View Full Version : Neurotransmitters: Messengers of the Brain

01-18-06, 05:50 AM
<i>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?</i></p><p>
<font face="verdana, geneva, helvetica" size="2">In the coming weeks and months we will be looking at several medications that are commonly prescribed for mood disorders such as manic depression. Included in these reviews will be a look at how each functions - or is thought to function, since many are still being studied. We will also take an in-depth look at why so many of these drugs cause weight gain - a subject of importance to an all-too-large percentage of people who take psychiatric medications.</font></p><font face="verdana, geneva, helvetica" size="2">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, because 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, called "neurotransmitters," operate, and then try to clarify the process by telling the illustrated story, "GABAs in the 'Hood."*</font><p>
<font face="verdana, geneva, helvetica" size="2"><b>Neurotransmitters</b></font></p><p>

<font face="verdana, geneva, helvetica" size="2">There are several of these, but the ones that are most concerned with mood disorders are:
<font face="verdana, geneva, helvetica" size="2"><li>The monoamines - serotonin, norepinephrine and dopamine;
</li><li>GABA (Gamma amino butyric acid); and
<font face="verdana, geneva, helvetica" size="2">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 but also affects sleep.</font><p>
<font face="verdana, geneva, helvetica" size="2">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 six things can occur for each molecule:
<font face="verdana, geneva, helvetica" size="2"><li>It may "bind" (attach) to the receptors in the adjacent nerve cell, sending the message on, then leave the receptor, repeat Step 1, or go on to one of the other steps;
</li><li>It may hang around in the synapse until a receptor becomes available, and then bind to it, release, and continue with Steps 1-3 until its activity is ended by Step 4, 5 or 6;
</li><li>It may bind (attach) 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;
</li><li>It may be rendered inactive by an enzyme;
</li><li>It may be reabsorbed by the first cell in the "reuptake" process, and recycled for later use or deactivated there; or
</li><li>It may diffuse out of the synapse and be deactivated elsewhere.

<font face="verdana, geneva, helvetica" size="2">Now, so many things can go wrong with this process that it's not surprising mood disorders are fairly common. For example:
<font face="verdana, geneva, helvetica" size="2"><li>The nerve cells (neurons) might not be manufacturing enough of a neurotransmitter
</li><li>Too many molecules of the neurotransmitter are being dissolved or deactivated by enzymes
</li><li>Too much of a neurotransmitter is being released
</li><li>The molecules are being reabsorbed too quickly by the reuptake transporters
</li><li>The autoreceptors are being activated too soon, shutting down the release of neurotransmitter molecules prematurely
<font face="verdana, geneva, helvetica" size="2">Or there could be some other circumstance involving electrically charged particles of potassium, sodium, chloride or calcium. <font color="#0000a0">It's enough to make your head hurt, isn't it?</font></font><p>
<font face="verdana, geneva, helvetica" size="2">Here, let's look at it another way.</font></p><p>
<font face="verdana, geneva, helvetica" size="2"><b>Communication at Brain Complex, or<br>
"GABAs in the 'Hood"</b></font></p><p>

<font face="verdana, geneva, helvetica" size="2">To start with, look at Figure 1, which is a very simplified drawing of a synapse.</font></p><p>
<font face="verdana, geneva, helvetica" size="2"><b>Figure 1</b><br>
<img src="" alt="Synapse, vesicles, autoreceptors, terminal button, axon and enzyme" height="400" width="400"></font></p><p>
<font face="verdana, geneva, helvetica" size="2"><b>Figure 2</b><br>
<img src="" alt="A call is received by the motor pool" align="left" height="233" width="233">For our story let's change the components shown above into something more familiar. The two neurons are Building A and Building B of Brain Complex, separated by a narrow street ("the 'hood," 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!)</font></p><p>
<font face="verdana, geneva, helvetica" size="2">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.</font></p><p>

<table align="right" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td align="right"><font face="verdana, geneva, helvetica" size="2">
<b>Figure 3</b><br>
<img src="" alt="The vesicles release neurotransmitters into the synaptic cleft" height="233" width="233"></font></td></tr></tbody></table>
<font face="verdana, geneva, helvetica" size="2">

