Mice Missing Major Cocaine Target in Brain Still Get Hooked
DURHAM, N.C. –- When Marc Caron created genetically
engineered mice missing a molecule thought to be the main
target of cocaine in the brain, he expected the resulting mice
would be relatively immune from cocaine's effects. But to his
surprise, he and his colleagues at Howard Hughes Medical
Institute at Duke University Medical Center found these mice
still self-administer cocaine, a behavior akin to addiction in
The researchers said the results, published in the June
issue of the journal Nature Neuroscience, may cause scientists
to rethink how the brain becomes dependent on addictive drugs
and could immediately broaden the approach clinicians take in
treating cocaine addiction by targeting several
neurotransmitters instead of just one, dopamine.
"The surprising thing is that in the absence of the primary
target for cocaine, these animals will still self-administer
cocaine," Caron said. "This goes against all of the dogma about
the reinforcing properties of cocaine. Our results show there
is something else going on."
For many years, scientists have theorized that cocaine's
addictive properties are related to its effects on dopamine, an
essential messenger of the nervous system, particularly in the
brain. Normally, brain cells release dopamine and other
neurotransmitters such as serotonin, norepinephrine, and GABA
(gamma aminobutyric acid) to alert their neighbors about
changing conditions – to signal that it is time to run instead
of walk, or to remember that red oven coils are burning
Because these neurotransmitters are so critical to the
smooth functioning of the nervous system, they are tightly
regulated. When a chemical, such as an addictive drug,
interferes with this process, the brain can be tricked, causing
people or animals to react in strange, uncharacteristic
"The dopamine system has always been thought to be the
brain's central reward pathway," said Caron, a Howard Hughes
Medical Institute investigator and James B. Duke professor of
cell biology. "Nearly all drugs of abuse, from nicotine to
heroin, are thought eventually to funnel through this
The reason cocaine is such a powerfully addictive drug,
Caron said, is that it inserts itself directly into essential
brain signaling systems. When a person snorts or smokes
cocaine, it travels through the bloodstream and finds its way
to the brain, where it nestles into transporters not only for
dopamine, but also for serotonin and norepinephrine. Once
settled, it effectively shuts down transport mechanisms, so
that neurotransmitters sit in the neural synapse signaling
neighboring neurons much longer than they should.
Scientists have long thought that it is blockade of the
dopamine transporter system that causes people to become
addicted. Researchers have focused their attention on dopamine
neurons in a part of the brain called the ventral tegmental
area (VTA), which projects to the nucleus accumbens, a part of
the mesolimbic system, since scientists first showed 20 years
ago that destroying this specific area in a rat's brain stopped
them from self-administering cocaine. In effect, the theory
goes, cocaine fools the dopamine system into thinking cocaine
is the best "food" it has ever had, and soon it wants more.
"Much of what we know about dopamine's functions comes from
studies in which whole neurons are surgically removed or
destroyed by chemical compounds," Caron said. "We wanted to use
genetics to specifically deleted one key element of the
To better understand the specific role of the dopamine
transporter in this process, Caron and his colleagues used
genetics to create a mouse that lacks the dopamine transporter,
the supposed key to cocaine addiction.
Lacking the dopamine transporter – the molecule that
normally scavenges dopamine back into the transmitting cell –
Caron's genetically altered mice have no way to turn off
dopamine signaling and are acutely hyperactive, as though they
are on cocaine all the time. Published in the Feb. 15, 1996,
issue of the journal Nature, the study first describing the
mice showed definitively that the dopamine system is indeed the
primary biological pathway of addiction.
In their current research, Caron and his colleagues wanted
to see how the mice would react when presented with
To do that, Caron collaborated with Dr. Beatrix Rocha or the
University of North Texas in Fort Worth. Rocha conducted
experiments in which she offered both normal mice and the
genetically altered mice cocaine as a reward for pressing a
lever. Because the brains of the transporter-deficient mice are
in a constant state of stimulation, much like that of an animal
permanently on cocaine, the researchers reasoned that the mice
would be indifferent to cocaine if they were presented the
drug. To their surprise, however, the transporter-deficient
animals self-administered cocaine anyway, although they
required more cocaine to become "hooked."
Caron and post-doctoral fellows Fabio Fumagalli, Raul
Gainetdinov, Sara Jones, Bruno Giros, and Gary Miller then
tested other areas of the brain to see which were being
stimulated by the cocaine. They found that cocaine was blocking
the serotonin transporter in three key brain areas, the
anterior olfactory nuclei, piriform cortex, and orbital cortex,
that have been shown to be stimulated by other drugs of abuse.
For example, lysergic acid diethylamide (LSD) and phencyclidine
(PCP) activate serotonin transmission in the piriform
The findings suggest that in addition to dopamine, serotonin
is a key contributor to the reinforcing and addictive
properties of cocaine.
Caron's research is further substantiated by a research
paper appearing in the May 14 issue of the journal Nature. Dr.
Rene Hen of Columbia University, who also collaborated with
Rocha, made mice lacking one of the receptors for serotonin.
These mutant mice are more aggressive than normal mice. When
the mice were allowed to give themselves cocaine, they
frantically self-administered the drug, much more so than
The Columbia researchers studied the brains of mice missing
the serotonin receptor and discovered their brains resembled
those of mice accustomed to receiving large amounts of cocaine.
In a sense, they are born addicted.
"The serotonin system has been thought to be a minor player
in cocaine addiction," Miller said. "People say the dopamine
system drives addiction. I think we've shown it is more
complicated than that. All the momentum in drug therapies is
geared toward the dopamine system, especially the transporter.
But a combined therapy that targets both the serotonin and
dopamine systems may be worth pursuing."