A HELPFUL STREET DRUG

PCP is a scourge, but it also holds promise for new treatments of
schizophrenia

In the early 1960s, emergency room doctors and psychiatrists in California
and New York noticed an alarming jump in young people with symptoms of
schizophrenia turning up in hospitals. Wild-eyed and agitated, drooling,
often hallucinating, the patients sometimes had to be strapped to beds until
they calmed down.

Before long, the source of the "epidemic" was tracked down to a white pill,
known on the streets as the PeaCePill, or angel dust, known to chemists as
phencyclidine, or PCP."

It creates a duplicate syndrome to schizophrenia," explains Jim Kennedy,
head of neurogenetics at the Centre for Addiction and Mental Health in
Toronto.

To scientists, PCP has become a valuable clue to mental disease. They hope
they can use their knowledge of how PCP works on the brain to help unravel,
and ultimately treat, schizophrenia.

The stakes are huge. Close to 1% of the world's population suffers from
schizophrenia. The disease costs Canada's health system about $4.5-billion a
year.

While medications help, they often have troubling side effects that lead
patients to quit taking them. In the late 1980s, researchers discovered PCP
and its chemical cousin, ketamine, affect brain cell communication by
blocking molecules called NMDA receptors. A new theory of schizophrenia was
born."

"Ketamine and PCP have been heralded as psychotogenic ... and so the NMDA
school of thought says these two street drugs make people crazy temporarily,
and maybe that's the basis of psychosis in schizophrenia," says Philip
Seeman, professor emeritus of neuropharmacology at the University of
Toronto.

Receptors are proteins on the surface of brain cells that ferry chemical
signals around the brain. NMDA receptors are important for normal
cell-to-cell communication and also for cell death. Scientists believe
schizophrenia -- like PCP -- may interfere with the function of the NMDA
receptors.

However, the theory faces a big obstacle. A different set of
neurotransmitters, known as the dopamine system, also plays a pivotal role
in schizophrenia. Dopamine is essential for movement, learning, attention
and memory. And in 1974, Dr. Seeman discovered a dopamine receptor called D2
is important in hallucinations. People with schizophrenia have elevated D2
activity.

"If you want delusions, you have to look at [the dopamine system]," Dr.
Seeman says.

Since his discovery, most drugs used to treat schizophrenia, such as
clozapine and quetiapine, have acted to dampen the urgent activity of the
dopamine system. But the dopamine theory has a few important shortcomings.
An excess of dopamine can explain the "positive" symptoms of schizophrenia,
such as hallucinations, delusions, disorganization of thought and bizarre
behavior. However, it cannot explain the "negative" symptoms, which include
loss of motivation, stunted emotional range, poverty of speech and reduced
ability to feel pleasure.

Not surprisingly, dopamine-based drug treatments are not as effective for
negative symptoms. Early studies show substances that boost NMDA activity,
such as glycine, may ease these negative symptoms much better.

The two theories have pitted psychiatric researchers against one another,
with patients and their families not knowing which camp to believe.

Now, a team of Toronto researchers has discovered a "missing link" that may
bridge the two theories.

"We found two pathways between [dopamine] and NMDA receptors," says lead
researcher Fang Liu, an assistant professor at the University of Toronto's
Department of Psychiatry.

The study, published today in the journal Cell, sheds new light on schizophr
enia and could lead to new treatments to prevent brain damage from epilepsy
and stroke.

By studying neurons in cell culture, Dr. Liu's team found two parts of the
D1 dopamine receptor can bind to two subunits of the NMDA receptor.

It's like "each of them has a left hand and a right hand, with two sides,"
explains Dr. Kennedy. "So if the right hand of the dopamine receptor shakes
hands with the right hand of the NMDA receptor, that is a normal kind of
handshake and that leads to normal transmission of signals across from one
cell to the next.

"But if the left hand of the dopamine receptor shakes hands with the left
hand of the NMDA receptor, then you can get bad effects. The NMDA receptor
fires too much and it causes too much overstimulation of the cell and the
cell can die. So you've got the good, normal handshake and you've got the
potential for the toxic handshake. Not only do these two receptors link to
each other directly, but they can link to each other in two different ways."

This findings means scientists can now design new treatments for the toxic
handshake.

For example, when people suffer a stroke, the brain is deprived of oxygen
and cells begin to die. One of the NMDA system's two main functions is to
transmit these death signals. The other is to carry on normal cell-to-cell
communication.

"When you have cell death, you try to shut down NMDA function," Dr. Liu
says. "But this also prevents normal communication and shuts down the
brain."

The beauty of working through the D1 receptor is that it may be possible to
block the toxic handshake with the NMDA receptor, preventing cell death
without shutting down the brain. A drug that performed this feat could
prevent the devastating loss of brain cells from strokes, epilepsy and other
brain traumas..

The discovery could also lead to an understanding of how schizophrenia is
caused.

One speculation is that the D1 receptor "primes" the NMDA system to keep
firing, keeping it in good shape, like muscles that need to be kept toned
and ready for activity. This effect is only harmful when it gets too revved
up, so the NMDA system is blocked.

Another hypothesis is that this toxic handshake causes too much cell death.
Apoptosis, or programmed cell suicide, sounds bad, but it actually plays a
role in keeping people healthy. At birth, we have many more neurons than we
need. These are culled back in a process called pruning that does not end
until we reach our 20s, by which time schizophrenia symptoms have begun to
be obvious. Researchers now speculate that too much cell death in brain
tissue may be a cause of schizophrenia.