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).</font></p><p>

<font face="verdana, geneva, helvetica" size="2">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 all make the same call if they get in.</font></p><p>
<font face="verdana, geneva, helvetica" size="2"><b>Figure 4</b><br>
<img src="" alt="Autoreceptors, enzymes, receptors and reuptake transporters" align="left" height="233" width="233">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 unconcscious by a motorcycle-riding Assassin (enzyme). His color change denotes that he has forgotten the Message now - in essense, he has been "deactivated."</font></p><p>
<font face="verdana, geneva, helvetica" size="2">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.</font></p><p>
<font face="verdana, geneva, helvetica" size="2">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.</font></p><p>
<font face="verdana, geneva, helvetica" size="2"><font color="#408080"><b>The whole event has taken no more than a millisecond.</b></font></font></p><p>
</p><hr align="center" size="2" width="300"><p>

<font face="verdana, geneva, helvetica" size="2">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, with neither too many nor too few of them being released into the cleft, the autoreceptors and enzymes working properly, and myriad other factors all contributing to a healthy process. When they don't, you can get illnesses like Parkinson's, which has a dopamine deficiency; or you may have tetanus, which prevents the release of GABA and can be fatal if breathing muscle control is therefore lost. Or you might have schizophrenia, which is thought to be caused by too much dopamine, or epilepsy, apparently caused in part by an overabundance of GABA.

Soon we will begin to look at individual medications and medication types used in the treatment of bipolar disorder, including lithium, depakote, SSRI and tricyclic antidepressants, tegretol, antipsychotics and more. Those articles will include information about specific neurotransmitters and receptors. 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 future articles!</font>

01-23-06, 11:03 PM
<a name="table"><font face="arial" size="5"><b></b></font></a><center><a name="table"><font face="arial" size="5"><b><font face="arial">Table of Neurotransmitters</font></b><font face="arial"></font></font></a>
<p><table bgcolor="white" border="2" cellpadding="5">
<tbody><tr valign="middle"><td align="center"><font face="arial" size="4"><b>Transmitter Molecule</b></font></td><td align="center"><font face="arial" size="4"><b>Derived From</b></font></td><td align="center"><font face="arial" size="4"><b>Site of Synthesis</b></font></td></tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="nerves.html#ach">Acetylcholine</a></font></td><td align="center"><font face="arial">Choline</font></td><td align="center"><font face="arial">CNS, parasympathetic nerves</font></td></tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="nerves.html#5ht">Serotonin</a><br>5-Hydroxytryptamine (5-HT)</font></td><td align="center"><font face="arial">Tryptophan</font></td><td align="center"><font face="arial">CNS, chromaffin cells of the gut, enteric cells</font></td></tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="nerves.html#gaba">GABA</a></font></td><td align="center"><font face="arial">Glutamate</font></td><td align="center"><font face="arial">CNS</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial">Glutamate</font></td><td align="center"><font face="arial">&nbsp;</font></td><td align="center"><font face="arial">CNS</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial">Aspartate</font></td><td align="center"><font face="arial">&nbsp;</font></td><td align="center"><font face="arial">CNS</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial">Glycine</font></td><td align="center"><font face="arial">&nbsp;</font></td><td align="center"><font face="arial">spinal cord</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial">Histamine</font></td><td align="center"><font face="arial">Histidine</font></td><td align="center"><font face="arial">hypothalamus</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="nerves.html#catecholamines">Epinephrine</a></font><p><font face="arial"><a style="text-decoration: none;" href="aminoacidderivatives.html#tyrosine">synthesis pathway</a></font></p></td><td align="center"><font face="arial">Tyrosine</font></td><td align="center"><font face="arial">adrenal medulla, some CNS cells</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="nerves.html#catecholamines">Norpinephrine</a></font><p><font face="arial"><a style="text-decoration: none;" href="aminoacidderivatives.html#tyrosine">synthesis pathway</a></font></p></td><td align="center"><font face="arial">Tyrosine</font></td><td align="center"><font face="arial">CNS, sympathetic nerves</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="nerves.html#catecholamines">Dopamine</a></font><p><font face="arial"><a style="text-decoration: none;" href="aminoacidderivatives.html#tyrosine">synthesis pathway</a></font></p></td><td align="center"><font face="arial">Tyrosine</font></td><td align="center"><font face="arial">CNS</font></td></tr><tr valign="middle"><td align="center"><font face="arial">Adenosine</font></td><td align="center"><font face="arial">ATP</font></td><td align="center"><font face="arial">CNS, periperal nerves</font></td></tr><tr valign="middle"><td align="center"><font face="arial">ATP</font></td><td align="center"><font face="arial">&nbsp;</font></td><td align="center"><font face="arial">sympathetic, sensory and enteric nerves</font></td>
</tr><tr valign="middle"><td align="center"><font face="arial"><a style="text-decoration: none;" href="aminoacidderivatives.html#no">Nitric oxide, NO</a></font></td><td align="center"><font face="arial">Arginine</font></td><td align="center"><font face="arial">CNS, gastrointestinal tract</font></td></tr></tbody></table></p></center>

