By John J. Fried
AROUND THE WORLD, scientists are in hot pursuit of the secrets of chemicals called neurotransmitters. These substances, found in the nervous systems of all living things, transmit messages from one nerve cell to another. The chase is intense because many researchers are convinced that neurotransmitters hold a major key to our understanding of the human brain and of a host of body disturbances ranging from cardiovascular disease to mental illness.
Neurotransmitters are not new to scientists; the concept of neurotransmission was introduced more than 80 years ago. But because they work so fast-some within a thousandth of a second-and then disappear, they are hard to study. Also, they are present only in miniscule amounts. “Trying to find a neurotransmitter in tissue,” said Dr. Donald Jenden, chairman of the department of pharmacology at the University of California at Los Angeles Medical School. “is like trying to find a pinch of salt dissolved in a swimming pool.”
Within the last decade, however, neurobiologists have made major advances in research techniques. They found, for example, that they could mark some neurotransmitters with radioactivity, then race them with a Geiger counter. And they discovered that at least three chemicals found in brain tissue-dopamine, serotonin and norepinephrine-if mixed with a form of formaldehyde and then exposed to ultraviolet light will shine brightly under a microscope. Dopamine and norepinephrine shine green; serotonin, yellow.
The known neurotransmitters-scientists are convinced that many others are yet to be found-have themselves turned into important research tools used to map nerve pathways in the brain. One green trail of norepinephrine has outlined a group of nerve cells in the hypothalamus, that part of the brain where hunger, thirst, body temperature and blood pressure are governed. A track taken by dopamine has defined a nerve-cell grouping in the brain where, among other functions, body movements are regulated. Serotonin’s yellow trail has outlined a brain area that apparently rules sleep and wakefulness.
Start or Stop. The growing understanding of neurotransmitters has also altered scientific understanding of how messages are transmitted from one nerve cell to the next. Individual nerve cells are actually composed of a central cell body from which extend several fibers known as axons and dendrites. These fibers do not actually touch, but come close to each other at an area between them called the synapse.
Until they began to unravel neurotransmitter mysteries, scientists believed that nerve messages were carried by electrical impulses that traveled down one nerve fiber and then jumped across the synapse to another fiber. Now they have learned that the electrical impulse travels only to the end of the nerve fiber. There, it stimulates small sac-like structures that contain the specific neurotransmitter associated with that particular nerve. The sacs release the transmitter; the transmitter crosses the synapse and acts on the adjacent nerve fiber. The neurotransmitter bears only one of two messages; start or stop. To bend an arm for example a neurotransmitter coming from a nerve whose origin is in the spinal cord tells the biceps muscle of the arm to contract and also orders the triceps muscle to relax.
In most cases, once the neurotransmitter has done its job, it is taken back up by the sacs that released it-presumably for recycling. There, it waits for the next electrical impulse to release it once more.
Dr. Samuel Barondes, professor of psychiatry at the University of California at San Diego and two former colleagues, Werner Schlapfer and Paul Woodson, found that the mechanism controlling the release of neurotransmitters has a “memory,” Working with the central nervous system of a sea snail, they discovered that if one of the snail’s large nerves is repeatedly stimulated, that nerve cell will increase its output of its neurotransmitter, acetylcholine. If the stimulations are stopped for a while and then started up again, the cell “remembers” the earlier stimulations and responds by emitting an even larger measure of acetylcholine. The nerve cell, Dr. Barondes says, may “remember” for hours that it should release more acetylcholine. But if the nerve cell is given dopamine, serotorun or alcohol experimentally, its “memory” span is dramatically shortened.
Because many basic neurological processes in a sea snail and in a human being are the same, the implication of this research is that other neurotransmitters can alter the durability of human memory- and that alcohol may have the same effect. “In time,” said Dr. Barondes, “our work may allow us to understand how alcohol interferes with the most basic neuro-logical processes in the human brain. We may also be able to learn how memory works-and how to sharpen it.”
Natural Painkillers? Theoretically, nerve cells that are tightly knit, as in the brain, can receive neurotransmitters from hundreds of other cells. Of course, if a nerve cell tried to respond to every different message, it would get contradictory instructions. What prevents such confusion?
Within the last few years, scientists have isolated so-called nerve-cell “receptors”-actually tiny specks of protein – which act as terminals for incoming neurotransmitters. A nerve cell will respond to a particular neurotransmitter only if it has the proper receptor for it.
Not too long ago researchers discovered the first nerve-cell receptors that would accept only chemicals that resemble morphine and heroin. It was a breathtaking finding. Because the body does not manufacture opiates, it implied that other nerve cells were producing a previously unknown neurotransmitter. And, because the receptors were found in pain-perception areas of the brain, this theoretical transmitter must play an important role in how we react to pain.
