Neuromodulators in General

Cross reference:  Neurotransmitters in General     Neuropeptides   

Neuromodulation (Wiki) 
http://en.wikipedia.org/wiki/Neuromodulation 
    "In Neuromodulation several classes of neurotransmitters regulate diverse populations of central nervous system neurons (one neuron uses different neurotransmitters to connect to several neurons). This is in contrast to direct synaptic transmission, in which one presynaptic neuron directly influences a postsynaptic partner (one neuron reaching one other neuron), neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons. Examples of neuromodulators include dopamine, serotonin, acetylcholine, histamine and others.               A neuromodulator is a relatively new concept. It can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Such neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid), influencing (or modulating) the overall activity level of the brain. For this reason, some neurotransmitters are also considered as neuromodulators.      
 
   Examples of neuromodulators in this category are serotonin and acetylcholine. More specifically, neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the transmitter acts on local postsynaptic receptors, but in the former case the receptors are typically 7-membrane spanning G-protein coupled receptors while in the latter case they are ligand-gated ion channels. The former type of synaptic transmission often involves effects on voltage-gated ion channels, and is quite slow. The latter type is much faster. A related distinction is also sometimes drawn between modulator and driver synaptic inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus causing that spiking.

My comments
    1.  Don't be mislead by their contrast between "...
synaptic transmission, in which one presynaptic neuron directly influences a postsynaptic partner (one neuron reaching one other neuron)
  ..." and "... neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons  ...". 
    This may make it sound like the 'presynaptic neuron' provides output to only one recipient neuron.  This is definitely not the truth.  The axon of the presynaptic neuron branches and rebranches multiple times so that each presynaptic neuron provides input to many, many postsynaptic neurons.  The point they're trying to make is that within each
Synapse , the presynaptic neuron provides input to only one postsynaptic neuron.  What they haven't mentioned is that the multiple branches of each presynaptic neuron have millions of synaptic connections with many, many different postsynaptic neurons. 
    It is, however, true that the many, many different postsynaptic neurons with which the presynaptic neuron synapses are probably closely bunched together in a few discrete nuclei while the 
"... neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons  ..."  and are not limited to influencing the behavior of recipient neurons in just a few discrete nuclei. 

    2.  The chart in this Wikipedia page shows
that the serotonergic output from the Dorsal Raphe Nucleus  (DRN)  to the  Nucleus Accumbens Septi (NAC) originates in the rostral  DRN.  Most other references cite the caudal DRN as the source of the Serotonin  supplied by the DRN to the NAC. 

    3.  For it to be true that " neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid), influencing (or modulating) the overall activity level of the brain" , it is necessary that they be able to cross the blood brain barrier.  Perhaps they do, but this isn't specifically stated with a reference. 

    4.  This provides a very helpful and important distinction: 

    Neurotransmitter:     
       
"classical fast synaptic transmission. ... the transmitter acts on local postsynaptic receptors, ... they are ligand-gated ion channels."   
        "
... much faster."  
        "
causing ... spiking

    Neuromodulator:     
     
   "... neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons."  
        "
A neuromodulator ... can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Such neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid), influencing (or modulating) the overall activity level of the brain."  
        "
... the receptors are typically 7-membrane spanning G-protein coupled receptors"  
        "
... often involves effects on voltage-gated ion channels, and is quite slow"  
        "...
modulating ongoing neuronal spiking ..."  

    5.  This distinction is supported by the Kimball reference in 
Synapse   which says: 
  • The neurotransmitter molecules bind to receptors on the postsynaptic membrane.
  • These receptors are ligand-gated ion channels.   

Catecholamine (Wiki)
http://en.wikipedia.org/wiki/Catecholamine

    "Two catecholamines, norepinephrine and dopamine, act as neuromodulators in the central nervous system and as hormones in the blood circulation. The catecholamine norepinephrine is a neuromodulator of the peripheral sympathetic nervous system but is also present in the blood (mostly through "spillover" from the synapses of the sympathetic system)."

 


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