New strain of mice may yield clues about addiction
Copyright =A9 1996 Nando.net
Copyright =A9 1996 N.Y. Times News Service=20
(Feb 20, 1996 00:58 a.m. EST) A new, superactive strain of=20
mice that dash about their cages as if.they are high on=20
cocaine is yielding fresh ideas about ways to treat devastating=20
human disorders, including drug addiction, schizophrenia and=20
Parkinson's disease.
The mice, which are at least five times as active as normal=20
ones, are described in the current issue of the journal Nature=20
by a team from the University of North Carolina and the Howard=20
Hughes Medical Institute at Duke University.
The animals run around for hours at a time, fail to eat enough=20
to maintain a normal weight and
sometimes drop dead from exhaustion. A Duke researcher, Dr. Marc=20
Caron, said their frenetic state was comparable to that of a=20
person high on cocaine or amphetamines.
But in these mice, bred in the laboratory through genetic=20
tinkering, the high is inborn rather than drug-induced. As a=20
result of the changes, the animals lack one of the major proteins=20
that regulate signal transmission in the brain. Circuits that=20
would normally switch on and off are, in their case, "on"
all the time.
That leads to still another extraordinary trait: the mice appear=20
completely immune to cocaine and amphetamines. Not even the highest=20
doses can make them any more active than they already are --
a finding that provides vital information about the way those=20
drugs work in humans.
The key to the animals' behavior, and its far-reaching implications=20
for people, is a brain chemical called dopamine, which plays an=20
important part in controlling movement, thought and emotion. It is
also involved in addiction. Moreover, too much dopamine in certain=20
parts of the brain is thought partly responsible for schizophrenia,=20
and too little is known to cause the tremors and rigidity of
Parkinson's disease.
Dopamine is a neurotransmitter, a molecule released by one brain=20
cell in order to signal another. It stimulates the receiving cell=20
by briefly attaching to a receptor site on that cell.
Normally, the same cell that emitted the dopamine begins reclaiming=20
it almost immediately, so that within a second or so, the signal is=20
shut off. The reclaiming is done by a protein called the dopamine
transporter, a molecule on the surface of the cell that pumps the=20
dopamine back in.
The new breed of mice have no dopamine transporter; they are=20
known as "knockouts," because researchers have knocked out, or=20
deleted the gene that would have enabled their bodies to make the
transporter. Once the knockouts' brain cells release dopamine, they=20
cannot pump it back in.
The substance lingers in the synapse, the junction between the two=20
nerve cells, and the signal persists for more than 100 seconds, until=20
the dopamine simply diffuses away. The lasting signal, multiplied by
millions of synapses, translates into a very hyper mouse.
It came as no surprise to most researchers that these hyperactive=20
animals are unaffected by cocaine. Rather, the finding confirmed a=20
popular theory. Scientists had long suspected that cocaine worked
by blocking the transporter, and that its stimulant effect was=20
produced by the resulting buildup of dopamine, not from the cocaine=20
itself. Addicts who craved cocaine, then, were assumed really to be
craving their own dopamine.
That theory is supported by the finding that mice lacking the=20
transporter do not get high: in them, cocaine has no target to work=20
on, no means of raising dopamine levels at the synapse.
The finding that the animals did not react to amphetamine did take=20
some researchers by surprise. There had been some controversy about=20
its mode of action, and the knockout mice establish for the
first time that amphetamine also targeted the dopamine transporter=20
and could not produce stimulant effects without it.
The knockout mice are a "major advance" in the study of addiction,=20
said Dr. Alan Leshner, director of the National Institute on Drug=20
Abuse. Many drugs of abuse, including cocaine, amphetamines,
opiates, marijuana and nicotine, affect a dopamine system that=20
runs along the base of the brain. Activating that system by taking=20
drugs makes many people feel good.
