The large brown monkeys sat in clear plastic restraining chairs as the drug dripped down through the intravenous tubes.
When it hit their systems, the result was sudden:
They froze, gripping their chairs tightly. They screeched. They wrung their hands, twisted in their seats. Their hearts raced and their adrenalin rose to as much as 10 times its usual level.
The monkeys were feeling a brief version of a disease that afflicts millions of Americans: extreme, crippling anxiety.
The illness is the fifth most common reason people go to the doctor. In its worst forms, it is as disabling as schizophrenia or major depression.
Not long ago, experimenters in Germany put two humans through the same artificial disease state. Where monkeys could only scream, the human subjects could describe their reaction: One spoke of "a strong inner tension, described as a feeling of impending doom." Another "quickly pleaded to be taken off the drug before the experiment was over."
The experiments with the monkeys, conducted a few weeks ago at the National Institute of Mental Health, are important to understanding the basis of such stress-related illnesses as heart disease and ulcers. More than that, they mark a new level of sophistication and power by brain researchers.
What was unusual about the experiment was that it was being induced artificially -- by manipulating, for just a moment, the monkeys' brain chemistry.
These experiments come at the end of nine years of startling BRAIN WAVES PART 2 research in brain chemistry, research that has identified scores of new brain chemicals with powers to affect behavior: Some are powerful controllers of mood and emotion. Some regulate appetite. Some induce sleep and some trigger wakefulness. Some cause pain and some relieve it. Some improve memory and some impair it.
The drug used on the monkeys was a new and unusual one, a sort of anti-Valium. It acts in the same place in the brain as the tranquilizer Valium, but it creates the dark opposite of Valium's mood, a fierce anxiety instead of calm.
And yet another new chemical was able to shut off the disease for the monkeys as instantly as it started.
A few years ago it was not even known that there was such a stress-anxiety system in the brain. Now scientists can turn the system on, turn it off, or adjust it to states in between.
After decades of laborious work devoted to tracking neurons -- the "hard wiring" of the brain -- a whole new terrain has opened to researchers.
It is "like discovering North America," said Jack Barchas of Stanford University. Philip Skolnick of the National Institutes of Health likened it to the opening of space and the appearance of a pantheon of new, unexplained objects and relations. There are scores of newly recognized brain chemicals, and "there may be dozens or even hundreds we haven't identified. Like outer space, this is the great inner space," he said.
These new explorers of the brain are focusing their attention not on the billions of nerve cells that make up the whole brain, but on the spaces between the cells, where they touch and communicate with each other.
The neurons of the brain form complex webs by which we pick up and respond to stimulation from the world. As signals move through brain networks, they must jump from one neuron to another billions of times along the way.
They must pass across tiny spaces, called synapses, that link neuron to neuron. The synapses outnumber the neurons by trillions, because each neuron connects to many others and every connection is a synapse.
"Consciousness, learning, and intelligence are all synapse-dependent," wrote British neuroscientist Steven Rose, "It is not too strong to say that the evolution of humanity followed the evolution of the synapse."
The brain is protected by bone and tissue and liquid cushions, the nerves are wrapped in sheaths and the main nerve cell bodies are wrapped in membranes, but these synapses are open and vulnerable. They are the weak point in the brain's system, the point open to attack by drugs.
As an example of the way the brain networks operate, music entering the ear is transformed into a cascade of pulses spreading along the neural webs. These pulses may enter many brain systems -- where they can be affected by memories, register pleasure or distaste, and perhaps be routed to the brain spot in charge of foot-tapping.
The message is carried through the brain by electrical impulses, gliding down a neuron, jumping to the next neuron, skipping at incredible speed through the brain.
When the electrical impulse reaches the end of each of the billions of neurons, however, it must be changed from an electrical to a chemical signal and passed across that vulnerable synaptic gap.
To do that, the impulse stimulates chemical sacs at the nerve ending. The sacs contain messenger chemicals, called "neurotransmitters", which are squirted out across the gap and land on the membrane of the opposite, receiving neuron.
Here, the transmitter chemical must couple with a "receptor" embedded in the neuron's membrane. The receptor is a uniquely shaped molecule that will not couple with most chemicals, only those that fit its shape, just as a key fits a lock. This prevents false messages, spurious signaling in the synapse.
As a key draws back a bolt, so the transmitter pulls on the receptor molecule and opens a chemical channel to let charged particles into the receiving nerve cell. This buildup of charge quickly becomes a new electrical pulse and is sent up the nerve.
