12 - Neurotransmitters

Cross references:   

Up until now, we've been dealing with the brain in fairly large chunks: the reticular formation, the medulla, etc.  Now, however, I think we've reached the point where it would be helpful to focus in a little more closely on the fine structure.

In addition to references to your book, I'll be giving links.  I urge you to spend as much time as you can exploring them.  However, there really are a lot of them.  I would suggest that you take the links in the order that I have given them.  I've put the WikiPedia link first, since that gives the broadest coverage and offers many additional links.

Next I've listed the link(s) from "The Brain from Top to Bottom".  This is a website which covers every topic on three levels (beginner, intermediate, and advanced) from five different perspectives (social, psychological, neurological, cellular and molecular).  That's 15 pages for each topic.  At first I only gave one representative page for each topic, leaving it up to you to find the others.  Later on I began listing many of them.  I don't know which is the better approach.

Finally I've given links from Neurogenesis, which is a company which makes supplements which help the body produce neurotransmitters.

If you find something that seems to contradict anything that I've said, please let me know.

To start off, your book gives a picture and description of a neuron on [K&W:80-81].  Relevant links:

http://en.wikipedia.org/wiki/Neurons
http://thebrain.mcgill.ca/flash/i/i_01/i_01_cl/i_01_cl_ana/i_01_cl_ana.html
http://www.neurogenesis.com/Neuroscience/neurons.php


The variety of synapses and the important distinction between excitatory (+) and inhibitory (-) messages is then discussed on [K&W:154-162].  Links:

http://en.wikipedia.org/wiki/Chemical_synapse
http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html
http://www.neurogenesis.com/Neuroscience/dendrites.php


The discussion of action potentials on [K&W:123-132] is well written and has good pictures.  Links:

http://en.wikipedia.org/wiki/Action_potential
http://thebrain.mcgill.ca/flash/a/a_01/a_01_cl/a_01_cl_fon/a_01_cl_fon.html
  (click on A, B, C to watch the action potential develop)
http://www.neurogenesis.com/Neuroscience/axons.php


Although the discussion of transmitters and receptors on [K&W:165-170] is quite detailed, it will be immediately relevant to our discussion, so I will expand on some of the details.  Links:

http://en.wikipedia.org/wiki/Neurotransmitters
http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html
http://www.neurogenesis.com/Neurotransmitters/neurotransmitters-overview.php
http://www.neurogenesis.com/Neurotransmitters/how-it-works.php


Most, but not quite all, of the transmitters we will be considering fall within the book's "small molecule" classification discussed on [K&W:164-166].  The two most important are glutamate and GABA, which are discussed in more detail on [K&W:166].  Although glutamate and GABA have very different names, as you can see from the diagram on [K&W:166], they have very similar chemical structures, and our bodies manufacture GABA from glutamate.  

 Glutamate Links:  (some are repeats)

http://en.wikipedia.org/wiki/Glutamate
http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html

GABA Links: (some are repeats)

http://en.wikipedia.org/wiki/GABA
http://thebrain.mcgill.ca/flash/d/d_04/d_04_m/d_04_m_peu/d_04_m_peu.html
http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html
http://www.neurogenesis.com/Neurotransmitters/gaba.php


The effect that neurotransmitters, such as glutamate and GABA, have on the neuron to which their message is being transmitted depends on the type of the receptor that is receiving the message on the recipient neuron.  Neuroreceptors are very specific both in the transmitters with which they bind and on the effect that such binding has on the recipient neuron.  Evolution has produced multiple receptors for each of the neurotransmitters, and two different receptors for the same transmitter can have quite different effects on the recipient neuron on whose surface they reside.

We have already seen on [K&W:162] that some synapses are excitatory (+) and some are inhibitory (-).  The synapse, of course, is the junction between two neurons where neurotransmitter from one binds with a receptor on the other.  The reason that some synapses are excitatory (+) and others inhibitory (-) is that some receptors are excitatory (+) while others are inhibitory (-).

There is one additional very important way in which receptors can vary. On [K&W:167-170], the book distinguishes between two kinds of receptors which it calls "ionotropic" and "metabotropic", but it fails to talk about the most important difference between the two.
 
Ionotropic receptors are fast.  They cause an immediate change in membrane potential, and this change lasts only a very short time.  In contrast, metabotropic receptors are relatively slow in changing membrane potential, and these changes are relatively long lasting.  Thus, I will refer to ionotropic receptors as "fast" (f) receptors and metabotropic receptors as "slow" (s) receptors.

