“W
hy did you ever try Marc Caron, an HHMI investigator at neurons and reinforcement loops runs
narcotics?” William Duke University, it may be evolution. from the prefrontal cortex through the lat-
Burroughs writes in “Survival of the species,” he says, is what eral hypothalamus to a small but potent
Junky, his classic tale of brought about a reward system in the bundle of neurons known as the nucleus
descent into the hell of brain that reinforces healthy behavior accumbens. It ends at the ventral tegmen-
drug addiction. “Why did you continue with a sense of pleasure. Prehistorically, tal area, atop the brain stem.
using it long enough to become an those behaviors involved food and procre- While Olds was at work with electrical
addict?” To Burroughs, the answer is sim- ation of the species. If something felt stimulation, psychologists and pharma-
ple, if not mundane: “You become a nar- good, you were more likely to do it again. cologists were using similar systems to
cotics addict because you do not have Over the centuries, however, mankind has characterize the pharmacology and phe-
strong motivations in any other direction. become adept at locating or manufactur- nomenology of drug abuse. In their labo-
Junk wins by default. I tried it as a matter ing substances that hijack these reward ratories, rats and monkeys pushed levers
of curiosity. I drifted along taking shots systems, putting pursuit of the particular to get intravenous amphetamines, cocaine
when I could score. I ended up hooked.” substance ahead of all else. or opiates. These researchers wanted to
To scientists, drug addiction is consider- James Olds, a psychologist at the know which brain chemicals these drugs
ably more complex. For half a century, California Institute of Technology, first affected, so they simultaneously gave the
they have searched for the biological identified and mapped the reward centers animals other drugs to interfere with some
mechanisms that lead to addiction—the of the brain. At McGill University in the of the brain chemicals to see what would
cascade of chemical and electrical phe- 1950s, Olds showed that he could induce happen. In particular, the researchers sus-
nomena that starts with an injection or a a sensation of pleasure in a rat by placing pected that a class of neurotransmitters
snort or a puff or a sip and ends with an electrode in its brain and applying a known as catecholamines—which includes
abuse and addiction. Why, they’ve asked, mild electric stimulus. The intensity of the norepinephrine, dopamine and sero-
have addictive drugs been constant com- pleasure seemed to depend on the precise tonin—might be involved. Sure enough,
panions to the human condition, used by position of the electrode. Drawing on the “what we found was that selective block-
the Sumerians in Mesopotamia, the work of the legendary Harvard psycholo- ade of the dopamine system made it so
ancient Egyptians, the Greeks of Homer’s gist B.F. Skinner, Olds developed a system rats wouldn’t work for cocaine or
era and the Romans of Virgil’s? Why are in which rats could administer their own amphetamines anymore,” says National
almost 2 million Americans today using stimuli by pushing a lever, and they would Institute of Drug Abuse psychologist Roy
crack cocaine and more than 200,000 do so as many as 6,000 times an hour if Wise, who pioneered research in this area
hooked on heroin? the electrode was placed to their liking. in the 1960s and 1970s. “And blocking
These biologists have learned about the He measured how frequently and mono- the dopamine system made animals lose
nature of human desires and the biochem- maniacally the rats pressed the lever for interest in the electrical brain stimulation
ical and genetic basis of pleasure. And they their cerebral buzz when the electrode was as well.”
have come upon at least one simple fact of
science’s
life and neuroanatomy: substances that
have the power to make us feel good, that
evoke a strong sensation of physical plea-
sure, seem to share remarkable similarities
once they hit the brain. Indeed, their most by Gary Taubes
profound effects take place in a few specif-
ic brain regions—known as “reward” or
GROWING
“pleasure” centers—and involve their
capacity to boost the levels of a single
brain chemical, dopamine. Research is
revealing that addiction is not evidence of
human weakness or lack of willpower but
rather a disease in which these reward cen-
ters become dysfunctional through some
combination of genes and environment.
