In 1996, neuroscientist Marc Caron glanced into a cage of genetically engineered mice in an animal room at Duke University and stopped in his tracks. The mice were behaving in a highly agitated manner. Indeed, they were acting, Caron recalls, as if they had been given a maximum dose of cocaine: They were jumpy, slow to calm down, and, as tests would show, about six times as active as normal animals.

"They were wired, so to speak," Caron says, "and we were totally amazed. It was almost beyond anything that somebody could have reasonably imagined."

What made the behavior so striking is that Caron, a Hughes investigator, and his colleagues had simply tinkered with a small housekeeping gene that in essence mops up after the brain's neurons, or nerve cells, have fired. That such a small genetic manipulation could lead to such large behavioral disturbances accounts for the current lure of research on the genetic bases of such fundamental human behaviors as motor activity and memory.

One of the molecules that has stimulated most research in the Caron lab is a blue-collar protein essential to neuronal well-being: the dopamine transporter, or DAT. DAT functions at the very tip of neurons that secrete dopamine, a neurotransmitter that plays a significant role in motor activity, mood, and cognition. When a nerve impulse travels through a nerve cell and arrives at the synapse (the point of contact between adjacent neurons), it causes a quick burst of dopamine to be released; this chemical flows across the synaptic gap and modulates activity in the adjoining neuron.

The DAT protein wheels into action after all the excitement is over. There is always some excess dopamine floating around in the fluid between nerve cells after a synapse fires, and DAT rapidly siphons it up, transporting it back into the neuron in a process known as "reuptake." Once back inside the neuron, the recovered dopamine is passed along to another protein, which deposits it in holding tanks called vesicles so that the dopamine can be used again.

"We knew these things must be important," Caron says. But researchers didn't know why, and didn't even have a way to find out until some of the genes for transporter proteins were identified and cloned in the late 1980s and early 1990s. That paved the way for the creation of knockout mice lacking DAT, and the results were, in Caron's words, "quite surprising."

Indeed, these results were impossible to ignore. Mice lacking the ability to recycle dopamine act exactly like animals that have been given high doses of psychoactive drugs, especially cocaine and amphetamines.

Even more surprising, the Caron group discovered in 1999 that mice without the Dat gene display several behaviors characteristic of the human condition known as attention deficit hyperactivity disorder, or ADHD, which may affect up to 6 percent of all school-age children. These behaviors include hyperactivity and impaired cognition. The researchers also observed the paradox that, like many ADHD children, the mice respond well to psychostimulant drugs. This calming effect was ultimately traced to another mood-related neurotransmitter, serotonin.

"We've found that transporter proteins play an enormously important role in maintaining the homeostasis of these cells," says Caron. "These mice are extremely hyperactive. They probably represent an interesting model system for neurological and psychological disorders that have been around for a long time, including schizophrenia and ADHD. And the mice become more hyperactive when they are stressed or in a novel situation, which is also reminiscent of the symptoms of ADHD kids."

This research complements what scientists know about a class of psychoactive drugs that affects the reuptake of another important neurotransmitter, serotonin. These drugs, the so-called selective serotonin reuptake inhibitors, or SSRIs, include Prozac and Zoloft. They produce their therapeutic effect by preventing the serotonin transporter protein from effectively mopping up the excess serotonin secreted by a firing nerve cell. In contrast, inhibiting the reuptake of dopamine aggravates behavioral problems.

Caron believes that working on these brain proteins in mice may ultimately lead to treatments for several human diseases that may be caused by disrupted dopamine maintenance, including schizophrenia, Parkinson disease, drug addiction, and an involuntary twitching disorder known as Tourette syndrome. The notion that serotonin may play a role in the treatment of DAT-related disorders makes these knockout mice extremely valuable as models of human diseases. "Prozac is somewhat of a dirty drug," says Caron. "It increases serotonin in the brain, but serotonin can interact with about 15 different receptor subtypes. So that's a dirty intervention. We think the real potential of using mice here is to decipher which of the serotonin receptors might be involved in attention or hyperactivity in our mice. Then we'll go back and ask, "Does this apply to humans?'"

One other line of research being done by Caron's group, together with HHMI investigator Robert Lefkowitz, has implications for human medicine—and it, too, began with a strain of knockout mice. In this case, the mice are engineered to lack the gene for a protein called beta-arrestin-2. This is one of several bucket-brigade-style messenger proteins that dampen some of the signals cascading from the surface of a neuron to its center. The protein is activated when a neurotransmitter such as dopamine or serotonin binds with a specialized receptor on the cell surface.

Fiddling with a single component of this cascade, Caron and his colleagues learned, can dramatically increase the effectiveness of opiate painkillers that act through similar receptors. When a standard dose of morphine is administered to mice lacking the beta-arrestin-2 gene, for example, the analgesic effect is much stronger and lasts much longer. "It really enhanced the potency of morphine severalfold," Caron says, "and it also enhanced the duration of the action." These are important leads toward developing new painkillers and perhaps even better remedies against drug addiction.

— Stephen S. Hall

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Marc Caron's research on brain chemicals in mice may lead to better treatments for mental disorders.

Photo: Scott Dingman

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