The time expended -- from the moment the impulse arrives at one neural end, through the chemical squirt, the transmitter key finding the receptor lock and the creation of a new pulse -- is about one-thousandth of one second.
This quick but complex action at the synapse is the premier bit of anatomy in brain science, under study in hundreds of laboratories around the world.
It is here that mind drugs act. Alcohol, marijuana, tranquilizers, sleeping pills -- for each drug to have an effect, it must seek and find a receptor. There it can bind, mimicking the natural brain neurotransmitter, or it can interfere with binding.
Drugs may block the normal firing across the synapses by locking up the receptors, or they may enhance the action at the synapse by helping a transmitter bind to the receptor.
An example of one transmitter-receptor pair at work for both good and ill is the chemical called dopamine and its receptor.
In one part of the brain, dopamine is a chemical transmitter that carries nerve signals important in coordinating muscle movements. In the disease called Parkinson's, some cells deteriorate and so fail to send dopamine across the synapses. The result is tremor, spasmodic movement and finally paralysis.
Replacing the missing dopamine transmitter, allowing the nerves to fire more normally, thus can relieve the symptoms of Parkinson's.
Another serious problem arises when there is not too little, but too much dopamine. New evidence indicates that too much dopamine causes an overactive system that is partly to blame for schizophrenia. Drugs that successfully halt schizophrenic symptoms work by blocking dopamine receptors -- in a sense plugging the lock to prevent the key from entering.
Unfortunately, the drug cannot be delivered only to that part of the brain where schizophrenics need less dopamine. It also goes to the part where blocking dopamine causes Parkinson's disease. So, over long periods of use, the drug may relieve one ailment only to induce another -- a sort of false Parkinson's disease called tardive dyskinesia.
Another interesting but more unusual receptor found recently at NIMH is the so-called "angel-dust receptor." Angel dust is the street name of phencyclidine, a drug once used as an anesthetic until it was found that the drug's after-effects can include psychosis. The drug produces symptoms that are almost indistinguishable from schizophrenia.
"A drug that mimicks paranoid schizophrenia is strange," said Candace Pert of NIMH, but even stranger is the idea that, if a receptor for such action exists, then the brain must produce "its own psychotic drug."
Though it is unclear what the function of that natural psychotic drug might be, it is possible that there is a brain system that manages imagination, creativity or dreaming under normal circumstances, but produces psychotic behavior when stimulated by angel dust.
Until 10 years ago, scientists supposed that the brain had a few different chemicals such as dopamine to act as neurotransmitters for all the thousands of discrete brain networks. Because the transmitters really do nothing more than pass or block the signals, there seemed no reason for the brain to create more to carry out such a function.
It was not until 1973 that the truth began to dawn: There are more than 50 and perhaps as many as 300 different chemical transmitters used in the brain.
It was about then that Pert and Solomon Snyder of Johns Hopkins University determined to find the mechanism by which opiates work.
They knew that very tiny amounts of these drugs, which include heroin, morphine and opium, could exert powerful effects in the brain. They believed that this might mean there was a receptor made specifically for the opiates.
Their work was greeted with both excitement and skepticism. Some asked the obvious question: Why would the brain have receptors built in specifically to accept the juice from the flower-pod of the poppy?
The answer to this question is at the heart of 10 years of discoveries in brain chemistry. Since we can't assume the brain made a receptor hoping someone would give it poppy juice, the juice must be an accidental mimic of some natural brain substance that belongs on the receptor.
So, researchers reasoned, the brain must have its own opiate. This substance would operate a brain system designed to relieve pain, possibly even to give a opiate-like high under some circumstances.
The discovery of such a brain system would be profound: It would, for example, offer a simple and elegant explanation for some medical mysteries, such as those soldiers who suffered extreme injuries, but seemed to feel no pain and even for a while experienced some calming detachment from their gruesome surroundings. Perhaps their trauma had triggered a flood of the natural opiate in the brain.
The discovery would also help explain why acupuncture could be a powerful anesthesia. Perhaps using needles to stimulate nerves could release the natural opiate.
Snyder and Pert, as well as John Hughes and Hans Kosterlitz in Scotland a little earlier, soon sought and found the natural opiate, which they called "enkephalin" from the Greek word meaning "in the head." The hypothesis of acupuncture as a stimulator of natural opiates has since been confirmed, and it has been discovered that women experience a release of the natural opiate substance during labor and childbirth.