<p><font face="arial"><dd>Many other neurotransmitters are derived from precursor proteins, the so-called <b><font color="red">peptide neurotransmitters</font></b><font color="red"></font>. As many as 50 different peptides have been shown to exert their effects on neural cell function. Several of these peptide transmitters are derived from the larger protein <a style="text-decoration: none;" href="peptide-hormones.html#pomc">pre-opiomelanocortin (POMC)</a>. Neuropeptides are responsible for mediating sensory and emotional responses including hunger, thirst, sex drive, pleasure and pain.

<br></dd></font><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top%22"></a></font></p><hr>
<a name="synaptic"><font face="arial" size="5"><b></b><center><b>Synaptic Transmission</b></center></font></a>
<p><font face="arial"><dd>Synaptic transmission refers to the propagation of nerve impulses from one nerve cell to another. This occurs at a specialized cellular structure known as the <b><font color="red">synapse</font></b><font color="red"></font>--- a junction at which the axon of the presynaptic neuron terminates at some location upon the postsynaptic neuron. The end of a presynaptic axon, where it is juxtaposed to the postsynaptic neuron, is enlarged and forms a structure known as the <b><font color="red">terminal button</font></b>. An axon can make contact anywhere along the second neuron: on the dendrites (an <b><font color="red">axodendritic synapse</font></b><font color="red"></font>), the cell body (an <b><font color="red">axosomatic synapse</font></b><font color="red"></font>) or the axons (an <b><font color="red">axo-axonal synapse</font></b><font color="red"></font>).
</dd><dd>Nerve impulses are transmitted at synapses by the release of chemicals called <b><font color="red">neurotransmitters</font></b><font color="red"></font>. As a nerve impulse, or <b><font color="red">action potential</font></b><font color="red"></font>, reaches the end of a presynaptic axon, molecules of neurotransmitter are released into the synaptic space. The neurotransmitters are a diverse group of chemical compounds ranging from simple amines such as <b><font color="red">dopamine</font></b><font color="red"></font> and amino acids such as <b><font color="red"><font face="symbol">g</font>-aminobutyrate (GABA)</font></b><font color="red"></font>, to polypeptides such as the <b><font color="red">enkephalins</font></b><font color="red"></font>. The mechanisms by which they elicit responses in both presynaptic and postsynaptic neurons are as diverse as the mechanisms employed by growth factor and cytokine receptors.
<br></dd></font><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top%22"></a></font>
<a name="muscle"><font face="arial" size="5"><b></b><center><b>Neuromuscular Transmission</b></center></font></a>
<p><font face="arial"><dd>A different type of nerve transmission occurs when an axon terminates on a skeletal muscle fiber, at a specialized structure called the <b><font color="red">neuromuscular junction</font></b>. An action potential occurring at this site is known as <b><font color="red">neuromuscular transmission</font></b><font color="red"></font>. At a neuromuscular junction, the axon subdivides into numerous terminal buttons that reside within depressions formed in the <b><font color="red">motor end-plate</font></b><font color="red"></font>. The particular transmitter in use at the neuromuscular junction is acetylcholine.
<br></dd></font><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top"></a></font>
<a name="receptors"><font face="arial" size="5"><b></b></font><center><font face="arial" size="5"><b>Neurotransmitter Receptors</b></font></center></a>
<p><font face="arial"><dd>Once the molecules of neurotransmitter are released from a cell as the result of the firing of an action potential, they bind to specific receptors on the surface of the postsynaptic cell. In all cases in which these receptors have been cloned and characterized in detail, it has been shown that there are numerous subtypes of receptor for any given neurotransmitter. As well as being present on the surfaces of postsynaptic neurons, neurotransmitter receptors are found on presynaptic neurons. In general, presynaptic neuron receptors act to inhibit further release of neurotransmitter.
</dd><dd>The vast majority of neurotransmitter receptors belong to a class of proteins known as the <b><font color="red">serpentine receptors</font></b><font color="red"></font>. This class exhibits a characteristic transmembrane structure: that is, it spans the cell membrane, not once but seven times. The link between neurotransmitters and intracellular signaling is carried out by association either with G-proteins (small GTP-binding and hydrolyzing proteins) or with protein kinases, or by the receptor itself in the form of a ligand-gated ion channel (for example, the acetylcholine receptor). One additional characteristic of neurotransmitter receptors is that they are subject to <b><font color="red">ligand-induced desensitization</font></b><font color="red"></font>: That is, they can become unresponsive upon prolonged exposure to their neurotransmitter.