"Everything you love causes a rush of dopamine in this area,"=20
Leshner said. "Every drug that is addicting and self-administered=20
causes an increase in dopamine there. These mice may be a tool to
understanding the essence of addiction. We've never had a tool like=20
this."
More specifically, they may help researchers to develop drugs to=20
treat both cocaine overdosing and addiction. "The biggest single=20
need in this country is for a cocaine medication," Leshner said. "We
have nothing now other than behavioral treatments."
Findings in the mice support the idea that drugs that block cocaine=20
at the transporter, without affecting dopamine levels, could reduce=20
cocaine highs and addicts' cravings. Several drug companies
are already trying to develop such drugs.
"Will they knock out cocaine's total reward value?" Leshner asked.=20
"I don't know, but I doubt it. That's probably more complex."=20
Cocaine, he said, affects other neurotransmitters in addition to
dopamine.
Future experiments planned by Caron's team will address that question.=20
"The next thing we'd like to do is to see if these animals will=20
autoinject cocaine or amphetamine," said Dr. Mohamed Jaber.
Those studies will be conducted in France by Dr. Bruno Giros, the=20
lead author of the current study.
"Normal mice will stimulate themselves almost continuously," Jaber=20
said. "We think the knockouts will not be interested. There is no=20
target for the drug in the brain. If cocaine is the key, the lock is
missing. Cocaine will flood the brain, but it will have no place to go."
The mice may also serve as a model to screen drugs for schizophrenia.=20
"Schizophrenia is thought to be due to hyperactivity of the dopamine=20
system," Jaber said. "We're not saying that's the only thing
going on. And we're not saying these animals are schizophrenic. We=20
are saying they can provide a tool, a model, to tell whether a drug=20
can dampen the dopamine system."
Drugs already used to treat schizophrenia, known as neuroleptics,=20
work by blocking dopamine transmission in the brain. New ones are=20
still being sought because the current drugs tend to cause
movement disorders and other side effects.
Jaber has already shown that one neuroleptic, Haldol, calms the=20
knockout mice. That, he said, supports the idea that the mice may be=20
useful in identifying active drugs worth testing in people.
"You wouldn't need to go so far in trials in human beings before you=20
knew whether you were on the right track or not," Caron said.
The knockout mice have also provided intriguing ideas about treating=20
Parkinson's disease. The disease develops when nerve cells that=20
produce dopamine in the motor-control center of the brain
begin to deteriorate and die.
The lack of dopamine causes tremors at first, and as the disease=20
progresses, patients become barely able to move. Current treatments,=20
which replace the missing dopamine, help at first but eventually
stop working.
Experiments with the knockout mice suggest a different approach to=20
treatment. Although the mice behave as if they have too much dopamine=20
in the brain, studies show that the levels are actually quite
low -- about the same as in a Parkinson's patient.
Caron and his team realized that the mice's brains, in an effort to=20
reduce the high levels of dopamine caused by lack of the transporter,=20
began to produce less and less dopamine. And yet the mice
remain as hyper as can be.
"The reason they're so hyper is that the dopamine stays around at=20
the synapse for so long," Caron said. "Well, in people with=20
Parkinson's, instead of trying to replenish the dopamine, or in=20
addition, we could try to prolong the effect of the little bit of=20
dopamine that they have, by making it last for a long, long time."=20
That might be accomplished if a drug could be found to block some of=20
the patients' dopamine transporters.
No such drug is available now, and developing one may be tricky,=20
because anything that blocks the transporter -- like cocaine and=20
amphetamine, which have not been shown to help people with
Parkinson's -- has the potential of being addictive as well as toxic.
Nonetheless, Jaber said, the research team has patented the idea=20
of treating Parkinson's in this manner.
John Cottingham "The parkinsn list brings Knowledge, Comfort, Hope, and=
=20
Homeboy Friendship to the parkinsonian world."
LibraryH Parkinson's Chat on the Undernet 8:30 PM CST -6 Daily.
If you access the Internet through a provider with a
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