The research is also generating a host of placed in different positions. What he By the late 1980s, researchers had
new clues and potential targets that might found were hotspots of pleasure sprinkled demonstrated that activation of this
be employed someday to cure or treat the throughout the brain but one common dopamine system in the reward pathways
affliction. neural pathway that rats would happily of the nucleus accumbens is the common
If there is a single villain in the neuro- die for. Known as the medial forebrain denominator in all drugs of abuse—
anatomical world of drug addiction, says bundle, this highway of pleasure-inducing whether “downers” such as heroin, mor-
HHMI BULLETIN
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R.J. SHAY
fix on
ADDICTION
phine and alcohol, or “uppers” such as mal will be satisfied for 5 to 30 minutes, dopamine is very low as it is packaged
cocaine and amphetamines. As Caron depending on what dose of what drug, away very rapidly in the vesicles,” says
describes it, the drugs are simply “hijack- and then dopamine falls back down to Caron. “When you destroy these vesicles,
ing” the evolutionary mechanism that some trigger point and it presses the lever you drive the dopamine transporter back-
rewards beneficial behaviors by making again and gets another injection.” ward, leading to a marked increase in the
the organism feel good. “Because we did Having identified which neurotransmit- extracellular concentration of dopamine.”
not evolve to just use drugs,” he says, ter was mediating the effect of addictive This is why the effects of amphetamines
“things like eating and any other kind of drugs, and where in the brain this was are usually much stronger than those of
pleasure, whether sex or eating chocolate, happening, researchers have spent the past cocaine.
will create the same changes in the decade dissecting the mechanism and its In the late 1980s, Amara cloned the
dopamine system that many of these drugs various interactions with both the drugs gene for the norepinephrine transporter.
do. But the drugs produce changes in the and other systems in the brain. Normally, This led other researchers to clone the
dopamine system that are much, much when dopaminergic neurons are given the genes for the transporters of other neuro-
greater than what natural behaviors signal to fire, dopamine is released into transmitters. It was a flurry of discovery
would ever do.” Drug abuse becomes a the extracellular space. There, in the gap that “opened up a whole series of experi-
search for chemical equilibrium in the between synapses, it binds to dopamine ments you could do,” Amara recalls.
brain, a homeostatic regulation mecha- receptors on downstream cells, thus trans- “You could now analyze how drugs inter-
nism to keep dopamine levels higher than mitting messages from neuron to neuron. act with the transporters, how the trans-
could be attained through normal activity. It’s a communication process controlled as porters function, under what conditions,
“Put an animal in a cage,” explains much by the firing signal as by the amount and how they’re regulated. It was clear it
Wise, “and let it start pushing a lever to of dopamine available, which in turn was going to be very informative.”
get an injection of heroin or cocaine. The depends on the cells’ ability to recapture Since then, Amara and her colleagues
drug will cause dopamine levels to go up the dopamine after it has been dispatched. have been meticulously picking apart the
two, three, four, even five times normal A molecule known as a dopamine trans- various mechanisms of transporter func-
levels in the nucleus accumbens. The ani- porter has the responsibility of recaptur- tion. “These carriers are actually electri-
ing the dopamine and returning it inside cally active,” she says. “As they transport
the nerve terminals where it is then dopamine, for instance, they transport
C. BRUCE FORSTER
repackaged into vesicles for the next fir- ions as well. When these ions are moved
ing. “The transporter is often thought of across the cell membrane, they generate a
as a pump that pumps neurotransmitters measurable current that we can observe in
into the cell against their concentration dopaminergic neurons from rat brains as
gradients,” says Susan Amara, an HHMI well as in cultured cells expressing the
investigator at the Vollum Institute in human dopamine transporter.” Not only
Oregon. dopamine but any package the transporter
Addictive drugs can prevent the might be carrying—amphetamines, for
dopamine transporter from performing instance, or even neurotoxin MPP+,
this job. Cocaine, for instance, competes which destroys dopamine neurons and
directly with dopamine for the binding produces a syndrome resembling
site on the transporter molecule. Like a Parkinson’s disease—will generate this
passenger unable to board an overcrowd- electrical activity as it is carried by the
ed bus, the dopamine is left behind in the transporter through the cell membrane.
extracellular spaces instead of being Amara and her colleagues have also
recaptured and repackaged in the vesicles found evidence that cocaine molecules do
for further firing. The dopamine hangs more at the transporter than interfere with
around to stimulate receptors down- neurotransmitter movement; they also
stream, causing the pleasurable rush of affect the movements of ions through
cocaine and hyperactivity. Amphetamines, these transporters and block the genera-
on the other hand, function in a more tion of these electric currents. “In the
complex way. They bind to the trans- past,” she says, “we thought cocaine had
porter and are carried by it back into the its effect solely by binding to the carrier
nerve cell, where they abolish the ability and blocking transport of the neurotrans-
of the vesicles to store dopamine. mitter. But we found that when we put
“Normally the amount of intracellular cocaine on the carrier, it blocks a current
that normally goes through the trans-
Susan Amara and her team are study- porter when no dopamine is present. So
ing the dopamine transporters and that may have its own effects in terms of
other molecular players involved in the direct impact of cocaine, one that isn’t
cocaine addiction. involved in the elevation of dopamine lev-
...scientists studying drug addiction now find themselves
with the neuroanatomical version of nested Russian dolls.