Recently the opiate-like transmitter, called enkephalin, was found. Its discovery will have almost immediate applications. People who suffer severe, long-lasting pain must now take addicting drugs such as morphine. But because, for the first time, researchers are learning how the brain may regulate the perception of pain, this knowledge of a natural pain regulator-enkephalin-will open up exciting new approaches to therapeutic drugs.
“Some drugs used in the treatment of disease,” said Dr. John Bevan of the U.C.L.A. Medical School, “would never have been developed had we not come to understand the function of neurotransmitters.” For instance, scientists now know that the neurotransmitter norepinephrine governs the constriction of the body’s blood vessels and plays an important role in the maintenance of blood pressure. Researchers also developed alpha-methyl-dopa, a compound which the body changes to a substance that acts as a “false” neurotransmitter in that it epinephrine, is stored in some of the same cells as those containing norepinephrine. By acting on a norepinephrine receptor in the brain, its release reduces the blood pressure.
Dopamine Drain. Research into neurotransmitters has also had a substantial impact on Parkinson’s disease. Between 1957 and 1959, Arvid Carlsson, a Swedish pharmacologist, investigated the role of dopamine in the brain, specifically the fact that experimental animals fed the drug reserpine developed symptoms similar to those suffered by Parkinson’s victims. When he studied the brains of reserpine-fed rabbits, rats and mice, Carlsson found that the striatum, a part of the brain important in the control of movements, was nearly drained of dopamine. If he gave dopa, a compound used by the body to make dopamine, the symptoms stopped.
Hearing of Carlsson’s work, Dr. Oleh Hornykiewicz of the University of Vienna decided to measure the dopamine content of brains of patients who had died of Parkinson’s disease. In them, he found that the striatum was also virtually drained of dopamine. In the early 1960s, the late Dr. George C. Cotzias and his colleagues, using a form of dopa known as L-dopa, worked out a therapy to correct the dopamine imbalance in the brains of Parkinson’s disease victims.
Neurotransmitter research eventually may help doctors mitigate the often crippling results of stroke. In a series of experiments, Dr. Richard Wurtman of M.I.T. and Dr. Nicholas Zervas of Beth Israel Hospital and Harvard Medical school induced strokes in gerbils and monkeys. When they autopsied the animals, they found that the dopamine levels in the area of the vrain where the stoke had been induced were drastically reduced. Because dopamine is essential to proper muscle use and because so many patients often have trouble coordinating their body movements after a stroke, the researchers believe that dopamine levels are also reduced in patients after stroke.
According to Dr. Wurtman, dopamine levels plummet in the area where the stroke has occurred because the dopamine-containing nerve cels die during the attack, allowing their load of neurotransmitter to escape into adjacent parts of the brain. The unrestricted flood of dopamine may be directly responsible for the death of some stroke patients. “Dopamine constricts the blood vessels in adjacent parts of the brain,” Dr. Wurtman says. “That denies them their share of blood and oxygen.”
Key to Mental Illness? Dopamine is also getting considerable attention from scientists interested in solving the riddle of schizophrenia. Under experimental situations, researchers have found that high doses of amphetamine can cause some of the same bizarre behavior often seen in schizophrenics. Work with animal brains have shown that amphetamines stimulate the release of dopamine from nerves, thus activating dopamine receptors. And one of the actions of some of the drugs that best relieve symptoms of schizophrenia is to block dopamine receptors in the brain. These and other findings, believes Dr. Julius Axelrod, who won a Nobel Prize for his work with neurotransmitters, “point to the involvement of the doapmi-nergic nerves in schizophrenia.”
According to enkephalin researcher Solomon Snyder of Johns Hopkins Medical School, that newly discovered neurotransmitter may also be involved with mental illness. “it may be,” says Dr. Snyder, “that our enkephalin systems medicate the way we react emotionally to psychologically painful things.” Thus, any abnormality in the neurotransmitter may lead to abnormalities in the way we interpret the world around us. What may be a minor slight to one person, for example, may become a deeply insulting offense to someone whose “pain” circuit is out of balance.
Researchers warn that they do not know enough yet to promise simple cures for psychiatric afflictions. But in one experiment they have shown that decreased norepinephrine transmission lowers animals’ ability to perceive pleasure while enhanced norepinephrine transmission increases their ability to derive pleasure. Thus, at least theoretically, problems in the pleasure circuits may also lead to psychiatric disturbances. “A lot of mental illnesses,” says one researcher, “may be caused by an inability to experience enough pleasureful rewards.”
Many researchers believe that understanding of neurotransmitters may profoundly affect human life. “In time, a few simple applications may help us affect our emotional states and our ability to learn,” says Dr. Eugene Roberts, a leading scientist who works at the City of Hope, a pilot medical center in Duarte, Calif. “Neurotransmitter techniques may allow us to help the human brain to achieve its maximum potential.”