|SOSTANZE D'ABUSO: COCAINA
I "COPING SKILLS" POSSONO AIUTARE I PAZIENTI A RICONOSCERE E A RESISTERE ALLA "VOGLIA DI COCA" (NATIONAL INSTITUTE ON DRUG ABUSE)
Volume 14, Number
Cocaine's Pleasurable Effects May Involve Multiple Chemical Sites
By Steven Stocker, NIDA NOTES Contributing Writer
Recent studies with genetically altered mice have suggested that
cocaine's euphoric effects may involve not just one, but several, chemical
sites in the brain. These studies indicate that medications for treating
cocaine addiction may need to target these multiple sites just as cocaine
Scientists have known for many years that cocaine blocks the reuptake
of certain chemicals by nerve cells, or neurons, in the brain. Neurons
release these chemicals, called neurotransmitters, to send messages to
other neurons in the vicinity. Once communication has taken place, the
neurons that sent the neurotransmitters recycle them for further use.
Proteins called transporters, located on the surface of the sending
neurons, latch onto the neurotransmitters outside the neurons in the
extracellular space and transport them back inside for re-release at a
Early studies showed that cocaine blocks the transporters for three
different neurotransmitters: dopamine, serotonin, and norepinephrine.
Later, one vein of research suggested that cocaine's blockade of the
dopamine transporter was most important for producing the drug's euphoric
effects. By blocking the dopamine transporter, some scientists theorized,
cocaine might raise the level of extracellular dopamine in brain regions
involved in the feeling of pleasure. This excess dopamine could continue
to affect neurons in these regions, giving rise to euphoria.
|Cocaine Disrupts Communication Between Neurons
During normal communication between nerve cells,
or neurons, the transmitting neuron releases neurotransmitter
molecules that stimulate the receiving neuron by binding to receptor
molecules on its surface. After this communication has occurred,
transporter molecules collect the released neurotransmitters and
transport them back into the transmitting neuron for later release.
When cocaine is present, the drug blocks the transporter, preventing
neurotransmitter reuptake so that the neurotransmitters continue to
stimulate the receiving neuron.
this hypothesis is true, then eliminating the dopamine transporter in the
brain should eliminate cocaine's euphoric effects. To test the hypothesis,
scientists produced mice lacking dopamine transporters by inactivating or
"knocking out" the gene for the transporter in mouse embryos. When these
dopamine transporter "knockout" mice matured, the researchers studied
whether they found cocaine to be rewarding. Researchers used two
techniques to study whether elimination of the dopamine transporter
nullified cocaine's rewarding effects.
Dr. Beatriz Rocha, then at the University of North Texas Health Science
Center in Fort Worth and now in NIDA's Intramural Research Program (IRP)
in Baltimore, and Dr. Marc Caron's group at Duke University in Durham,
North Carolina, used a procedure in which the mice pressed a lever to
receive a cocaine injection. If the mice continually pressed the lever at
a high rate, this would indicate that they found cocaine rewarding.
Dr. Ichiro Sora, Dr. George Uhl, and their colleagues in NIDA's IRP,
the IRP of the National Institute of Mental Health in Bethesda, Maryland,
and the University of WŸrzburg in Germany used a different procedure
called conditioned place preference. In this procedure, mice were given
cocaine injections when they were in one compartment of a two-compartment
chamber and were given nothing when they were in the other compartment.
Later, the researchers would observe which compartment the mice moved to
when they were given a choice. If the mice found cocaine rewarding, they
would spend more time in the compartment where they had received the
Using the different procedures, both groups found that their knockout
mice found cocaine rewarding despite not having the dopamine transporter.
The mice either self-administered cocaine or chose the side of the cage
where they had received cocaine.
"This finding surprised us at first," says Dr. Uhl. "It shows that the
dopamine transporter is not necessary for cocaine reward." Dr. Rocha says
that she, too, was surprised by her findings, but the fact that she and
her colleagues and Dr. Uhl's group had complementary results adds weight
to the findings.
If the dopamine transporter is not the crucial site for producing
cocaine reward, then what is? Apparently not the serotonin transporter,
because Dr. Uhl's group also studied serotonin transporter knockout mice
and found that these mice also found cocaine rewarding.