els.” Now Amara and her colleagues are tion, and they are the receptors that define area,” says Caron, “but we hope that we
trying to put this knowledge to work by the specificity of signals,” says Caron. can start looking at these brain pathways
finding a molecule that would block the “For example, signal transduction and understand how serotonin interacts
transporter molecule from binding through G protein-coupled receptors is with the dopamine system to produce a
cocaine but leave it free to do its work how we perceive light, how we perceive calming effect.”
with the dopamine. Such a molecule, a odors, how we perceive tastes, how our After a half century of research, scien-
kind of “cocaine antagonist,” might help heart basically beats and how essentially tists studying drug addiction now find
ease withdrawal symptoms for addicts. many of the cells in our body function.” themselves with the neuroanatomical ver-
As it turns out, the receptors for cate- sion of nested Russian dolls. The more
SCOTT DINGMAN
cholamines, and specifically dopamine, they learn about how drugs of abuse alter
are also G protein-coupled receptors, the electrical and chemical circuitry of the
which is why Caron and his colleagues brain’s reward centers, the deeper they
found themselves studying first neuro- have to go to understand the ultimate
transmitters and then addiction. After nature of addiction. They now know, for
Amara and her colleagues cloned the example, that cocaine blocks the transport
norepinephrine transporter gene, they fol- and re-uptake of dopamine, which in turn
lowed it up, as did Caron and his activates dopamine receptors, but it’s far
colleagues, by cloning the dopamine less clear what happens next. “Dopamine
transporter. Caron has been studying the activating its receptors for longer periods
molecule ever since. His primary tool has of time will lead to changes in secondary
been “knockout” mice that are bred with- messengers, and that will alter the activity
out the gene for the dopamine transporter of other neurons, which will fire more or
molecule, which makes them unable to fire less, depending on which they are,”
produce the transporter. “The absence of explains Eric Nestler, a neurobiologist and
the transporter,” says Caron, “created psychiatrist at the University of Texas
havoc in the brain dopamine system. It Southwestern Medical Center. “That has
changed just about every parameter we long-term consequences. The neurons
ever looked at. The receptors were down- adapt to that excessive stimulation
regulated and the storage of dopamine through other changes, which in turn
was almost abolished. Yet the small means those cells are now different in a
amount of dopamine left in the cell was stable way. Even without the drug present,
more active than the big load that was they’re different. The neurons are differ-
there before.” ent. The brain is different. The behavior is
Physically, the mice were smaller than different. Those are the changes that cause
average, and they seemed to stay small an addictive brain, and they are the
because they were so hyperactive that they changes we have to understand.”
rarely stopped to eat. Indeed, they seemed Most researchers are confident, howev-
to show many of the symptoms of atten- er, that they will eventually nail down
Marc Caron hopes that growing under- tion deficit hyperactivity disorder these and other details of addiction, at
standing of the brain pathways involved (ADHD), illustrating just how complicat- least enough to speed the development of
in addiction may lead to new therapies. ed these systems can be. When Caron and new pharmaceutical treatments. “The
his colleagues gave cocaine or ampheta- process of addiction is as old as mankind,”
mines to these mice, doing so actually says Caron, “and there may be mecha-
Caron has also been studying the calmed them, mimicking the effect of the nisms involved that we haven’t even
dopamine transporter molecules—with stimulant Ritalin on children with ADHD. dreamed of yet. But we now understand an
some surprising results. He is a biochemist To Caron, this suggests that cocaine and awful lot about what brain pathways are
who has spent a quarter century studying amphetamines must also interact with the involved in rewards and behavioral mani-
a class of cellular receptors known as G re-uptake of serotonin. In other words, festation of drug abuse. We still don’t
protein-coupled receptors. “They are one when the dopamine transporter molecule know how to modulate them, we still
of the most important families of mole- is removed, stimulants may work just like don’t have any successful therapeutic inter-
cules that mediate cellular communica- Prozac. “This is a pretty controversial ventions, but that’s the ultimate goal.”
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