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Biologists ponder how molecules, cells interact to turn mind upside down

By Tom Siegfried and Sue Goetinck

The mind is a universe unto itself.

Planets, stars and galaxies compose the cosmos; atoms, molecules and cells make the mind. Coincidentally, the number of galaxies in the universe if about the same as the number of nerve cells in the brain, 100 billion or so.

The difference is galaxies are isolated islands of stars, while the cells of the mind reach out and touch one another, constantly signaling back and forth, forming networks more elaborate than the World Wide Web.

And in the universe at large, things rarely go wrong. An occasional asteroid might wipe out a planet, and starts blow up now and then, but for the most part galaxies and their stars spin steadily through space for eons.

The brain is more like the Internet. Just as clogged phone lines or misrouted signals can slow down or lock up a computer, misplaced molecules and malfunctioning nerve cells can slow down, confuse or lock up the mind.

Disorders of thought and emotion have perplexed medical scientists for centuries. Only half a century ago, few scientists understood that mental disorders reflected faulty brain chemistry. Today, the molecular basis of mental illness is as well-established as Copernican astronomy. But just Copernicus didn't really know how the planets orbited the sun, biologists don't yet know exactly how the interactions of molecules and cells turn a normal mind into a mental nightmare.

"Anybody who's interested in serious mental illness must recognize that we have to know more about every aspect of the brain," says Samuel Barondes, a psychiatrist at the University of California, San Francisco.

Nevertheless, neuroscientists have already found out a lot, though far from everything, about the molecules that mastermind normal behavior and what goes wrong with them in mental illness. Abundant research shows that mental disorders stem from chemical glitches in the brain's complicated network for signaling between nerve cells.

Drugs treat, probe

The first and best evidence that chemistry controls mental illness was the discovery that chemicals can treat it. In the 1950s ant-ipsychotic drugs showed clearly that certain chemicals altered aberrant mental behavior for the better, although nobody knew how. But studying those drugs turned out to be a good way to get clues.

"Drugs are not only treatments," says Steven Hyman, director of the National Institute of Mental Health. "They're also probes into how the brain works."

Drugs that treat the psychotic symptoms of schizophrenia block the action of the chemical dopamine, for example. Most drugs for depression affect brain levels of serotonin, norepinephrine or both, implicating those chemicals in mood problems.

Those chemicals - and dozens of others - are the brain's messenger molecules, known technically as neurotransmitters. Nerve cells communicate by squirting those chemicals on one another.

"Understanding the brain begins with determining which chemicals a nerve cell will make and which chemicals it will respond to," says Floyd Bloom, a neuroscientist at the Scripps Clinic and Research Foundation in La Jolla, Calif.

A nerve cell manufactures its messenger chemicals and then stores them near the end of its axon, a long tubular tentacle extending from the cell's body like an octopus arm.

When a nerve cell "fires," an electrical signal zips down the axon to its tip. There packets of the messenger molecules are released at the interface, or synapse, with another cell.

To receive such chemical signals, the receiving nerve cell needs molecular "antennae" called receptors. Receptors are intricate protein molecules that protrude through the receiving cell's outer membrane. Arrival of a messenger molecule at a receptor outside the cell induces the receptor to change its shape, a signal to the inside of the cell that the messenger has arrived.

A given messenger molecule - say, dopamine - can stimulate several different receptors (five types of dopamine receptors are known). But in general, a dopamine receptor responds only to dopamine. It's as if a receiving nerve cell has hands wearing different kinds of gloves - some kinds shaped to catch only baseballs, others shaped only for footballs. But more than one kind of glove can catch a given ball. Just as a catcher's mitt or first baseman's glove could both catch baseballs, a nerve cell can catch dopamine with different versions of dopamine receptors.

Chemical carriers

Of course, the brain is much more complicated. Instead of just two balls, more than 100 different chemicals can carry a message.

On top of that, any given nerve cell receives thousands of inputs. A cell decides what to do based not on any one message, but from the combined effect of thousands. And nerve cells don't act alone, but as parts of interconnected circuits.

"When you think about that level of complexity - which of course is not surprising, given the remarkable things we can do and feel - you recognize the task we've set for ourselves," Hyman said.

Adding therapeutic drugs makes the situation even more complicated.

"We are really just at the beginnings of understanding what these long-term processes are by which the antidepressant or anti-psychotic drugs or lithium works," said Hyman, a molecular neurobiologist.

He said he thinks clues to this delayed-action effect might come from the study of addictive drugs, which also produce long-term symptoms in addition to the immediate high.

When exposed to any drug, the brain adapts, changing its chemistry in an attempt to regain its usual chemical balance. Such changes explain why a drug abuser often needs higher an higher doses to get the pleasurable effect.

Similar changes in the brain explain the delay in the beneficial effects of treatment drugs for mental illness. It's much like building muscles by lifting weights, Hyman says. Daily weight lifting induces muscle cells to produce more proteins, building muscles. In a mental patient treated with drugs, brain cells respond by making more or less of various proteins, such as receptor molecules.

"Lifting weights for enough weeks or months is the same as taking your medication for enough weeks or months to treat the depression or psychotic symptoms," Hyman said.

Studies of abused drugs also provide clues about the role of dopamine in schizophrenia. Psychotic symptoms similar to those in schizophrenia are produced by some drugs of abuse, notable cocaine, which disables the system that clears dopamine out of synapses.

In any event, there is much more to be learned about the molecules of the brain, and even then a complete molecular picture would be only a small part of the whole story of mental illness. Studies with drugs may identify faulty wiring, but may not reveal what cause those flaws.

©1996, Dallas Morning News

Modified February 19, 2003