UCSF researchers move in on role of brain's naturally occurring Marijuana

Nearly a decade ago, researchers determined that the brain contains a molecule
that mimics the active ingredient in marijuana, but its location and role in
the brain were unclear. Now, UCSF researchers have discovered that the molecule
acts, at least in part, in a region of the brain that plays a key role in
learning and memory.

The study, reported in the March 29 issue of Nature, suggests, the researchers
say, that the molecule, known as a cannabinoid, plays a role in particular
cognitive functions within a structure known as the hippocampus. Paradoxically,
marijuana disrupts cognitive function and the likely explanation, the
researchers say, is that marijuana disrupts the very cognitive system the
cannabinoid normally supports.

The circumstances under which cannabinoid might act are unknown, but one
possibility is that it contributes to the formation of new memories, says the
lead author of the study, Rachel I. Wilson, a graduate student in the
laboratory of Roger A. Nicoll, PhD, UCSF professor of cellular and molecular
pharmacology and physiology and a member of the Keck Center for Integrative
Neuroscience at UCSF.

Another possibility is that cannabinoid enables neurons to shift from one
behavioral state to another. “We know that when the brain is carrying out
different behaviors - whether directing the body to a desired destination or
sleeping - it has different patterns of synchronous rhythms. Cannabinoid might
enable neurons to shift from one behavioral state to another,” she says.

In either case, she says, the cannabinoid system would be supporting cognitive
processes. While merely speculative at this point, the hypothesis is
reasonable, says Wilson, as the cell receptor through which cannabinoid acts
has been conserved through evolution, suggesting the cannabinoid molecule is
beneficial to many species.

“It seems to me than anything expressed so heavily and conserved throughout
evolution must be good for you. Why would we express the receptor at high
levels if it just made us stupid?”

Marijuana, meanwhile, could be disrupting the system by acting in a
nondiscriminatory manner, says Wilson.

The researchers, conducting their study in rats, discovered that cannabinoid is
the signaling molecule within a unique system of communication that is
activated intermittently between two of the brain’s most ubiquitous nerve cells
—neurons containing the inhibitory neurotransmitter GABA, and neurons
containing the excitatory neurotransmitter glutamate. The modulation of
inhibitory and excitatory signals leads to the regulation of excitation and
inhibition within clusters of neurons that is the basis for all action and

Normally, brain cells containing the inhibitory neurotransmitter GABA release
their signal and it diffuses across a synapse and on to receptors on cells
containing the excitatory neurotransmitter glutamate, thereby dampening
excitatory behavior. This orderly flow of information from pre-synaptic to
post-synaptic cell is the classical form of communication in the nervous

But, of interest to the researchers, when excitatory glutamate neurons are
highly charged electrically, they release a molecular signal that moves
backwards, across the synapse, to a subset of inhibitory GABAergic neurons that
have a receptor known as CB1. The event briefly inhibits the release of
inhibitory GABA neurotransmitters, thus allowing the excitatory neurons to fire
messages of excitation repeatedly and intensely, thereby “strengthening” their
synaptic connections with other nerve cells. The strengthening of synapses,
otherwise known as long term potentiation, or LTP, is thought to be the basis
of learning and establishing memories. The signal inciting this event, the
researchers determined, is a cannabinoid molecule.

“Signaling by the cannabinoid system represents a mechanism by which neurons
can communicate backwards across synapses to modulate their inputs,” says
senior author Nicoll.

Notably, this rare, so-called retrograde system is only activated when
excitatory neurons are in a particularly heightened electrical state, which
probably explains a unique characteristic: While neurons package and store
classical neurotransmitters in compartments known as vesicles, and then release
them on demand, neurons must make cannabinoid when they need it.

“Prepackaging is for speed, which this system doesn’t need,” says Nicoll.
“There’s no need to waste energy storing the molecule if it’s only going to be
used occasionally.”

The conditions under which the retrograde system might be ignited are unknown,
but one possibility is that the cannabinoid system might be recruited in
situations where the hippocampus is particularly active—meaning situations
where the brain has to form new memories, says Wilson.

Another possibility is that cannabinoid helps orchestrate a shift in behavioral
states. Cannabinoid acts only on GABA cells containing the CB1 receptor. These
cells, a subtype of a class of cells known as interneurons, are interspersed
among the glutamate-releasing cells. Researchers are just beginning to
understand the role of interneurons. In the hippocampus, just one inhibitory
interneuron orchestrates the actions of hundreds of glutamatergic cells,
prompting them to fire their neurotransmitters in synchrony. It may be, the
researchers say, that the cannabinoid system breaks down synchrony, enabling
glutamatergic neurons to move out of one synchronous rhythm and into another.

“There may be times when the synchrony should be powerful, and at times when it
should be weak,” says Wilson.

Marijuana, meanwhile, could be inciting changes in synaptic strength left and
right, causing a chaotic pattern of changes in synaptic strength.
Alternatively, the drug could be disrupting synchrony at the wrong time.

The researchers drew their conclusion that cannabinoid was the signaling
molecule by determining that the receptor on the pre-synaptic cells was CB1.
Other scientists had previously determined that this receptor for marijuana
existed, though it had not been clear where or how it acted in the brain. Still
others had determined the existence of two naturally occurring cannabinoids,
though, again, their location and role in the brain was unknown. A third is
expected to be reported shortly. Most likely, the scientists say, the molecule
they are studying is one of these three.

The fact that the CB1 cannabinoid receptor is found throughout the brain
suggests, says senior author Nicoll, that cannabinoid may have functions in
other parts of the brain, as well.

“Cannabinoid joins a small group of molecules identified as fast retrograde
signals in the nervous system. As such, it provides a tool for sorting out the
roles of various classes of inhibitory interneurons, whose roles we’re just
beginning to understand,” he says.

The study was funded by grants from the National Institutes of Health, the
Bristol-Myers Squibb Corporation, the National Science Foundation Fellowship
and a UC Regents Fellowship.