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Category: Neurochemistry

Term Paper Code: 8

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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).


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)


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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