Further, researchers found that enkephalin receptors exist not only in man, but right down the evolutionary chain through mammals, frogs, even down to the level of insects.
The discovery of the opiate receptor and then the enkephalins were the opening guns in a sudden rush of research. Hundreds of scientists moved from other work and quickly began to expand the same principle to other drugs, receptors and brain systems.
One of the most interesting tales of discovery since has been the one that began with the search for what was called "the brain's own Valium." Again, researchers looked for a receptor and transmitter that would operate some natural system in the brain involved in anxiety and its relief.
By 1977, groups in Denmark and Switzerland had found the so-called "Valium receptor".
As soon as the receptor for these drugs was found, the next obvious thing for scientists to do was find the natural neurotransmitter, the brain's Valium-like substance, that worked on it. But the search for that substance turned out to lead in several directions at once.
Valium-like drugs, called benzodiazepines, are known to have four separate effects: They quiet anxiety. They also relax muscles, and thus are sometimes prescribed to ease the pain of whiplash or similar injuries. They prevent seizures, and so are taken by epileptics. And finally, they cause sedation and sleep, and are used as sleeping pills.
At NIMH, the world's leading research establishment in brain science, researchers found a group of body chemicals called purines that act on what is now called the benzodiazepine receptor. A lab in Europe found another group, beta-carbolines. At St. Elizabeths Hospital, NIMH's Erminio Costa and Alessandro Guidotti found another.
It is now unclear which, if any, of these agents is the real substance used by the body to attach to this receptor.
One further surprise was that some of the substances sought as the natural one to operate on the "Valium receptor" turned out to have just the opposite effect of Valium. Substances found in the brain that bind to the "Valium receptor" are not tranquilizers, but anxiety-producers.
Steven Paul, one of the NIMH psychiatrists working on these receptors, points out that, after some reflection, this seemed quite natural.
Animals need a system that makes them anxious and vigilant, with their systems pumped up and ready to act. Man, too, needs such a system, and it is only in recent millenia that man's anxiety system may be triggered more often by social hazards than physical ones.
With the discovery of the anxiety system and drugs that act on it, and some chemical details of how that action occurs, NIMH's Paul says, "For the first time, we may have a reasonable understanding of the biochemistry of anxiety. This understanding has enormous implications for the study and prevention of stress-related disorders such as ulcers and heart disease."
Because Valium and other tranquilizers act not only to curb anxiety, but also to induce sleep, relax muscles and prevent seizures, researchers have begun to check the properties of such brain chemicals as beta-carbolines to see if they reverse these other effects of Valium as well.
Wallace Mendelson and Paul at NIMH experimented with beta-carboline and sleep. "Here is a drug that has several effects that are opposite of the benzodizepines. So we wondered, if the benzodiazepines put you to sleep, will this drug wake you up?"
They found that the more of the drug taken, the longer it took animals to get to sleep and the shorter their total sleep time was.
"One lesson here is that maybe this receptor has a physiological role in controlling sleep. The other lesson is that maybe these chemicals would be useful drugs for people with disorders in which they get too much sleep. In a case study of 5,000 patients at sleep centers around the country, the most common problem among them was not, as you might think, insomnia. The single most common problem was diseases that made them sleep too much such as narcolepsy," Mendelson said.
Such a drug might also be efficient enough an arouser to replace caffeine or other wake-up drugs. (Caffeine is already known to block a receptor related to the one affected by Valium.)
Perhaps most fascinating of all, Mendelson found a substance whose effect is neither to cause sleep or wakefulness completely. It causes something in between, a new and unusual state of mind, which as yet has no name.
In mice, the drug quieted the animals. They stopped running around and sat largely immobile. But they were not sleepy, they were in fact more alert than normal.
"This seems a little paradoxical because people are used to the idea of drugs that will slow you down and put you to sleep. But this study shows that these things are separable. They induce a state of quiet wakefulness," Mendelson said.
A drug to induce such a state might be very useful to quiet agitated people such as schizophrenics gently, without putting them to sleep or giving them the drawn, pale "mask" of sedation that sometimes accompanies use of anti-schizophrenic drugs.
In brain chemistry, the distance between research and application is very short. The substances studied in the brain are themselves drugs, and so the compounds in the lab can make their way quickly to the drug companies.
There, they are transformed from exciting intellectual problems to substances of social use and concern.
NEXT: A cornucopia of chemicals