Ionotropic Links:

http://en.wikipedia.org/wiki/Ionotropic

Metabotropic Links:

http://en.wikipedia.org/wiki/Metabotropic


We now have two independent parameters for describing receptors: direction and speed.  The four possibilities are:  

    (+f) = excitatory and fast
    (+s) = excitatory and slow
    (-f) = inhibitory and fast
    (-s) = inhibitory and slow.  


Glutamate is by far the most important transmitter in the human brain.  It is the major transmitter of most "long" axons, including the reticular formation, all primary sensory neurons and the neurons providing both output from and interconnection within the cerebral cortex.  Virtually all glutamate receptors are excitatory (+), and most are fast (+f).  

The changes at a glutamatergic synapse associated with learning are described on [K&W:181-184].  The NMDA and AMPA receptors are named by the artificial drugs with which they react.  The AMPA receptors are fast (+f), and they are, by far, the most common receptors in the central nervous system.  NMDA receptors, as you will see from the pages cited above, are an exception to the slow-fast dichotomy. They are ionotropic, but slow.  


Learning Links:

http://thebrain.mcgill.ca/flash/d/d_07/d_07_p/d_07_p_tra/d_07_p_tra.html
http://thebrain.mcgill.ca/flash/d/d_07/d_07_cl/d_07_cl_tra/d_07_cl_tra.html
http://thebrain.mcgill.ca/flash/i/i_07/i_07_cl/i_07_cl_tra/i_07_cl_tra.html
http://thebrain.mcgill.ca/flash/a/a_07/a_07_cl/a_07_cl_tra/a_07_cl_tra.html

AMPA Links:

http://en.wikipedia.org/wiki/AMPA
http://thebrain.mcgill.ca/flash/i/i_07/i_07_m/i_07_m_tra/i_07_m_tra.html


NMDA Links:

http://en.wikipedia.org/wiki/NMDA
http://thebrain.mcgill.ca/flash/i/i_07/i_07_m/i_07_m_tra/i_07_m_tra.html

 
In a similar, but opposite, fashion, all GABA receptors are inhibitory (-), with some being fast (-f) and some being slow (-s).  Unlike the neurons which use glutamate as a transmitter, neurons which use GABA as a transmitter range between moderately short and extremely short.

GABA is the second most important transmitter in the human nervous system after glutamate.  The two transmitters work together.  Becoming overly excited can quite literally kill a neuron, and the input of excitatory (+) sensory neurons into excitatory (+) reticular neurons has the potential of causing fatal over excitation.  This is prevented by GABA neurons which counter the excitation which is transmitted by the sensory neurons and amplified by the reticular neurons.  

GABA Links:

(See above.)

The neurons of the four ascending systems depicted on [K&W:173-174] have receptors which can be either excitatory (+) or inhibitory (-) and either fast (f) or slow (s).  However, not all transmitters have all kinds of receptors.  I will list the kinds of receptors for each of the four ascending systems for your future reference.  We will be coming back to this many times in the future.  


Acetylcholine (ACh) receptors can be either excitatory and fast (+f) or excitatory and slow (+s).  Acetylcholine does not have any inhibitory receptors, and in this way it is similar to glutamate.  However, unlike glutamate, most of whose receptors in the central nervous system are fast (+f), most acetylcholine receptors in the central nervous system are slow (+s).  The fast (+f) acetylcholine receptors are at the neuromuscular junction where they excite the muscle to contact [K&W:141&164-166] .  

ACh Links:

http://en.wikipedia.org/wiki/Acetylcholine
http://thebrain.mcgill.ca/flash/i/i_11/i_11_cr/i_11_cr_cyc/i_11_cr_cyc.html
http://thebrain.mcgill.ca/flash/a/a_06/a_06_m/a_06_m_mou/a_06_m_mou.html


Dopamine (DA) is the neurotransmitter which is most involved in psychological behavior, and it is probably fair to say that it is the third most important transmitter, after glutamate and GABA.  All dopamine receptors are slow, but some are slowly excitatory (+s), and some are slowly inhibitory (-s).

DA Links:

http://en.wikipedia.org/wiki/Dopamine
http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_nicotine.html

NOTE:  The Brain Top to Bottom search engine at the bottom of each page gives 62 hits for "dopamine".  This attests to its importance.  I'll list a few, below, and leave it up to you to look for the rest, if you have time and interest.

http://www.neurogenesis.com/Neurotransmitters/dopamine.php


The "dopamine hypothesis" of drug addiction is briefly mentioned in the caption to Figure 6-18 on [K&W:219].  You will note that, in addition to the parts of the brain labeled in Figure 5-19 on [K&W:174], Figure 6-18 also labeles the Ventral Tegmental Area (VTA) of the midbrain and the Nucleus Accumbens Septi (NAC) of the basal ganglia.  The nucleus accumbens septi (NAC) is frequently said to form the interface between the emotions and behavior and UCSF researcher James Olds, who spent many years studying it, dubbed it the "pleasure center".

