NARSAD-Supported Researchers Win Nobel Prize in Medicine in 2000

Not just one, but all three of this year's Nobel Laureates in Medicine or Physiology have close links with NARSAD-Arvid Carlsson received NARSAD's Lieber Prize in 1994, Paul Greengard was awarded a Distinguished Investigator grant in 1992 and the Lieber Prize in 1996, and Eric Kandel won Distinguished Investigator grants in 1995 and 2000.

Their work laid the foundation for modern neuroscience, and with NARSAD's assistance, is leading to a growing understanding of the biological basis of mental disorders. Drs. Greengard and Kandel both serve on NARSAD's Scientific Council, which helps select grantees and find areas of research which deserve greater recognition and funding.

Discovering Dopamine as a Neurotransmitter
Arvid Carlsson, M.D., now Professor and Chairman of the Department of Pharmacology at the University of Gothenburg in Sweden, discovered in the 1950's that dopamine acts as a neurotransmitter in the brain, sending signals from one cell to another. Previously, researchers had believed that dopamine was just a precursor to the transmitter norepinephrine and not a neurotransmitter itself. Much of what we know about how the brain works comes from the study of these chemicals and what happens when they are out of balance.

To test his hypothesis, Dr. Carlsson injected a drug called reserpine, which depletes both norepinephrine and dopamine, into rabbits. This caused the rabbits to "freeze" and become incapable of initiating voluntary movement. L-Dopa, the chemical from which the brain synthesizes dopamine, could reverse this effect.

If dopamine had to be made into norepinephrine to allow the rabbits to move again, Dr. Carlsson should have found increased norepinephrine in their brains after they recovered. Instead, he found only dopamine, proving that, as he had theorized, this was the chemical responsible for their behavior.

Awakenings
Dr. Carlsson then made another important observation. He noticed that the symptoms displayed by the "frozen" rabbits were similar to those of patients with advanced Parkinson's disease - a neurological illness which causes movement disorders. Some Parkinson's patients, like the rabbits, were paralyzed in rigid postures, sometimes for years; others couldn't stop themselves from performing rapid, meaningless gestures.

In human trials, L-Dopa transformed many with the illness-allowing those who had become living statues to move freely again and helping others to control their tics. Their story is probably best known to the public through Robert DeNiro's Oscar-nominated portrayal of one patient, in the 1990 film based on neurologist Oliver Sacks' best-selling book, Awakenings.

Unfortunately, because Parkinsonism can be progressive and because of brain feedback mechanisms, L-Dopa's effect can wear off. Nonetheless, it has been crucial to clarifying the pathology of the disease and is still an important tool for treatment.

Dr. Carlsson's discovery led to an understanding that Parkinsonism results from the death of dopamine neurons in the substantia nigra and that dopamine is a key neurotransmitter involved with motivation-literally the ability to decide to start or stop moving.

The Dopamine Hypothesis of Schizophrenia
But Dr. Carlsson's pioneering work on dopamine didn't end there. He showed that drugs used to treat schizophrenia work by blocking dopamine signals-preventing dopamine from activating receptors on the cells that would normally receive messages from dopamine neurons.

This illustrated that schizophrenia, at least in part, is a problem related to too much dopamine; whereas Parkinsonism is caused by too little. Hallucinations and paranoia may be related to excesses of this transmitter, which is also released in high doses in those who suffer psychosis related to cocaine or amphetamine use.

The fact that many anti-schizophrenic drugs can cause movement disorders completes the connection. What happens here is that the blockade of dopamine is so strong that there is not enough active dopamine to properly control movement, just as in Parkinson's disease.

The "dopamine hypothesis of schizophrenia," which posits that schizophrenia results from too much dopamine and which has been one of the most fruitful ideas in schizophrenia research, was developed by Dr. Carlsson following his dopamine receptor experiments in 1963.

Dr. Carlsson received the Lieber Prize for Outstanding Research in Schizophrenia in 1994, for his work on dopamine and in establishing that tricyclic antidepressants affect the neurotransmitter serotonin. He also developed the first selective serotonin re-uptake inhibitor antidepressant, zimeldene-the first of the family of drugs which includes Prozac.