Dr. Uhl and Dr. Rocha speculate that perhaps cocaine produces its
rewarding effects by blocking the dopamine transporter and the serotonin
transporter at the same time. Thus, the elevation in the levels of both
dopamine and serotonin might produce the feelings of pleasure.
for cocaine's powerful attraction may be that it affects several
neurotransmitters, all of which are involved in mediating
In Dr. Rocha's study,
the researchers found that the extracellular dopamine level in a key brain
region in the dopamine transporter knockout mice was nearly five times
higher than normal because the transporters were no longer there to
shuttle the dopamine molecules back inside the neurons. When the knockout
mice were given cocaine, the extracellular dopamine level did not go any
higher because the animals had no dopamine transporters for cocaine to
block. Although the researchers have yet to measure the extracellular
serotonin levels in these knockouts, Dr. Rocha figures that the levels
increased and then decreased as other studies have shown they do in normal
mice because knocking out the dopamine transporter probably would not
affect cocaine's blockade of the serotonin transporter. (See "Effects
of Cocaine on Neurotransmitter Levels.")
The increase in serotonin, combined with the already high level of
dopamine, may be why cocaine is rewarding for the dopamine transporter
knockout mice, according to Dr. Rocha.
Dr. Uhl also believes that more than one neurotransmitter in the brain
probably mediates cocaine reward, if only because more than one
neurotransmitter probably mediates pleasure in general. "If a species is
not rewarded by activities such as eating or sexual interactions, that
species is not going to survive," he says. "So it makes sense that the
brain would have redundant systems so that if a mutation or some other
factor disrupts one system, the other systems can still operate normally
to produce reward." Different neurotransmitters might mediate different
aspects of reward, he says. The explanation for cocaine's powerful
attraction may be that it affects several neurotransmitters, all of which
are involved in mediating pleasure.
Selective or Nonselective?
Both Dr. Uhl and Dr. Rocha think that the results of their dopamine
transporter knockout studies support the idea that medications for
treating cocaine addiction should target other neurotransmitters in
addition to dopamine. Dr. David McCann, chief of NIDA's Pharmacology and
Toxicology Branch, notes that starting in the early 1990s NIDA, in
collaboration with pharmaceutical firms, began developing a number of
potential cocaine treatment medications that prevent cocaine from acting
at neurotransmitter transporters. Some of these compounds are selective
for the dopamine transporter, while others act more or less equally at
dopamine, serotonin, and norepinephrine transporters.
|Effects of Cocaine on Neurotransmitter
|In normal mice, researchers have
found that cocaine raises the levels of dopamine and serotonin
outside neurons about 150 percent, but the levels return to normal
after about 2 hours. In Dr. Rocha's study, the researchers found
that the dopamine levels in dopamine transporter knockout mice were
about 500 percent higher than normal because no transporters were
available to shuttle the dopamine molecules back inside the neurons.
Although the researchers have yet to measure the extracellular
serotonin levels in these knockouts, Dr. Rocha theorizes that the
levels increase then decrease as in normal mice because knocking out
the dopamine transporter probably would not affect cocaine's
blockade of the serotonin transporter.
A compound that is selective for the dopamine transporter is GBR12909
Show Strong Promise For Treating Cocaine Addiction," NIDA
NOTES, May/June 1997.). A compound that blocks all three transporters
about equally is NS2359, which was developed by NIDA and NeuroSearch, a
Danish pharmaceutical firm. Animal studies with these compounds have
indicated that they are safe and potentially effective in humans, and they
are now in the early phases of human clinical trials.
Rocha, B.A.; Fumagalli, F.; Gainetdinov, R.R.; Jones, S.R.; Ator, R.;
Giros, B.; Miller, G.W.; and Caron, M.G. Cocaine self-administration in
dopamine-transporter knockout mice. Nature Neuroscience
Sora, I.; Wichems, C.; Takahashi, N.; Li, X-F; Zeng, Z.; Revay, R.;
Lesch, K-P; Murphy, D.L.; and Uhl, G.R. Cocaine reward models: Conditioned
place preference can be established in dopamine- and in
serotonin-transporter knockout mice. Proceedings of the National
Academy of Sciences USA 95(13):7699-7704, 1998.
|NIDA Notes - Volume
14, Number 2|
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