May 14, 1998
Studies Spark New Thinking on Cocaine Addiction
By SANDRA BLAKESLEE
he leading hypothesis for how cocaine works in the brain appears to be wrong, or at least incomplete, according to two studies released on Thursday.
For 30 years, cocaine research has been driven by the theory that dopamine, a brain chemical involved in sensations of reward and pleasure, is required for the euphoria and compulsive need produced by the drug. Now, Duke University researchers have found that the high can be induced in mice without dopamine.
In a Columbia University study, scientists discovered a genetic abnormality that makes mice extremely vulnerable to cocaine addiction -- but the flaw is not based on dopamine. Rather, the abnormality involves a brain chemical called serotonin, which is not usually studied by cocaine researchers. The finding may help explain why some people are instantly seduced by cocaine while others can take it or leave it.
Experts said that both studies opened the door to new ways of thinking about cocaine addiction and possible treatments.
"This is the first convincing evidence that serotonin is involved in the reinforcing and sensitizing effects of cocaine," said Dr. Francis White, a professor of pharmacology at the Chicago Medical School in Illinois. "It raises the important possibility that we might be able to develop drugs that act on this molecule to treat cocaine addiction." No such drug is available, he said.
The Duke study will be published in the May 18 issue of Nature Neuroscience but was released Thursday. It was led by Dr. Marc Caron, a biologist at Duke in Durham, N.C. The Columbia study, described in the May 14 issue of the journal Nature, was conducted by Dr. Rene Hen, an associate professor of pharmacology at the university's Center for Neurobiology and Behavior, and colleagues from other institutions.
Both studies exploit lively areas of research: brain receptors and genetically altered "knockout" mice.
The brain is awash in chemicals, called neurotransmitters, that carry messages from one cell to the next. Cells that receive the messages have on their surface receptors -- docking sites that receive a chemical, then pass a message into the cell. Recently, scientists have learned that each neurotransmitter has a number of receptor subtypes that carry different messages into cells. The neurotransmitter dopamine has five subtype receptors. The neurotransmitter serotonin has 14 subtype receptors. Different subtypes tend to cluster in different parts of the brain.
In "knockout mouse technology," a gene is removed from a fertilized mouse egg and the animal is raised to maturity. Researchers study the mouse's behavior to learn the function of the missing gene.
Two years ago, Caron developed a knockout mouse that was missing the dopamine transporter. This molecule works by mopping up or reabsorbing excess dopamine in the brain. Under the leading hypothesis of cocaine addiction, cocaine blocks the transporter molecule, keeping more dopamine -- and more feelings of reward and pleasure -- loose in the brain. The mutant mice were hyperactive and did not increase their activity when given cocaine. This seemed to confirm the dopamine hypothesis, he said.
But in the new study, the researchers let the knockout mice give themselves cocaine. Because they lacked the transporter, they should not have wanted the drug. But the animals kept giving themselves cocaine. The rewarding effect of cocaine in these mice appears to be independent of any effects on dopamine but may be linked to increased serotonin transmission, the researchers said.
Five years ago, Hen and his colleagues knocked out the gene for a serotonin subtype receptor called 1B. Serotonin is a transmitter, which modulates all our behaviors by interacting with many other receptors.
These mutant mice were aggressive, Hen said. In novel environments, they appeared hyperactive. It is not clear how the lack of the serotonin 1B receptor subtype promotes aggression. Hen decided to give the knockout mice cocaine. "We know that serotonin and dopamine cross talk," he said. "If you touch one system, you will see repercussions in the other." It was one of the first experiments to explore the role of serotonin in drug addiction, and it produced a surprise.
The first time the altered mice got cocaine, they ran around more frenetically than before, Hen said.
Next, the mice were allowed to give themselves cocaine: Each time an animal pressed a lever, it received an intravenous shot of cocaine, with the task made more difficult with each round. To get the first injection, they pressed once; to get the second injection, they pressed twice. The question was, How long would they press to get the cocaine? Normal mice press up to eight times, then give up, Hen said. The altered mouse pressed 25 to 30 times.
These mice are born without the serotonin 1B receptor subtype. Perhaps, the researchers thought, their brains developed differently, turning on or off other genes to compensate. This was the case, Hen said. The knockout mice have high levels of a cellular protein called Fos B, which means that the gene that makes this protein is highly active. The protein is a so-called transcription factor that turns other genes on and off, he said. It is known to affect genes that traffic in dopamine.
In normal mice, the protein is only found in high amounts after the animal has been given chronic doses of cocaine. It is a molecular adaptation thought to be closely associated with the processes that underlie cocaine addiction, Hen said. The knockout mouse is born as if it had been exposed to cocaine. They are born addicts, he said. Given the chance, the mice also give themselves large amounts of alcohol, which suggests that they are biologically vulnerable to many drug addictions.
Humans may carry the same sorts of genetic vulnerabilities, Hen said. Researchers are actively looking for mutations in human receptor subtype genes to see if people are "born addicts" like the mice.
But this does not mean that there is "a gene for cocaine addiction," he said. "Life is not that simple," he added. "There are probably many genes that when mutated will result in vulnerability to drugs of abuse. And don't forget that the environment plays a major role in everything that happens to an organism."