November 25, 2005
Grabbing Addiction by the Tail
Canadian scientists have developed some clever molecular trickery
that is helping to reduce the drug cravings of addicted rats. One of
the problems in addiction is that neurons in some parts of the brain
lose glutamate receptors from the cell surface, and those receptors are
important for communication between neurons. The researchers have
sidestepped this problem by crafting a peptide that mimics a portion of
the tail of the glutamate receptor and, once inside a neuron, serves as
a decoy to prevent the loss of glutamate receptors.
Yu Tian Wang, an HHMI international research scholar, and colleagues
at the University of British Columbia in Vancouver report their
findings in the November 25, 2005, issue of the journal
Science.
“We think this is a good candidate for a drug against addiction that has very few side effects.”
Yu Tian Wang
In addicted rats, cell-to-cell communication is compromised as a
result of certain long-term changes at the level of individual neurons.
Their research has produced a targeted drug that tricks brain cells
into preventing those changes. “We think this is a good candidate
for a drug against addiction that has very few side effects,”
said Wang, a neuroscientist . Although the initial studies are
promising, Wang cautioned that the drug is in the early stages of
development and is years away from testing in humans.
During addiction to drugs, cells in the nucleus accumbens—a
tiny ball of tissue deep in the brain involved in pleasure and
motivation—miscommunicate. Normally, one neuron triggers activity
in a neighbor by using neurotransmitters such as glutamate. “This
is the 'go' signal,” said Wang. “The receiving cell uses
glutamate receptors on its surface to listen to the signal.
But after repeated abuse of a drug, cells in the nucleus accumbens
internalize glutamate receptors, compromising their ability to listen
to the signals. Earlier research showed that receptor internalization
in addicted rats accompanies behavioral sensitization, a model of
craving.
Until now, though, no one knew how these receptors were removed from
the cell surface, whether the process could be halted, and, if it
could, whether the addicted rats would exhibit fewer signs of
behavioral sensitization. Wang's research has made significant progress
toward answering these questions.
The researchers began by building a peptide—a long molecule
made from a string of amino acids—with a structure similar to the
tail of the glutamate receptor that is anchored inside the cell. In
addiction, cellular machinery tugs on this tail, pulling the entire
receptor into the cell. Without its business end sticking out into the
synapse, or space between neurons, the receptor no longer works.
Wang's peptide tricks the cellular machinery into tugging on it
instead of the receptor's tail. “Once it gets inside the neuron,
the peptide competes with the receptor for binding to the
machinery,” Wang explained. With the cellular machinery otherwise
occupied, the glutamate receptors stay on the cell surface, where they
continue to receive signals.
After confirming these results in cell cultures, Wang and colleagues
tested the peptide in rats that had been given amphetamine once every
other day for 20 days. During this period, the animals displayed
stereotypical behavior such as repeated sniffing, licking, and
grooming, indicating a craving for the drug. Such behavior parallels
the compulsive thought patterns that people addicted to drugs
experience, said Anthony Phillips, Wang's colleague at the University
of British Columbia and a co-author of the article.
After keeping the rats drug-free for 21 days, the researchers gave
the animals a small amount of drug again. The rats immediately
displayed intense stereotypical behavior—a sign of behavioral
sensitization. The behavior meant that the glutamate receptors in the
animals' neurons were rapidly internalized, said Wang. “It's the
trigger that leads to sustained motivation to seek a drug.”
In contrast, addicted animals who received an intravenous injection
of the artificial peptide displayed no sensitized behavior. “The
effect was immediate and very noticeable,” said Wang.
There are several types of glutamate receptors involved in memory
and learning, but because the artificial peptide specifically targets
only the deleterious internalization process of addiction-affected
neurons, and not normal receptor function, the animals who received it
behaved normally and were able to learn as usual. “So far, we
have not seen any obvious side effects at all,” said Wang.
By inserting a tiny tube into the rats' brains, the researchers
delivered the peptide directly to the nucleus accumbens and to another
area of the brain involved in reward and motivation, the ventral
tegmental area. The peptide reduced the rats' drug-seeking behavior
only when injected into the nucleus accumbens, evidence that the
structure is critical for the expression of some of the devastating
behaviors of addiction.
Wang and colleagues recently received grants from the Brain Repair
Program of NeuroScience Canada and the Canadian Institutes of Health
Research to continue testing the peptide.
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Cindy Fox Aisen
