Messengers of the Brain

by Marcia Purse

You're taking Prozac, and you've heard it described as an SSRI. Maybe you know that SSRI stands for selective serotonin reuptake inhibitor. But that's quite a mouthful -- what does it mean?

In other pages on this site, we look at medications that are commonly prescribed for mood disorders, such as manic depression. Included in these reviews is a brief description of how each functions -- or is thought to function, since many are still being studied.

In order to make sense of any of this, it is necessary to understand something about how impulses are transferred from one nerve to the next, since medications such as mood stabilizers, antidepressants and antipsychotics all affect this process to bring about changes. In this article, I will give a brief, simplified description of how the brain's message carriers (neurotransmitters) operate, and then try to clarify the process by telling the illustrated story, "GABAs in the 'Hood." *

Neurotransmitters

There are several of these, but the ones that are most related to mood disorders are:

• The monoamines - serotonin, norepinephrine and dopamine
• GABA (gamma amino butyric acid)
• Glutamate

Others that come into play, with some side effects, are acetylcholine, which transmits orders to the muscles, and histamine, which has a lot to do with allergies, appetite regulation, weight gain (for those on certain medications), and sleep quality.

When a message comes in at one end of a nerve cell, an electrical impulse travels down the "tail" of the cell, called the axon, and causes the release of the appropriate neurotransmitter. Molecules of the neurotransmitter are sent into the tiny space between nerve cells, called the synaptic cleft. There, one or more of the following can occur for each molecule:

1. It may bind (attach) to the receptors in the adjacent nerve cell, send the message on, leave the receptor, then repeat this process or go on to one of the other steps.
2. It may hang around in the synapse until a receptor becomes available, bind to it, release, and continue with steps 1 to 3 until its activity is ended by steps 4, 5 or 6.
3. It may bind to the first cell's autoreceptors, which tell that cell not to release any more of the neurotransmitter molecules, then leave the autoreceptor and continue trying to bind again somewhere until its activity is ended by step 4, 5 or 6.
4. It may be rendered inactive by an enzyme.
5. It may be reabsorbed by the first cell in the "reuptake" process, and recycled for later use or deactivated.
6. It may diffuse out of the synapse and be deactivated elsewhere.

Now, so many things can go wrong with this process that it's not surprising mood disorders are fairly common. For example:

• The nerve cells (neurons) might not be manufacturing enough of a neurotransmitter.
• Too many molecules of the neurotransmitter may be dissolved or deactivated by enzymes.
• Too much of a neurotransmitter may be released.
• The molecules may be reabsorbed too quickly by the reuptake transporters.
• The autoreceptors may be activated too soon, shutting down the release of neurotransmitter molecules prematurely.

Or there could be some other circumstance involving electrically charged particles of potassium, sodium, chloride or calcium. It's enough to make your head hurt, isn't it?

Here, let's look at it another way.

Communication at Brain Complex, or "GABAs in the 'Hood"

To start with, look at Figure 1, which is a very simplified drawing of a synapse.

Figure 1


Figure 2
For our story, let's change the components shown above into something more familiar -- parts of a neighborhood. The two neurons are Building A and Building B of Brain Complex. They are separated by a narrow street (the synaptic cleft). The GABA terminal button is now a motor pool. Each vesicle containing neurotransmitter molecules becomes a minibus filled with GABA Team messengers. The receptors and autoreceptor become phone booths. The reuptake transporter, where neurotransmitters are sucked back in to be recycled, changes to an inviting coffee shop. And the enzymes are assassins on motorcycles. (No offense meant to motorcycle lovers!)

So over in Building A, the driver of each minivan gets a call from the front office (that's the neuron's cell body, not shown) on his cell phone: "Send this Message over to Building B!" And right away things start to happen.

Figure 3

Immediately the drivers take their vehicles (that is, vesicles) to the garage exit and release the GABA Team messengers (neurotransmitters) into the street (synaptic cleft) between Building A (the sending neuron) and Building B (the receiving neuron). Like sprinters, the GABAs take off quickly, each looking for a phone booth that matches his or her uniform (they could not get into any other color booth). Gertrude, Gerald and Gloria get there first. Quickly each slips into a booth (Figure 4) and makes a call into the office (cell body) of Building B, relaying the Message. Then each backs out and looks for another booth. All the GABA messengers are elbowing each other out of the way (and dodging motorcycles) to get into the available booths and make the same call if they get in.