<br></dd></font><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top"></a></font>
<a name="ach"><font face="arial" size="5"><b></b><center><b>Acetylcholine</b></center></font></a>
<p><font face="arial"><dd>Acetylcholine (<b><font color="red">ACh</font></b><font color="red"></font>) is a simple molecule synthesized from choline and acetyl-CoA through the action of choline acetyltransferase. Neurons that synthesize and release ACh are termed <b><font color="red">cholinergic neurons</font></b><font color="red"></font>. When an action potential reaches the terminal button of a presynaptic neuron a voltage-gated calcium channel is opened. The influx of calcium ions, Ca<sup>2+</sup>, stimulates the exocytosis of presynaptic vesicles containing ACh, which is thereby released into the synaptic cleft. Once released, ACh must be removed rapidly in order to allow repolarization to take place; this step, hydrolysis, is carried out by the enzyme, acetylcholinesterase. The acetylcholinesterase found at nerve endings is anchored to the plasma membrane through a glycolipid.
</dd><dd>ACh receptors are ligand-gated cation channels composed of four different polypeptide subunits arranged in the form [(<font face="symbol">a</font>2)(<font face="symbol">b</font>)(<font face="symbol">g</font>)(<font face="symbol">d</font>)]. Two main classes of ACh receptors have been identified on the basis of their responsiveness to the toadstool alkaloid, muscarine, and to nicotine, respectively: the <b><font color="red">muscarinic receptors</font></b><font color="red"></font> and the <b><font color="red">nicotinic receptors</font></b><font color="red"></font>. Both receptor classes are abundant in the human brain. Nicotinic receptors are further divided into those found at neuromuscular junctions and those found at neuronal synapses. The activation of ACh receptors by the binding of ACh leads to an influx of Na<sup>+</sup> into the celland an efflux of K<sup>+</sup>, resulting in a depolarization of the postsynaptic neuron and the initiation of a new action potential.
<br></dd></font><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top"></a></font>
<a name="cholinergic"><font face="arial" size="5"><b></b><center><b>Cholinergic Agonists and Antagonists</b></center></font></a>
<p><font face="arial"><dd>Numerous compounds have been identified that act as either agonists or antagonists of cholinergic neurons. The principal action of cholinergic agonists is the excitation or inhibition of autonomic effector cells that are innervated by postganglionic parasympathetic neurons and as such are refered to as <b><font color="red">parasympathomimetic agents</font></b><font color="red"></font>. The cholinergic agonists include choline esters (such as ACh itself) as well as protein- or alkaloid-based compounds. Several naturally occurring compounds have been shown to affect cholinergic nerons, either positively or negatively.
</dd><dd>The responses of cholinergic neurons can also be enhanced by administration of cholinesterase (ChE) inhibitors. ChE inhibitors have been used as components of nerve gases but also have significant medical application in the treatment of disorders such as glaucoma and myasthenia gravis as well as in terminating the effects of neuromuscular blocking agents such as atropine.
<p><a name="agonists"><b></b></a></p><center><a name="agonists"><b><font face="arial" size="5">Natural Cholinergic Agonist and Antagonists</font></b></a></center><font face="arial" size="5"></font><p></p><center><table bgcolor="white" border="4" cellpadding="10" width="80%"><tbody><tr valign="middle"><td align="center"><font face="arial" size="4"><b>&nbsp;</b></font></td><td align="center"><font face="arial" size="4"><b>Source of Compound</b></font></td><td align="center"><font face="arial" size="4"><b>Mode of Action</b></font></td></tr><tr valign="middle"><td align="center"><font face="arial"size="4"><b>Agonists</b></font></td><td colspan="2">&nbsp;</td></tr><tr valign="middle"><td align="center"><font face="arial" size="3">Nicotine</font></td><td align="left"><font face="arial" size="3">Alkaloid prevalent in the tobacco plant</font></td><td align="left"><font face="arial" size="3">Activates nicotinic class of ACh receptors, locks the channel open</font></td></tr><tr valign="middle"><td align="center"><font face="arial" size="3">Muscarine</font></td><td align="left"><font face="arial" size="3">Alkaloid produced by <i>Amanita muscaria</i> mushrooms</font></td><td align="left"><font face="arial" size="3">Activates muscarinic class of ACh receptors</font></td>

