Brain Chemicals Mimic Marijuana

By Johnathan S. Choi

NEW YORK (Reuters) Two chemicals found in the brain seem to
mimic some of the effects of marijuana and bind to the same brain
receptor, according to two studies to be published Thursday. The
research offers new clues on how the brain regulates memory and
learning, and may lead to the development of new drugs.

The substances anandamide and sn2 arachidonylglycerol (2AG)
bind to the same receptors in the brain as tetrahydrocannabinol
(THC), the active compound in marijuana and hashish. Besides their
psychoactive properties, THC has some therapeutic effects such as
pain relief and appetite stimulation. THC also interferes with a
process in the hippocampus of the brain called longterm
potentiation (LTP), which is important to memory and learning.

``Normally, these brain cells would communicate with a certain
level of efficacy or strength. However, under certain conditions
these are the conditions under which we tend to remember things
the strength of the communication will be increased,'' explains
Daniele Piomelli of the Neurosciences Institute in San Diego,
senior author on the report published in Science. ``This phenomenon
is called potentiation of synaptic (nerve) transmission.
Potentiation that is prolonged for many hours is therefore called
longterm potentiation.''

The fact that the cannabinoid receptors are highly concentrated in
the hippocampus is very important in understanding LTP and
learning, says Piomelli. ``The hippocampus is a small region of the
brain present in all mammals, including man, that participates in
shortterm memory formation and learning. The way people look at
the hippocampus is as a 'relay station' where sensory inputs go to
become either discarded, or become prolonged memories. In fact,
patients who have lesions in the hippocampus, while they can retain
old memories, cannot form new memories.'' By blocking LTP, drugs
like THC interfere with this memoryrelaying process.

The study found that 2AG mimicked the effect of THC by blocking
longterm potentiation. They believe this is the same mechanism by
which smoking marijuana may cause shortterm memory lapses. In
contrast, there was no production of anandamide detected in the
hippocampus. This suggests that 2AG, but not anandamide, modulates
the formation of shortterm memories, producing a type of
``physiological forgetting.''

In a separate study published in the journal Nature, scientists
report on the mechanism by which anandamide becomes biologically
inactivated. Anandamide released from neural cells binds to the
cannabinoid receptors present on the surface of neighboring cells.
Once it is bound, a way to stop its actions is required. Otherwise,
THC stimulation could continue indefinitely, and a perpetual 'high'
could be maintained from just a few puffs of marijuana. The
researchers discovered that anandamide was deactivated by being
transported into the cell and broken down into nonfunctional
fragments. Though anandamide was not found in the hippocampus, it
is believed that THC is inactivated in a similar manner.

``This is of course a hypothesis, but we think that there is a
division of labor between anandamide and 2AG. 2AG is produced in
certain areas and subserves certain functions, whereas anandamide
is produced in other areas and subserves other functions,''
explains Piomelli. ``In both cases, the compounds bind to the
cannabinoid receptors, but they're not necessarily produced
together or at the same time.... Now that's important, because it
opens a number of perspectives from the standpoint of therapy. As I
mentioned before, there are certain effects of THC which are
favorable and interesting therapeutically, such as analgesia. There
are others that are not considered favorable such as the
psychotropic effects. If they could be split apart... they would be
very useful, therapeutically. They might have some of the positive
effects of anandamide and THC, without most of the negative
effects.''

SOURCE: Science (1997;277:10941096); Nature (1997;388:773777)