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| | MARIJUANA'S CANNABIS EFFECTS ON MEMORY
Category: Neurochemistry
Term Paper Code: 8
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Introduction
Of the many things in this world we probably know the least about the human
nervous system. The "neural network" as one may call it, is extremely
complex; consisting of over 10^10 neurons, and these neurons interconnect with
each other making over 10^16 neural connections. It is no wonder that the brain
has evaded the scientific eye. While taking steps to elucidate the brain, many
great discoveries have been made that uncover a piece of this seemingly
impossible puzzle. One such piece is Marijuana (Cannabis sativa). Its popularity
came largely in part from its "mind altering effects" and
"medicinal" value. Much of the interest lies in the mind-altering
attributes. This paper will try to elucidate some of the chemical effects of
marijuana on the brain, and in particular its affects on the cells of the
hippocampus where short-term memories are formed.
Historical Usage of Cannabis
Marijuana's botanical history is quite interesting in that its origin can be
traced as far back as ancient China, where it has been used extensively in their
societies dating as far back as the 4th century B.C. (Axelrod and Felder 1997).
The Chinese Emperor Shen-nung prescribed marijuana as medicine in the third
millenium B.C. to his people (WWW 1). The next instance of its use was in the
Atharva Veda of India, which dates back to around 2000 B.C. In this book it is
referred to as a "sacred grass". From India, it traveled to Persia by
600 B.C. where it was cited in their holy books in a medical context. Next,
circa 450 B.C. Greece has literature describing various social events involving
marijuana. Finally, it arrived in Europe by the 19th century, where its
medicinal qualities were widely used (Axelrod and Felder 1997).
During the latter half of the nineteenth century several physicians of the
Western world advocated the use of marijuana for various ailments. For a long
while it was the best treatment for migraine headaches. Soon enough however,
"western thought" believed that marijuana was being abused by certain
peoples and decided to outlaw it. Only until recently did the use of marijuana
for medicinal purposes become appropriate once more. Worthy of note are
marijuana's analgesic, appetite stimulating, muscle relaxing, and
anti-inflammatory properties, which has spurned increasing interest amongst the
scientific community.
9-THC and Cannabinoid Receptors
The active component in marijuana is delta-9-tetrahydrocannabinol (9-THC). This
is a tricyclic molecule with a five carbon long tail. It is not a very polar
molecule in fact it is quite hydrophobic. The hydrophobicity of this molecule
allows it to cross the blood brain barrier without too much difficulty and into
the brain. From there it can interact with a small variety of receptors known as
the cannabinoid receptors.
There are three main cannabinoid receptors that are known in the human body,
which bind 9-THC. The three receptors CB1, CB1A, and CB2 are found throughout
the brain localized in various regions. In particular, large densities of
cannabinoid receptors are in the cerebellum, basal ganglia, cerebral cortex,
hippocampus and much of the immune tissue. The localization of these receptors
in the brain makes sense since each of these areas corresponds to a particular
type behavior that is affected when 9-THC is in the system. For example, the
cerebellum is mostly responsible for initiating movement. So, when 9-THC is
present in this part of the brain the subject will have trouble initiating
movement, which is exactly what we observe. Another example of this is the
cerebral cortex, which is involved in reasoning and perception. Once again if
9-THC is present then the subject will have trouble holding a logical
conversation. The underlying mechanisms for these behaviors are not well
understood just as of yet, since the signaling pathway for 9-THC is quite
complex.
The CB1, CB1A, and CB2 receptors are G-protein coupled receptors. Each contains
the standard seven transmembrane domains. In addition to this, since they are
G-protein coupled they affect a wide variety of other cascading events, which as
of yet aren't known too well (Matsuda et al. 1990). However, a few 9-THC
pathways are known, and they give insight into the ultimate physiological
effects of 9-THC.
Receptor Coupled Effects of 9-THC
9-THC affects the nervous system in a variety of ways, only a handful of which
are understood. Cannabinoid receptors couple to several pathways, including the
cyclic-Adenosine-mono-phosphate (cAMP) transduction pathway (Axelrod and Felder
1997). When 9-THC binds to the Cannabinoid receptor it induces a change in the
receptor increasing its affinity for a G-protein. At this point an inhibitory
G-protein will interact with the receptor and become activated. Activation of
this inhibitory G-protein will cause several downstream events to occur one of
which is the inhibition of the adenylyl cyclase (Axelrod and Felder 1997). The
active G-protein does this through direct interaction with the protein and
prevents further cAMP from being produced. Although evidence has shown that the
Cannabinoid receptor has a stimulating effect as well, it is far outweighed by
its inhibitory counterpart. A downstream affect of this decrease in cAMP pathway
is the inhibition of N- and Q-type voltage dependent calcium channels, which are
at length inhibited by this decrease in cAMP (Axelrod and Felder 1997).