Upon receiving the prize, Dr. Carlsson remarked, "The Lieber Prize serves a purpose far beyond making the awardees happy. First of all, it serves to focus on schizophrenia as an important target for research. Secondly, thanks to the careful work of the selection panel, this research field is being continuously analyzed in order to identify those areas and those achievements that appear especially important for the progress of the field."

The Second Messenger
Paul Greengard's work began to explore the next phase of neural signaling: what happens to a cell after a transmitter fits into one of its receptors. For years, his research was scorned because this was not believed to be a particularly fruitful or interesting area.

At a news conference held after he received his prize, Dr. Greengard, a Ph.D. who is currently the Vincent Astor Professor and director of the Laboratory of Cellular and Molecular Neuroscience at Rockefeller University, joked "We worked on this for many years without competition because people thought we were insane."

Dr. Greengard persisted nonetheless and, as a result, made important discoveries. When a neurotransmitter acts after crossing a synapse, it sets off a complex chain of what are called "second messengers" and these messengers affect various proteins by switching on chemicals called protein kinases, which then add or remove a phosphate group to the proteins. This changes the shape of the proteins, which in turn changes the electrochemical properties of the cell.

Working with Dr. Eric Kandel, Dr. Greengard demonstrated that this phosphorylation is crucial to the effects of neurotransmitters on a cell. Using just the protein kinases that would have normally been activated by transmitters, Drs. Kandel and Greengard were able to prompt the cells to respond as though they'd received the transmitter. This showed that the kinases were an important link in the chain of events by which neurotransmitters send their messages.

Learning, Memory and Sea Slugs
Dr. Eric Kandel's work has taken him in a different direction. Rather than focusing on the effects of various neurotransmitters, he became interested in understanding how the process of learning itself takes place. Dr. Kandel, an M.D., is currently University Pro-fessor and Senior Investigator at the Howard Hughes Medical Institute, Center of Neurobiology and Behavior at Columbia University.

Anyone who has studied neuroscience hears the name Kandel and thinks of sea slugs. This is not an insult: the Aplysia slug is famous for having gigantic neurons and Dr. Kandel's classic research involved recording their output and determining how outside events changed them.

Aplysia don't do very much- but they do respond to painful or novel sensations by attempting to protect their gills. Dr. Kandel found that after Aplysia received a large shock, they would respond for days or even weeks afterwards by withdrawing their gills more quickly. This change was reflected in their neurons by an increase in neurotransmitter release in the cells connecting the sensory neurons to the muscle neurons which moved the gill. The increased neurotransmitter action would then trigger the second messenger system to change the shape and phosphorylation of proteins. Ultimately, this would result in the production of new proteins which altered the sensory neurons' sensitivity to stimulation.

Smaller shocks would result in less transmitter action and a more short-lived response that affected second messengers but did not spur the synthesis of new proteins.

Dr. Kandel was thus the first to connect short and long term memory to measurable physiological changes in nerve cells. Without understanding the biological bases of learning and memory, of course, there is little chance of understanding much about the brain at all-let alone about what goes wrong in mental illness.

Fear and Loathing in the Amygdala
NARSAD funding has allowed Dr. Kandel to expand his work in two crucial directions. One was the discovery of a novel mechanism for long-term memory storage in a brain area called the amygdala; the other was the development of genetic techniques to study the effects of particular proteins by preventing the expression of the genes that make them. This allows researchers to pinpoint the connection between a protein or transmitter in a particular area and the behavior it is linked with by watching what happens when it is not available.

This year, Dr. Kandel received a Distinguished Investigator grant from NARSAD to study the proteins and genes involved in the development of anxiety and fear. The amygdala is crucial to the experience of fear: animals or humans who have had this area removed or obliterated by a tumor can be inappropriately fearless. Since many mental disorders involve the opposite problem-too much fear and anxiety- understanding how this area processes fearful events could lead to treatments for conditions like depression, anxiety disorders, post-traumatic stress disorder and schizophrenia.

By funding and rewarding the most important figures in neuroscience-and by helping promising researchers start their careers and advance within the field-NARSAD is having a tremendous impact on the direction and speed of progress in the understanding of mental illness. This year's Nobelists aren't even the first NARSAD-affiliated researchers to win the top prize in science. That honor went to the current Honorary Chairman of the Scientific Council, Julius Axelrod, in 1970. With your support, we can continue to ensure that the best scientists have the resources they need to move as quickly as possible toward cures.

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