Studies shed light on marijuanalike chemicals

By Mari N. Jensen / The Dallas Morning News

Webdeck:Scientists aim to decipher substances' role in brain

Scientists may someday be able to create medicines that can supply the
medicinally useful effects of marijuana without the mindaltering ones,
new studies suggest.

Writing last week in the journal Science, researchers reported that they
have figured out how the brain disposes of anandamide, a marijuanalike
brain chemical. And in separate research, appearing in the journal
Nature, scientists reported that the brain produces a second natural
marijuanalike chemical.

By learning how cannabinoids, natural marijuanalike chemicals, act in
the brain, scientists may ultimately create medicines that provide the
beneficial effects of marijuana, such as painkilling and appetite
stimulation, without the bad effects, such as memory loss, the
researchers said.

"We believe if we tinker with the mechanism of anandamide activation and
inactivation, we can obtain a more selective drug," said Daniele
Piomelli of The Neurosciences Institute in San Diego, a coauthor on
both studies. "For people with AIDS or 'cancer wasting syndrome' a
little bit more appetite can mean life. . . . Marijuana is one of the
few drugs that can produce weight gain in people with cancer or AIDS."

However, scientists need to learn much more about the brain's
cannabinoid system before drug development can become a reality.
Scientists do know that the brain is loaded with cellular docking
stations, called cannabinoid receptors, that can hold cannabinoids and
similar chemicals. But cannabinoids' function in the brain is still
unknown.

Scientists knew in the mid1980s that THC (tetrahydrocannabinol), a
plant cannabinoid that is the active ingredient in marijuana, causes its
effects by fitting into receptors on the surface of brain cells, said
Steven Childers, presidentelect of the International Cannabinoid
Research Society and a pharmacologist at Bowman Gray School of Medicine
in WinstonSalem, N.C. However, scientists did not find a naturally
produced brain chemical that fit those receptors until anandamide was
discovered in 1992.

"We don't know for sure what is the physiological function of
anandamide. . . . It's still very much a black box," said Christian
Felder, a molecular biochemist at Eli Lilly Research Laboratories in
Indianapolis. "The frustration is we really don't know what this system
is doing in the brain. . . . What Daniele is doing is providing more
tools to probe this interesting system."

Dr. Piomelli and his colleagues Nephi Stella of The Neurosciences
Institute and Paul Schweitzer of The Scripps Research Institute in La
Jolla, Calif., found that the new cannabinoid chemical, called 2AG, is
present in much larger amounts than anandamide in rat brain tissue
appearing in quantities 170 times greater. Brain cells from the
hippocampus, a region involved in shortterm memory and learning,
produced additional 2AG when activated, but did not produce more
anandamide. The researchers also showed that 2AG affects part of the
hippocampal cells' activity thought to be involved in memory and
learning.

2AG and anandamide, although both capable of docking with the brain's
cannabinoid receptors, may be produced in distinct parts of the brain or
under different conditions, the researchers wrote in Nature.

In the Science article, Dr. Piomelli, along with colleagues from The
Neurosciences Institute, the University of Naples in Italy and the
University of Connecticut in Storrs, reported how the brain eliminates
anandamide.

Brain chemicals like cannabinoids are thought to affect brain cells by
docking with receptors on the cell's surface. However, just as a light
switch turns both on and off, scientists knew that the brain has
mechanisms to turn off cannabinoids once they are no longer needed.

Scientists had thought that unneeded anandamide might be carried into
cells or that it might be destroyed outside the cells. For anandamide to
be ferried into the cell, a special transporter system would be
required.

So the researchers created a synthetic chemical, AM404, that would block
such a transporter system. When the researchers treated nerve cells with
the AM404, preventing cells from taking in anandamide, anandamide levels
outside the cells remained high. Without the blocking chemical,
anandamide levels outside the cells fell, indicating that anadamide was
being removed by being ferried into cells rather than being destroyed
outside the cells.

"Certain brain cells produce and release anandamide outside themselves,"
Dr. Piomelli said. "The brain gets rid of anandamide by a mechanism
called uptake. . . . The cells take up anandamide, chew it up and make
it harmless."

The blocking chemical developed by Dr. Piomelli's lab can be used by
scientists to learn more about the brain's cannabinoid system.

"It's a nice first step," Dr. Childers said. "We are on the foundation
of some very interesting things. . . . I never would have predicted we
would have gotten this far this fast."