Non-Receptor Coupled Effects of 9-THC
Another notable physiological effect of 9-THC is the arachidonic acid pathway.
It is not known how this pathway is activated since tests indicate that the
Cannabinoid receptors are not necessary for arachidonic acid release (Chan et al
1998). This was proven by saturating the cell with pertussis toxin, which
inactivates the Cannabinoid G-protein coupled receptor, and then adding a
sizable quantity of 9-THC. Even with the G-protein inhibited there was an
increase in the amount of arachidonic acid that was released. This means that
9-THC somehow activates the Phospholipase2 (PLA2) pathway. Once there is a large
enough abundance of arachidonic acid, cyclooxygenase (COX) becomes activated.
The active COX then catalyzes the formation of the reactive oxygen species (ROS).
Once ROS is active it will stimulate the peroxidation of lipids, proteins, and
DNA.
Further testing of 9-THC on neurons showed varied effects. The addition of 9-THC
directly added to cultured neurons showed a substantial increase in the number
of breaks in the DNA strands of the cell. Also a definite size decrease of the
cell body was observed. To add to these observations, nuclear condensation was
also noticed. All of these signs indicate that 9-THC is somehow involved in
apoptosis or cell death (Chan et al 1998).
Memory
The molecular mechanisms for storing memories in the brain are for the most part
unknown to us. There are however, a few things that are known which provide a
strong basis for what we do know today about memories. Memory can be broken down
into two basic types: Reflexive and Declarative. Reflexive memory has a highly
mechanical characteristic in that the repetition of many trials will cause this
memory type to grow. This characteristic can be seen in tasks that require
repetition, eventually there will be an increase in the performance on
particular repetitive tasks, and soon enough these tasks will be executable
without any conscious thought or effort. The part of the brain that handles
these reflexive types of memories is the cerebellum, which is involved with the
initial storage of reflexive memories before they are committed to long term
memory. Declarative memory on the other hand is quite different. The storage of
declarative memory is through the conscious act of reflection. And the memory's
retrieval is determined by cognitive processes such as evaluation and
comparison. The processing involved in this type of memory is far greater.
Information must be processed from several areas in the brain and then brought
together to make sense of "what" happened. The initial formation of
these memories is the job of the hippocampus(Irving Kupfermann 1991).
The hippocampus is a very important part of the brain that is used in the
initial formation of short-term memories. There is a famous patient HM, who
unfortunately had an accident, which left him with a damaged hippocampus.
Interested by HM's unique case doctors wished to study him and his memory
capabilities. It turns out that all of his memories before the accident are
intact. However, any attempts to establish declarative new memories would fail
due to the damaged hippocampus. His condition was such that the doctor would
have to introduce himself every couple of hours. Aside from the declarative
aspect of memory, HM's reflexive memory attributes were just fine. Attempts to
store reflexive memories were highly successful since the accident did not
damage the cerebellum, which is associated with the storage of reflexive
memories (Yang Dan 1999). From this example it was obvious that the hippocampus
was a necessary component in the establishment of declarative memories.
The hippocampus contains a mapping of the world. The neurons of the hippocampus
are often referred to as "place-cells", since the hippocampus allows
for spatial recognition. The hippocampus initially encodes "the
place", and changes over the course of a few days will eventually encode
"the place" in a different part of the brain. Thus freeing the
hippocampus and allowing us to encode something new. So, the model for memory is
basically storage into a short-term memory apparatus and then later conversion
to long-term by moving the memory to a different area in which the memory is to
be stored.