</tr><tr valign="middle"><td align="center"><font face="arial" size="3"><font face="symbol">a</font>-Latrotoxin</font></td><td align="left"><font face="arial" size="3">Protein produced by the black widow spider</font></td><td align="left"><font face="arial" size="3">Induces massive ACh release, possibly by acting as a Ca<sup>2+</sup> ionophore</font></td>

</tr><tr valign="middle"><td align="center"><font face="arial" size="4"><b>Antagonists</b></font></td><td colspan="2">&nbsp;</td>

</tr><tr valign="middle"><td align="left"><font face="arial" size="3">Atropine (and related compound Scopolamine)</font></td><td align="left"><font face="arial" size="3">Alkaloid produced by the deadly nightshade, <i>Atropa belladonna</i></font></td><td align="left"><font face="arial" size="3">Blocks ACh actions only at muscarinic receptors</font></td>

</tr><tr valign="middle"><td align="center"><font face="arial" size="3">Botulinus Toxin</font></td><td align="left"><font face="arial" size="3">Eight proteins produced by <i>Clostridium botulinum</i></font></td><td align="left"><font face="arial" size="3">Inhibits the release of ACh</font></td>

</tr><tr valign="middle"><td align="center"><font face="arial" size="3"><font face="symbol">a</font>-Bungarotoxin</font></td><td align="left"><font face="arial" size="3">Protein produced by <i>Bungarus</i> genus of snakes</font></td><td align="left"><font face="arial" size="3">Prevents ACh receptor channel opening</font></td>

