That electric feeling  pg. 4

The role of these genes in ADHD also is supported by studies of “knockout” mice, in which the genes have been altered so the proteins they encode do not function properly. Pioneering studies by Marc Caron, Ph.D., and his colleagues at Duke University, for example, have shown that disruption of the gene for the dopamine transporter in mice results in hyperactivity when they’re put in a novel environment.

The mice also “have a lot of problems in learning and memory tests,” says Caron, James B. Duke Professor of Cell Biology. When put in an eight-arm radial maze with a sweet breakfast cereal at the end of some of the arms, the knockout mice have a harder time finding the treat, compared to normal mice. “They keep going back to the same arm they’ve just been in,” he said. “They don’t learn.”

What was most surprising, however, was that when the knockout mice were given methylphenidate, they became less hyperactive and their cognitive skills improved. This finding challenged the conventional wisdom that the drug acts through the dopamine transporter to increase the brain’s supply of dopamine. Knockout mice didn’t have a functional transporter, and methylphenidate didn’t boost their dopamine levels. Yet the drug still calmed them.

The Prozac clue

Caron believes serotonin may be involved. In a 1999 study, he and his colleagues reported that the antidepressant Prozac, which blocks the serotonin transporter, reduced hyperactivity in mice with the “knocked out” dopamine transporter. So did L-tryptophan, the amino acid from which serotonin is synthesized. Both agents boost serotonin levels.

Mice are not humans, Caron cautions. In human studies, for example, Prozac has not been found to be effective in relieving symptoms of ADHD. But the mouse model suggests that ADHD is more than a dysfunction of the dopamine system. “My guess is that it’s probably 20, 30 or 50 genes that are involved in modulating pathways in the brain that could give you symptoms of ADHD,” he says. “It’s probably an imbalance between neurotransmitter systems.”

Randy Blakely, Ph.D., director of the Center for Molecular Neuroscience and Allan D. Bass Professor of Pharmacology at Vanderbilt, agrees that a lack of dopamine by itself cannot explain ADHD. There is evidence that norepinephrine is involved, he says.

For one thing, a new ADHD drug, Strattera, blocks the norepinephrine transporter, and seems to be particularly good at improving attention. Another clue, discovered recently at Vanderbilt, is the link between a mutation in the norepinephrine transporter and attentional problems in children and adults.

In the early 1990s, Blakely and his colleagues at Yale and Emory were the first to clone the genes that encode the norepinephrine and serotonin transporters. The identification of these genetic sequences, coupled with automated, high throughput screening techniques for evaluating them, has speeded the search for new drugs that may affect the function of the transporter proteins. These methods also are aiding the search for mutations in transporter genes, or variations in those genes that might be associated with a greater risk for disease.

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