montague created a computer program that
simulated the nectargathering activity of bees.
Programmed with a dopaminelike reward system and set loose on a field of
virtual "flowers," some of which were dependably
sweet and some of which were either very sweet or not sweet at all, the
virtual bees chose the reliably sweet flowers 85% of
the time. In laboratory experiments real bees behave just like their
virtual counterparts. What does this have to do with drug
abuse? Possibly quite a lot, says Montague. The theory is that
dopamineenhancing chemicals fool the brain into thinking drugs
are as beneficial as nectar to the bee, thus hijacking a natural reward
system that dates back millions of years.

The degree to which learning and memory sustain the addictive process is
only now being appreciated. Each time a
neurotransmitter like dopamine floods a synapse, scientists believe,
circuits that trigger thoughts and motivate actions are etched
onto the brain. Indeed, the neurochemistry supporting addiction is so
powerful that the people, objects and places associated
with drug taking are also imprinted on the brain. Stimulated by food, sex
or the smell of tobacco, former smokers can no more
control the urge to light up than Pavlov's dogs could stop their urge to
salivate. For months Rafael Rios lived in fear of catching
a glimpse of bare armshis own or someone else's. Whenever he did, he
remembers, he would be seized by a nearly
unbearable urge to find a drugfilled syringe.

Indeed, the brain has many devious tricks for ensuring that the
irrational act of taking drugs, deemed "good" because it
enhances dopamine, will be repeated. petscan images taken by Volkow and
her colleagues reveal that the absorption of a
cocainelike chemical by neurons is profoundly reduced in cocaine addicts
in contrast to normal subjects. One explanation: the
addicts' neurons, assaulted by abnormally high levels of dopamine, have
responded defensively and reduced the number of sites
(or receptors) to which dopamine can bind. In the absence of drugs, these
nerve cells probably experience a dopamine deficit,
Volkow speculates, so while addicts begin by taking drugs to feel high,
they end up taking them in order not to feel low.

PETSCAN images of the brains of recovering cocaine addicts reveal other
striking changes, including a dramatically impaired
ability to process glucose, the primary energy source for working
neurons. Moreover, this impairmentwhich persists for up to
100 days after withdrawalis greatest in the prefrontal cortex, a
dopaminerich area of the brain that controls impulsive and
irrational behavior. Addicts, in fact, display many of the symptoms shown
by patients who have suffered strokes or injuries to
the prefrontal cortex. Damage to this region, University of Iowa
neurologist Antonio Damasio and his colleagues have
demonstrated, destroys the emotional compass that controls behaviors the
patient knows are unacceptable.

Anyone who doubts that genes influence behavior should see the mice in
Marc Caron's lab. These tireless rodents race around
their cages for hours on end. They lose weight because they rarely stop
to eat, and then they drop from exhaustion because
they are unable to sleep.

Why? The mice, says Caron, a biochemist at Duke University's Howard
Hughes Medical Institute laboratory, are high on
dopamine. They lack the genetic mechanism that sponges up this powerful
stuff and spirits it away. Result: there is so much
dopamine banging around in the poor creatures' synapses that the mice,
though drugfree, act as if they were strung out on
cocaine.

For years scientists have suspected that genes play a critical role in
determining who will become addicted to drugs and who
will not. But not until now have they had molecular tools powerful enough
to go after the prime suspects. Caron's mice are just
the most recent example. By knocking out a single genethe socalled
dopaminetransporter geneCaron and his colleagues
may have created a strain of mice so sated with dopamine that they are
oblivious to the allure of cocaine, and possibly alcohol
and heroin as well. "What's exciting about our mice," says Caron, "is
that they should allow us to test the hypothesis that all
these drugs funnel through the dopamine system."

Several dopamine genes have already been tentatively, and
controversially, linked to alcoholism and drug abuse. Inherited
variations in these genes modify the efficiency with which nerve cells
process dopamine, or so the speculation goes. Thus, some
scientists conjecture, a dopaminetransporter gene that is
superefficient, clearing dopamine from the synapses too rapidly, could
predispose some people to a form of alcoholism characterized by violent
and impulsive behavior. In essence, they would be
mirror images of Caron's mice. Instead of being drenched in dopamine,
their synapses would be dopaminepoor.

The dopamine genes known as d2 and d4 might also play a role in drug
abuse, for similar reasons. Both these genes, it turns
out, contain the blueprints for assembling what scientists call a
receptor, a minuscule bump on the surface of cells to which
biologically active molecules are attracted. And just as a finger lights
up a room by merely flicking a switch, so dopamine
triggers a sequence of chemical reactions each time it binds to one of
its five known receptors. Genetic differences that reduce
the sensitivity of these receptors or decrease their number could
diminish the sensation of pleasure.