</tr><tr valign="middle"><td align="center"><font face="arial" size="3"><i>d</i>-Tubocurarine</font></td><td align="left"><font face="arial" size="3">Active ingredient of curare</font></td><td align="left"><font face="arial" size="3">Prevents ACh receptor channel opening at motor end-plate</font></td>
</dd></font><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top"></a></font>
<a name="catecholamines"><font face="arial" size="5"><b></b><center><b>Catecholamines</b></center></font></a>
<p><font face="arial"><dd>The principal catecholamines are <b><font color="red">norepinephrine</font></b><font color="red"></font>, <b><font color="red">epinephrine</font></b><font color="red"></font> and <b><font color="red">dopamine</font></b><font color="red"></font>. These compounds are formed from phenylalanine and tyrosine. Tyrosine is produced in the liver from phenylalanine through the action of phenylalanine hydroxylase. The tyrosine is then transported to catecholamine-secreting neurons where a series of reactions convert it to dopamine, to norepinephrine and finally to epinephrine (see <a style="text-decoration: none;" href="aminoacidderivatives.html#tyrosine">Specialized Products of Amino Acids</a>).
</dd><dd>Catecholamines exhibit peripheral nervous system excitatory and inhibitory effects as well as actions in the CNS such as respiratory stimulation and an increase in psychomotor activity. The excitatory effects are exerted upon smooth muscle cells of the vessels that supply blood to the skin and mucous membranes. Cardiac function is also subject to excitatory effects, which lead to an increase in heart rate and in the force of contraction. Inhibitory effects, by contrast, are exerted upon smooth muscle cells in the wall of the gut, the bronchial tree of the lungs, and the vessels that supply blood to skeletal muscle.
</dd><dd>In addition to their effects as neurotransmitters, norepinephrine and epinephrine can influence the rate of metabolism. This influence works both by modulating endocrine function such as insulin secretion and by increasing the rate of glycogenolysis and fatty acid mobilization.
</dd><dd>The catecholamines bind to two different classes of receptors termed the <font face="symbol">a</font>- and <font face="symbol">b</font>-adrenergic receptors. The catecholamines therefore are also known as <b><font color="red">adrenergic neurotransmitters</font></b><font color="red"></font>; neurons that secrete them are <b><font color="red">adrenergic neurons</font></b><font color="red"></font>. Norepinephrine-secreting neurons are <b><font color="red">noradrenergic</font></b><font color="red"></font>. The adrenergic receptors are classical serpentine receptors that couple to intracellular G-proteins. Some of the norepinephrine released from presynaptic noradrenergic neurons recycled in the presynaptic neuron by a reuptake mechanism.
<p><b></b></p><center><b><font face="arial" size="5">Catecholamine Catabolism</font></b></center><font face="arial" size="5"></font>
<p></p></dd><dd>Epinephrine and norepinephrine are catabolized to inactive compounds through the sequential actions of catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO). Compounds that inhibit the action of MAO have been shown to have beneficial effects in the treatment of clinical depression, even when tricyclic antidepressants are ineffective. The utility of MAO inhibitors was discovered serendipitously when patients treated for tuberculosis with isoniazid showed signs of an improvement in mood; isoniazid was subsequently found to work by inhibiting MAO.
</p><center><table bgcolor="white" border="4" cellpadding="5">
<tbody><tr valign="middle"><td align="center">
<img src="catecholamine-metabolism.jpg" height="380" width="700"></td>
</tr><tr valign="middle"><td align="left"><font fac="arial">Metabolism of the catecholamine neurotransmitters. Only clinically important enzymes are included in this diagram. The catabolic byproducts of the catecholamines, whose levels in the cerebrospinal fluid are indicative of defects in catabolism, are underlined. Abbreviations: TH = tyrosine hydroxylase, DHPR = dihydropteridine reductase, H<sub>2</sub>B = dihydrobiopterin, H<sub>4</sub>B = tetrahyrobiopterin, MAO = monoamine oxidase, COMT = catecholamine-<i>O</i>-methyltransferase, MHPG = 3-methoxy-4-hydroxyphenylglycol, DOPAC = dihydroxyphenylacetic acid.</font></td>
<br><font face="arial" size="3"><a style="text-decoration: none;" href="nerves.html#top"> </a></font>
<a name="5ht"><font face="arial" size="5"><b></b><center><b>Serotonin</b></center></font></a>