A highly debated topic to this date is the molecular mechanism underlying the
memory capability of the brain. The accepted models for memory currently are
long term potentiation (LTP) and long term depression (LTD). LTP occurs in the
hippocampus. Its ultimate effect is the prolonged increase in the strength of a
particular synaptic response. This strengthening occurs after sending a train of
stimuli to a particular synapse. Later, sending a stimulus to the post-synaptic
terminal, will show a "higher" response in the post-synaptic terminal,
from a standard stimulus. The mechanism for this phenomenon is maintained by two
very important mechanisms. The first mechanism involves the NMDA receptors on
the post-synaptic terminals. In order for the NMDA receptors to open and let
calcium and sodium into the post-synaptic neuron, glutamate must be present and
a depolarizing event must occur. Once this has happened sodium and calcium can
enter the post-synaptic terminal. Then, the increased intracellular calcium
levels will in turn activate kinases. These kinases have unknown
"downstream effects", which alter the efficiency of the synapse. It is
thought that there is a retrograde messenger that is activated by these kinases
and this messenger affects kinases in the pre-synaptic neuron thus affecting it
as well. The second mechanism is the effect that the post-synaptic terminal has
on the presynaptic one. The retrograde messenger, which has yet to be
identified, is the one responsible for increasing the amount of neurotransmitter
that will be released per depolarization event. As a result, a synapse with LTP
will give a greater response to the same stimulus than a synapse without LTP.
Ultimately the effect is that this one particular synapse (out of the thousands
that this one cell must make) is much stronger. All of these synapses that have
been induced by LTP are pertinent in maintaining short-term memories (Kandel
1991).
If synapses keep getting stronger there will be a point where the synapse will
have to stop getting stronger; this is where LTD comes in. LTD on the other hand
works in an opposing manner within the hippocampus. The large amounts of calcium
that were required for LTP are not required for LTD. In LTD when a small influx
of calcium is let in then a protein called calcinuerin (a phosphatase) with a
high binding affinity for calcium becomes activated. Once calcinuerin is
activated it will cleave the phosphate groups off of all the kinases that were
involved in the LTP pathway, thus creating an inhibitory effect. This however
brings up the question as to the competitive nature of calcinuerin and the other
kinases. It turns out that at high concentrations of calcium the kinases with
low binding affinity win, but otherwise during low calcium concentrations,
calcinuerin will win. Therefore this self-inhibiting mechanism controls the
strength of the various synapses in the hippocampus.
9-THC's Neurotoxic Effects on the Hippocampus
The hippocampus contains a large abundance of cannabinoid receptors. It is no
wonder that 9-THC would greatly affect this area of the brain due to this fact.
However, there is more than one pathway through which 9-THC affects the
hippocampus, which lead one to believe that memory loss undisputedly
attributable to the neurotoxicity of 9-THC.
A well-known pathway in this area of neurotoxicity is the arachidonic pathway.
As mentioned previously 9-THC induces the release of arachidonic acid through
the PLA2 pathway. This increase in arachidonic acid will then activate the COX
pathway and increase the activation of ROS. Once ROS is activated the
peroxidation of the various lipids, proteins and DNA will cause the break down
of the cell, and eventually lead to cell death. On a side note an experiment was
done to see the effects of arachidonic acid on cultured hippocampal neurons in
rats. Within 24 hours of application of arachidonic acid to the cultured cells
100ell death was observed. This however was not an accurate model because the
application of arachidonic acid in this manner is not likely the same as that
caused by the activation of PLA2 (Chan et al 1998). In the same experiment it
was also found that vitamin E or aspirin protects the cells from any sort of
neurotoxicity in regards to this pathway. This pathway is thought to be the main
cause of cell death within the hippocampus, and therefore it is a good reason to
believe that marijuana ultimately causes short-term memory loss.
In addition to this, marijuana has also been known to interfere with LTP. This
is easily shown since 9-THC inhibits the influx of calcium through the
inhibition of N- and Q-type calcium channels. In the hippocampus this leads to a
lack of LTP. A loss of LTP in the hippocampus where memories are formed would
prove to be an accurate assessment of the fact that marijuana causes loss of
short-term memory (Diana et al 1998). In fact evidence has been found that 9-THC
destroys short-term memory (Heyser, 1993)
Conclusion
There is a lot to be gained from the study of 9-THC and its affects on the
brain. In particular this drug has been a marvelous tool in helping elucidate
the mechanism of memory formation. Although it's affects on the hippocampus are
for the most part negative. It is still nice to have a mechanism with which to
calibrate a system within the brain that is yet mostly unknown. In addition to
9-THC, the endogenous ligand anandamide also plays an important part in the
brain, which as of yet is not understood. Although research suggests that it is
a part of a whole family of molecules that are all lipid permeable. By having a
receptor type for this exogenous ligand in the brain there are many possible
doors that could be opened to help us conceive the human brain.
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