Newly Found Target In Brain May Lead To Novel Parkinson's Disease Therapies

Their preliminary findings suggest that blocking the activity of a specific class of receptors in the brain area responsible for muscle movement could eventually help patients in the later stages of Parkinson's, when traditional medication fails and begins to cause debilitating side effects.

Yoland Smith, Ph.D., will describe his discovery of the location of these receptors at the Sixth Triennial Meeting of the International Basal Ganglia Society in Brewster Mass., on October 16. Dr. Smith's mapping and characterization of the receptors lends new hope to finding a combination therapy that might make smaller doses of L-dopa work longer without side effects.

Parkinson's disease results from a deficiency of the neurotransmitter dopamine in a group of brain structures called the basal ganglia, a network of neurons which controls movement. Symptoms include stooped posture, tremors, rigidity of movement and even periodic "freezing" of muscles, making movement impossible. Taken several times a day, L-dopa restores dopamine levels and the ability to move more freely with less trembling and rigidity. But L-dopa remains effective only for a period of a few years. After that, the drug loses its potency and begins to cause severe side effects, such as jerky, involuntary movements called dyskinesia. For some patients, the side effects are so severe they cannot sit still, walk, or hold a utensil. Thus, the social and economic costs of the disease are high, especially because people often live with the disease for 10 to 20 years.

In a normal brain, neurons release a common neurotransmitter called glutamate. It is abundant throughout the brain, playing a role in communication between the various types of neurons. Without glutamate, the brain would seize up and cease to function. Researchers have determined over the past few years that for Parkinson's patients, insufficient levels of dopamine induce one tiny group of cells in the basal ganglia, called the subthalamic nucleus, to dramatically increase their activity. This hyperactivity means they produce extra glutamate -- so much that it overloads the glutamate receptors. Scientists believe that this extra glutamate causes the movement problems in Parkinson's; in fact, in both animals and humans, a small lesion made in the subthalamic nucleus can abolish most of the symptoms of the disease. However, not all Parkinson's patients are good candidates for this procedure. It is also invasive and expensive, making it unavailable for many people.

"So theoretically, a drug that blocks the activity of glutamate released from neurons in the subthalamic nucleus should have the same beneficial effects as the surgery," says Dr. Smith. "However, because glutamate is vital everywhere in the brain, the trick is to block it only in the areas where there's too much."

There are two different types of glutamate receptors in the brain. One type mediates rapid neuronal communication. Earlier efforts to target those cells in Parkinson's disease animal models adversely affected glutamate throughout the entire brain. The second type of glutamate receptor, recently discovered, mediates the slow communication between neurons. These are called metabotropic receptors. "We've just started having some success in finding where they are in the basal ganglia and what they do," says Smith.

Glutamate is released at a synapse, a very short gap between two neurons which allows them to communicate. Usually receptors involved in fast glutamate activity are found in the center of the synapse. "However," Dr. Smith explains, "we found that the metabotropic receptors are located not in the center of the synapse, but on its distant edge." Since the receptor is relatively far from the site of glutamate release, a large amount of glutamate is needed to jump the gap. In a normal brain, the need to jump the gap for slow communication is not constant, required only at certain times. In Parkinson's disease, the overflow of glutamate remains constant and floods the receptors. This suggests that these receptors are likely targets for treating Parkinson's disease.

Dr. Smith hopes next to identify highly specific drugs that will selectively block only these slow-communication receptors in the subthalamic nucleus. "Blocking them could help change the glutamate transmission from subthalamic neurons without affecting the whole brain's activity," he said.

To locate the metabotropic receptors, Dr. Smith uses a technique called immunocythochemistry in which antibodies labeled with gold particles bind to the receptors. Using an electron microscope, the "labeled" receptors show up in gold, creating a map of every synapse where the receptors are found. Using this technique, Dr. Smith and his colleagues have mapped the brains of rats and monkeys to find where those metabotropic receptors are located.

Other studies being reported from Dr. Smith's laboratory at this meeting involve defining the location of these receptors in other parts of the basal ganglia, to aid in understanding their basic functioning in the normal brain.

These studies are funded by grants from the National Institutes of Health and the American Parkinson's Disease Association. Dr. Smith is part of a multi-disciplinary research team developing novel pharmacological and surgical therapies for Parkinson's disease.

The Yerkes Primate Center is part of the Woodruff Health Sciences Center of Emory University, and is the oldest scientific institute in the world dedicated to primate research. Its programs cover a wide range of biomedical and behavioral sciences.