<p><font face="arial"><dd>Serotonin (5-hydroxytryptamine, <b><font color="red">5HT</font></b><font color="red"></font>) is formed by the hydroxylation and decarboxylation of tryptophan (see <a style="text-decoration: none;" href="aminoacidderivatives.html#tryptophan">Specialized Products of Amino Acids</a>). The greatest concentration of 5HT (90%) is found in the enterochromaffin cells of the gastrointestinal tract. Most of the remainder of the body's 5HT is found in platelets and the CNS. The effects of 5HT are felt most prominently in the cardiovascular system, with additional effects in the respiratory system and the intestines. Vasoconstriction is a classic response to the administration of 5HT.
</dd><dd>Neurons that secrete 5HT are termed <b><font color="red">serotonergic</font></b><font color="red"></font>. Following the release of 5HT, a portion is taken back up by the presynaptic serotonergic neuron in a manner similar to that of the reuptake of norepinephrine.
</dd><dd>The function of serotonin is exerted upon its interaction with specific receptors. Several serotonin receptors have been cloned and are identified as 5HT<sub>1</sub>, 5HT<sub>2</sub>, 5HT<sub>3</sub>, 5HT<sub>4</sub>, 5HT<sub>5</sub>, 5HT<sub>6</sub>, and 5HT<sub>7</sub>. Within the 5HT<sub>1</sub> group there are subtypes 5HT<sub>1A</sub>, 5HT<sub>1B</sub>, 5HT<sub>1D</sub>, 5HT<sub>1E</sub>, and 5HT<sub>1F</sub>. There are three 5HT<sub>2</sub> subtypes, 5HT<sub>2A</sub>, 5HT<sub>2B</sub>, and 5HT<sub>2C</sub> as well as two 5HT<sub>5</sub> subtypes, 5HT<sub>5a</sub> and 5HT<sub>5B</sub>. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase C<font face="symbol">g</font>. The 5HT<sub>3</sub> class of receptors are ion channels.
</dd><dd>Some serotonin receptors are presynaptic and others postsynaptic. The 5HT<sub>2A</sub> receptors mediate platelet aggregation and smooth muscle contraction. The 5HT<sub>2C</sub> receptors are suspected in control of food intake as mice lacking this gene become obese fromincreased food intake and are also subject to fatal seizures. The 5HT<sub>3</sub> receptors are present in the gastrointestinal tract and are related to vomiting. Also present in the gastrointestinal tract are 5HT<sub>4</sub> receptors where they function in secretion and peristalsis. The 5HT<sub>6</sub> and 5HT<sub>7</sub> receptors are distributed throughout the limbic system of the brain and the 5HT<sub>6</sub> receptors have high affinity for antidepressant drugs.
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<a name="gaba"><font face="arial" size="5"><b></b><center><b>GABA</b></center></font></a>
<p><font face="arial"><dd>Several amino acids have distinct excitatory or inhibitory effects upon the nervous system. The amino acid derivative, <font face="symbol">g</font>-aminobutyrate, also called 4-aminobutyrate, (<b><font color="red">GABA</font></b><font color="red"></font>) is a well-known inhibitor of presynaptic transmission in the CNS, and also in the retina. The formation of GABA occurs by the decarboxylation of glutamate catalyzed by glutamate decarboxylase (<font color="red">GAD</font>). GAD is present in many nerve endings of the brain as well as in the <font face="symbol">b</font>-cells of the pancreas. Neurons that secrete GABA are termed <b><font color="red">GABAergic</font></b><font color="red"></font>.
</dd><dd>GABA exerts its effects by binding to two distinct receptors, GABA-A and GABA-B. The GABA-A receptors form a Cl<sup>-</sup> channel. The binding of GABA to GABA-A receptors increases the Cl<sup>-</sup> conductance of presynaptic neurons. The anxiolytic drugs of the benzodiazepine family exert their soothing effects by potentiating the responses of GABA-A receptors to GABA binding. The GABA-B receptors are coupled to an intracellular G-protein and act by increasing conductance of an associated K<sup>+</sup> channel.
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<font face="arial" size="3"><font><font face="arial" size="3">Michael W. King, Ph.D / IU School of Medicine / miking at</font>
<font face="arial" size="3"><font><font face="arial" size="3">Last modified:</font>&nbsp;&nbsp; <b><font face="arial" size="3">Monday, 22-Aug-2005 08:08:44 EST
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01-23-06, 11:52 PM
Awesome, Andi...Thank you for posting this!

02-17-06, 01:49 AM
This information is absolutely outstanding !!
Thank you, Andi !!!!

08-16-06, 12:38 AM
Posted to two other forums recently saying I was looking for this!


03-02-09, 02:03 PM
:)Wow thank you for such an alluminating post. I am trying to help my Dr. find the right meds for me and this really helps.