The problem is, studies that have purported to find a basis for addiction
in variations of the d2 and d4 genes have not held up
under scrutiny. Indeed, most scientists think addiction probably involves
an intricate dance between environmental influences
and multiple genes, some of which may influence dopamine activity only
indirectly. This has not stopped some researchers from
promoting the provocative theory that many people who become alcoholics
and drug addicts suffer from an inherited condition
dubbed the rewarddeficiency syndrome. Low dopamine levels caused by a
particular version of the d2 gene, they say, may
link a breathtaking array of aberrant behaviors. Among them: severe
alcoholism, pathological gambling, binge eating and
attentiondeficit hyperactivity disorder.

The more science unmasks the powerful biology that underlies addiction,
the brighter the prospects for treatment become. For
instance, the discovery by Fowler and her team that a chemical that
inhibits the moppingup enzyme mao b may play a role in
cigarette addiction has already opened new possibilities for therapy. A
number of welltolerated mao binhibitor drugs
developed to treat Parkinson's disease could find a place in the
antismoking arsenal. Equally promising, a Yale University team
led by Eric Nestler and David Self has found that another type of
compoundone that targets the dopamine receptor known as
d1seems to alleviate, at least in rats, the intense craving that
accompanies withdrawal from cocaine. One day, suggests Self, a
d1 skin patch might help cocaine abusers kick their habit, just as the
nicotine patch attenuates the desire to smoke.

Like methadone, the compound that activates d1 appears to be what is
known as a partial agonist. Because such medications
stimulate some of the same brain pathways as drugs of abuse, they are
often addictive in their own right, though less so. And
while treating heroin addicts with methadone may seem like a copout to
people who have never struggled with a drug habit,
clinicians say they desperately need more such agents to tide
addictsparticularly cocaine addictsover the first few months of
treatment, when the danger of relapse is highest.

Realistically, no one believes better medications alone will solve the
drug problem. In fact, one of the most hopeful messages
coming out of current research is that the biochemical abnormalities
associated with addiction can be reversed through learning.
For that reason, all sorts of psychosocial interventions, ranging from
psychotherapy to 12step programs, can and do help.
Cognitive therapy, which seeks to supply people with coping skills
(exercising after work instead of going to a bar, for
instance), appears to hold particular promise. After just 10 weeks of
therapy, beforeandafter pet scans suggest, some
patients suffering from obsessivecompulsive disorder (which has some
similarities with addiction) manage to resculpt not only
their behavior but also activity patterns in their brain.

In late 20th century America, where drugs of abuse are being used on an
unprecedented scale, the mounting evidence that
treatment works could not be more welcome. Until now, policymakers have
responded to the drug problem as though it were
mostly a criminal matter. Only a third of the $15 billion the U.S.
earmarks for the war on drugs goes to prevention and
treatment. "In my view, we've got things upside down," says Dr. David
Lewis, director of the Center for Alcohol and Addiction
Studies at Brown University School of Medicine. "By relying so heavily on
a criminalized approach, we've only added to the
stigma of drug abuse and prevented highquality medical care."

Ironically, the biggest barrier to making such care available is the
perception that efforts to treat addiction are wasted. Yet
treatment for drug abuse has a failure rate no different from that for
other chronic diseases. Close to half of recovering addicts
fail to maintain complete abstinence after a yearabout the same
proportion of patients with diabetes and hypertension who fail
to comply with their diet, exercise and medication regimens. What doctors
who treat drug abuse should strive for, says Alan
Leshner, director of the National Institute on Drug Abuse, is not
necessarily a cure but longterm care that controls the
progress of the disease and alleviates its worst symptoms. "The
occasional relapse is normal," he says, "and just an indication
that more treatment is needed."

Rafael Rios has been luckier than many. He kicked his habit in one
lengthy struggle that included four months of inpatient
treatment at a residential facility and a year of daily outpatient
sessions. During that time, Rios checked into 12step meetings
continually, sometimes attending three a day. As those who deal with
alcoholics and drug addicts know, such exertions of will
power and courage are more common than most people suspect. They are the
best reason yet to start treating addiction as the
medical and public health crisis it really is.

With reporting by Alice Park/New York

For more on addiction and alcoholism, see our Web report at
time.com/alcoholism

HIGH AND LOWS
Number who used
in the past month
HEROIN
200,000
Triggers release of dopamine; acts on other neurotransmitters

AMPHETAMINES
800,000
Stimulate excess release of dopamine

COCAINE/CRACK
1,500,000
Blocks dopamine absoption

MARIJUANA
10,000,000
Binds to areas of brain involved in mood and memory;
triggers release of dopamine

ALCOHOL
11,000,000 abusers
Triggers dopamine release: acts on other neurotransmitters

NICOTINE
61,000,000
Triggers release of dopamine

CAFFEINE
130,000,000*
May trigger release of dopamine