Neuromodulators vs Neurotransmitters

Cross references:  Neuromodulators in General    Neuropeptides     @ 
Neurotransmitters in General     GABA/Glycine Inhibition   

This is a new page focused on the distinction between Neuromodulators  and Neurotransmitters.  I'll be working on it, little by little, as we go along. 

As can be seen, below, the major difference is the specificity of their actions.  Neurotransmitters transmit signals from one presynaptic neuron directly to a postsynaptic partner (one neuron reaching one other neuron ).  In contrast, in neuromodulation transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons.

Neurotransmitters in General  
"Neurotransmitters are endogenous chemicals which transmit signals from a neuron to a target cell across the synapse.[1]    
    Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse.  
    Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may follow graded electrical potentials.  
    Low level "baseline" release also occurs without electrical stimulation.

Neuromodulators in General   
"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."   


The references in  Reticulospinal Transmission  discuss both electrical and chemical experimental procedures.  Unfortunately, the chemical experimental procedures always seem to conflate Neuromodulators with Neurotransmitters.  I wonder at what point in history was a clear distinction made between the two.  I searched PubMed for "neurotransmitter neuromodulator" and found 1,186,567 references.  Adding "history" to the search terms reduced the number of references, but only to 16,169.  Perhaps I should accept the electrical data and reject the chemical data.  Are all the papers which present data on "neurotransmitters" in reality discussing "neuromodulators" without realizing it?   

Searching PubMed for just "neuromodulators" identified 1,187,082 references:  

The oldest, #1,187,082, was dated 1944, 

Using the "Advanced" search function to search for "neuromodulators" in the Title reduced the number of identified references to 181  , 

the oldest of which was dated 1975.  So it's not a new concept.      

    The reference, "Monosynaptic excitatory amino acid transmission ..." (1989)  discussed in Reticulospinal Transmission  provides an example of data which is not corrupted by conflation between Neuromodulators and Neurotransmitters , so I'm going to build on that.  In particular,  the use of simultaneous paired intracellular recordings from one pre- and one postsynaptic cell seems pretty unambiguous.       

Reticulospinal neurones provide monosynaptic glycinergic inhibition of spinal neurones in lamprey.   
Simultaneous intracellular recordings from a reticulospinal neurone and spinal target neurone shows that the former may evoke an IPSP in the latter.
    Discussed in Reticulospinal Transmission

Trigeminal inputs to reticulospinal neurones in lampreys are mediated by excitatory and inhibitory amino acids.  
The in vitro brainstem/spinal cord preparation of the lamprey was used for characterizing trigeminal inputs to RS neurones as well as the transmitter systems involved. The trigeminal nerve on each side was electrically stimulated and synaptic responses, which consisted of mixed excitation and inhibition, were recorded intracellularly in the middle and posterior rhombencephalic reticular nuclei."  
My Comment
    This reference starts out by describing electrical stimulation of a nerve and electrically monitoring the response, but then discusses receptors which were apparently activated by bath-applied ligands.  These would have been neuromodulators rather than neurotransmitters.