Pleasure Center Links:

http://en.wikipedia.org/wiki/Pleasure_center
http://thebrain.mcgill.ca/flash/d/d_03/d_03_cl/d_03_cl_par/d_03_cl_par.html
http://thebrain.mcgill.ca/flash/d/d_03/d_03_cr/d_03_cr_par/d_03_cr_par.html
http://thebrain.mcgill.ca/flash/i/i_03/i_03_cr/i_03_cr_par/i_03_cr_par.html
http://thebrain.mcgill.ca/flash/i/i_03/i_03_cl/i_03_cl_par/i_03_cl_par.html
http://thebrain.mcgill.ca/flash/a/a_03/a_03_cr/a_03_cr_par/a_03_cr_par.html
http://thebrain.mcgill.ca/flash/a/a_03/a_03_cl/a_03_cl_par/a_03_cl_par.html

Drug Addiction Links:

http://en.wikipedia.org/wiki/Drug_addiction
http://thebrain.mcgill.ca/flash/i/i_03/i_03_p/i_03_p_par/i_03_p_par.html
http://thebrain.mcgill.ca/flash/a/a_03/a_03_p/a_03_p_par/a_03_p_par.html


Norepinephrine (Nor) receptors are always excitatory and slow (+s).  Norepinephrine is very closely related to the hormone adrenaline.

Links:

http://en.wikipedia.org/wiki/Norepinephrine
http://thebrain.mcgill.ca/flash/d/d_11/d_11_cl/d_11_cl_cyc/d_11_cl_cyc.html
http://thebrain.mcgill.ca/flash/i/i_11/i_11_cl/i_11_cl_cyc/i_11_cl_cyc.html
http://thebrain.mcgill.ca/flash/a/a_11/a_11_cl/a_11_cl_cyc/a_11_cl_cyc.html
http://thebrain.mcgill.ca/flash/d/d_11/d_11_m/d_11_m_cyc/d_11_m_cyc.html
http://thebrain.mcgill.ca/flash/i/i_11/i_11_m/i_11_m_cyc/i_11_m_cyc.html
http://www.neurogenesis.com/Neurotransmitters/norepinephrine.php


Serotonin (5HT) - (the abbreviation stands for "five hydroxytryptamine", the transmitter's chemical name) receptors can be quickly excitatory (+f), slowly excitatory (+s) or slowly inhibitory (-s).  Serotonin is the second most important neurotransmitter, after dopamine, in psychological processes, and the fourth most important neurotransmitter overall, after glutamate, GABA and dopamine.

Links:

http://en.wikipedia.org/wiki/Serotonin
http://thebrain.mcgill.ca/flash/a/a_08/a_08_m/a_08_m_dep/a_08_m_dep.html
http://thebrain.mcgill.ca/flash/d/d_08/d_08_m/d_08_m_dep/d_08_m_dep.html
http://thebrain.mcgill.ca/flash/i/i_08/i_08_m/i_08_m_dep/i_08_m_dep.html

NOTE:  See also many of the links given for norepinephrine, above, which deal with sleep and waking.

http://www.neurogenesis.com/Neurotransmitters/serotonin.php


All of the above are among the small molecule transmitters listed in Table 5-1 on [K&W:166].  I anticipate that we will be discussing only two of the peptide neurotransmitters listed in Table 5-2 on [K&W:167], enkephaline and oxytocin.

You will notice that enkephaline (which is sometimes called endorphin) is listed as being in the family of the opioids.  Your book provides a general discussion of drugs on [K&W:190-233], and we will talk more about them after we have looked more closely at the nucleus accumbens septi.  Enkephaline is an inhibitory slow (-s) transmitter, and it is accepted that opium has a similar effect when acting at an enkephaline receptor.

Links:

http://en.wikipedia.org/wiki/Enkephaline
http://en.wikipedia.org/wiki/Opium

NOTE:  See also the links under "Pleasure Center", above.

http://www.neurogenesis.com/Neurotransmitters/enkephalin.php

Oxytocin is both a neurotransmitter and a hormone.  Like enkephaline, when it is functioning as a neurotransmitter, its action is inhibitory and slow (-s).  It's function as a hormone is discussed on [K&W:416], and we will discuss it at greater length when we discuss the endocrine system.

Links:

http://en.wikipedia.org/wiki/Oxytocin






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