Engineered Mice Mimic Drug Use And Mental Ills
by DENISE GRADY
Published: February 20, 1996
A NEW, superactive strain of mice that dash about their cages as if they are high on cocaine is yielding fresh ideas about ways to treat devastating human disorders, including drug addiction, schizophrenia and Parkinson's disease.
The mice, which are at least five times as active as normal ones, are described in the current issue of the journal Nature by a team from the University of North Carolina and the Howard Hughes Medical Institute at Duke University.
The animals run around for hours at a time, fail to eat enough to maintain a normal weight and sometimes drop dead from exhaustion. A Duke researcher, Dr. Marc Caron, said their frenetic state was comparable to that of a person high on cocaine or amphetamines.
But in these mice, bred in the laboratory through genetic tinkering, the high is inborn rather than drug-induced. As a result of the changes, the animals lack one of the major proteins that regulate signal transmission in the brain. Circuits that would normally switch on and off are, in their case, "on" all the time.
That leads to still another extraordinary trait: the mice appear completely immune to cocaine and amphetamines.
Not even the highest doses can make the mice any more active than they already are, a finding that provides vital information about the way those drugs work in humans.
The key to the animals' behavior, and its far-reaching implications for people, is a brain chemical called dopamine, which plays an important part in controlling movement, thought and emotion. It is also involved in addiction.
Moreover, too much dopamine in certain parts of the brain is thought partly responsible for schizophrenia, 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 cell in order to signal another. It stimulates the receiving cell by briefly attaching to a receptor site on that cell.
Normally, the same cell that emitted the dopamine begins reclaiming it almost immediately, so that within a second or so, the signal is shut off. The reclaiming is done by a protein called the dopamine transporter, a molecule on the surface of the cell that pumps the dopamine back in.
The new breed of mice have no dopamine transporter; they are known as "knockouts" because researchers have knocked out, or deleted, the gene that would have enabled their bodies to make the transporter. Once the knockouts' brain cells release dopamine, they cannot pump it back in. The substance lingers in the synapse, the junction between the two nerve cells, and the signal persists for more than 100 seconds, until 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 animals are unaffected by cocaine. Rather, the finding confirmed a popular theory.
Scientists had long suspected that cocaine worked by blocking the transporter, and that its stimulant effect was produced by the resulting buildup of dopamine, not from the cocaine 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 transporter do not get high: in them, cocaine has no target to work on, no means of raising dopamine levels at the synapse.
The finding that the animals did not react to amphetamine did take some researchers by surprise. There had been some controversy about its mode of action, and the knockout mice establish for the first time that amphetamine also targeted the dopamine transporter and could not produce stimulant effects without it.
The knockout mice are a "major advance" in the study of addiction, said Dr. Alan Leshner, director of the National Institute on Drug Abuse. Many drugs of abuse, including cocaine, amphetamines, opiates, marijuana and nicotine, affect a dopamine system that runs along the base of the brain. Activating that system by taking drugs makes many people feel good.
"Everything you love causes a rush of dopamine in this area," Dr. Leshner said. "Every drug that is addicting and self-administered 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 this."
More specifically, they may help researchers to develop drugs to treat both cocaine overdosing and addiction.
"The biggest single need in this country is for a cocaine medication," Dr. Leshner said. "We have nothing now other than behavioral treatments."
Findings in the mice support the idea that drugs that block cocaine at the transporter, without affecting dopamine levels, could reduce cocaine highs and addicts' cravings. Several drug companies are already trying to develop such drugs.
"Will they knock out cocaine's total reward value?" Dr. Leshner asked. "I don't know, but I doubt it. That's probably more complex." Cocaine, he said, affects other neurotransmitters in addition to dopamine.