Differences between neurotransmitters and neuromodulators

Question

According to the Wikipedia article on neuromodulation

a neuromodulator can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite.

In another Biology SE answer I read that

neurotransmitters can be considered neuromodulators when their action is on channels outside of the synaptic cleft.

Trying to bring these two conceptualizations together I come up with the following more specific differences between neurotransmitters and neuromodulators:

• Neurotransmitters have typical short delay times (until they reach a receptor). Neurohormones may have arbitrary long delay times (the time they need to diffuse through the extracellular fluid). As a slogan: "Neurotransmitters work at once, neurohormones with a distance-dependent delay."

• Neurotransmitters have specific target neurons (via the receptors of the synapse where they are released). The number of target neurons of a neuron (affected by the neurotransmitters it releases at its synapses) is rather well-defined (and goes into the thousands). The number of target neurons affected by the neurohormones a neuron releases is not so well-defined (and I'm missing an idea of the order of magnitude).

• Neurotransmitters are effective only once and for a short time (due to fast reabsorption or break down into metabolites). Neurohormones can be effective for a long period of time.

• This is due to different biochemical mechanisms by which specific neurotransmitters and neuromodulators affect specific receptors.

I wonder if this list is somehow correct and complete. (This is my question.)

Next to this list a list of commonalities would be interesting:

• The same molecules can be neurotransmitters and neuromodulators.

• Both are stored in and released from vesicles by similar mechanisms.

• Both get effective by interacting with receptors and affect if a ligand-gated ion channel opens or not.

Answer 1

Key points:

• Neurotransmitters directly stimulate or inhibit ionotropic receptors (the receptors of ion channels) in the postsynaptic membrane within a single synapse.
• Neuromodulators act on metabotropic receptors within or outside the synapses of many neurons at the same time; they modulate the release of neurotransmitters and excitability of ionotropic receptors; the signaling between metaboreceptors and ionoreceptors usually involves a cascade of secondary messengers.

Neurotransmitters

"Classical neurotransmitters" stimulate or inhibit the fast-acting ionotropic receptors of ion channels. Their actions last few milliseconds and are limited to a single synapse, which means they are released from a presynaptic membrane of one neuron and they target the postsynaptic membrane of one (or, sometimes two or maybe more) postsynaptic membranes of the neurons involved in the same synapse, or a single muscle cell or other target cell (Oxford Scholarship, The Revisionist).

Examples of neurotransmitters: noradrenaline, acetylcholine, dopamine.

Neuromodulators

Neuromodulators act on the slow-acting metabotropic receptors inside or outside the synapse of "thousands" of neurons at the same time. In long-term (minutes), they modulate the release of neurotransmitters and excitability of ionotropic receptors. They are usually (but not necessary) released from presynaptic membranes into the synapse by the same mechanisms as classical neurotransmitters but can then leave the synapse through "spillover" and act on the neurons other than those involved in the synapse. So, their action is diffuse, but usually still limited to to certain neural pathways. (International Encyclopedia of the Social & Behavioral Sciences, 2001, Encyclopaedia Britannica, Wikipedia, Current Opinion in Neurobiology)

Examples of neuromodulators: dopamine (D receptors), serotonin (5HT receptors), acetylcholine (M and nicotinic receptors), noradrenaline (alpha and beta receptors), histamine (H receptors), endorphins and neuropeptides (Wikipedia, Journal of Chemical Neuroanatomy, 2011.)

Neurohormones are released from neurons into the bloodstream and have a systemic effect, for example:

• Oxytocin and vasopressin, which are produced in the hypothalamus travel to neurohypophysis from where they are secreted into the blood and act on the mammary glands and uterus.
• Adrenaline, which is secreted from adrenal medulla acts, via sympathetic nervous system on various tissues, usually on the smooth muscles of the blood vessels, heart, gut, etc.

Can a certain molecule can be a neurotransmitter, neuoromodulator and neurohormone at the same time?

Yes, for example:

Noradrenaline acts as a classical neurotransmitter and neuromodulator in the postganglionic neurons of the sympathetic nervous system and as a neurohormone secreted from the adrenal medulla (International Encyclopedia of the Social & Behavioral Sciences, 2015)

Dopamine acts as a classical neurotransmitter and neuromodulator in the dopaminergic pathways in the deep areas of the brain, such as thalamus and pituitary gland (picture); as a hormone, it inhibits the secretion of prolactin from the pituitary gland.

Are both neurotransmitters and neuromodulators stored in and released from vesicles by similar mechanisms?

Yes or no. Neurotransmitters are always released into the synapse, while neuromodulators may or may not be released into the synapse (Oxford Scholarship).

Do both neurotransmitters and neuromodulators get effective by interacting with receptors and affect if a ligand-gated ion channel opens or not?

Neurotransmitters can be effective if the ligand-gated ion channel are open and neuromodulators can open or close the ion channels.

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Since the same molecule can be both a neurotransmitter and neuromodulator, it may not be that important to define the differences between the both in detail:

It could, therefore, be concluded that the aspect of defining neurotransmitters has taken a back seat to the investigation of the actions of individual signaling molecules. (International Encyclopedia of the Social & Behavioral Sciences, 2015)