Figure 4
But there are some traps and hazards for the GABA team. George GABA never makes it to Building B at all -- he has been knocked unconscious by a motorcycle-riding assassin (enzyme). His color change denotes that he has forgotten the message now -- in essence, he has been "deactivated."

Meanwhile, Glenn GABA has gone to the phone booth attached to Building A. "There's too many of us out here," he tells the front office. "Don't send any more." Then he, too, goes back out into the street. When the front office gets enough similar calls, the minivan drivers will be told to return to the motor pool and not send any more messengers out.

And then there is that seductive coffee shop (reuptake transporter) on the other corner of Building A. If a messenger gets close enough to smell the heavenly aroma of fresh coffee and doughnuts, he or she will surely be sucked in, and once inside, will be refreshed and then return to the motor pool to await the next assignment. Eventually all the surviving GABAs will return home via the coffee shop.

The whole event has taken no more than a millisecond.

---

Now as you have probably realized, it isn't really this simple. But this illustration will give you a basic idea of how neurotransmitters operate and why it is so important that they operate correctly. It's crucial that neither too many nor too few of them are released into the cleft, the autoreceptors and enzymes are working properly, and that a myriad of other factors fall into place to contribute to a healthy process. When they don't, you can get illnesses like Parkinson's, which is caused by a dopamine deficiency; or you may have tetanus, which prevents the release of GABA and can be fatal if breathing muscle control is lost. Or you might have schizophrenia, which is thought to be caused by an imbalance of dopamine, or epilepsy, apparently caused in part by an overabundance of GABA.

My goal with "GABAs in the 'Hood" has been to provide an easy-to-understand description of basic neurotransmitter functions. Remember the team messengers and their adventures in the 'hood as you read other articles!


_{Thanks to Richard Schuergar, Former About Guide to Neuroscience, for his contributions to this article.}

Lithium: The First Mood Stabilizer

Part 1: History and a Mystery Solved

By Kimberly Read & Marcia Purse, About.com

Lithium, discovered in 1817, was noticed to have mood stabilizing properties in the late 1800s when doctors were using it to treat gout. (At least one doctor, in fact, concluded from this that gout was the cause of mood disorders.) It was Australian psychiatrist John Cade who, in 1949, published the first paper on the use of lithium in the treatment of acute mania. The U.S. Food and Drug Administration did not approve lithium for use until 1970.

It's important to know that bipolar disorder is not caused by a lithium deficiency. Rather, it happens that this naturally occurring substance has the fortunate effect of acting as a mood stabilizer.

For almost 50 years, manic-depressive people were treated with lithium even though medical science did not know why or how it worked. Then in 1998, University of Wisconsin researchers unlocked the mystery. It has to do with nerve cells in the brain, and the receptors for the neurotransmitter glutamate.

As I described in the article "Messengers of the Brain," neurotransmitters are released from one neuron (nerve cell) and may bond to the receptors of a neighboring cell or be picked up by autoreceptors from the releasing cell (among other things). The result varies depending on what the type of receiving cell and the type of neurotransmitter.

The University of Wisconsin researchers found that lithium exerts a dual effect on receptors for the neurotransmitter glutamate - acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little.

UW Medical School professor of pharmacology Dr. Lowell Hokin, who directed the research, said that from their research it could be postulated that too much glutamate in the space between neurons causes mania, and too little, depression. There has to be more to it than that, since antidepressant medications, for example, work on the receptors of other neurotransmitters such as serotonin and dopamine. However, this is certainly a giant step forward in understanding the biological basis of bipolar disorder.

Note: a large amount of extra glutamate can lead to epileptic seizures or even kill the second cell from overstimulation. Because of Lithium's stabilizing effect on glutamate receptors, scientists are also studying whether this medication can protect from the cell death that occurs in conditions such as Parkinson's, Huntington's and Alzheimer's.

Part 2: Tests and Toxicity
Part 3: Precautions and Warnings
Part 4: Whoa, Fat!