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Dale’s law is one of the principles of neurobiology that states that a single neuron releases the same neurotransmitter, or in its case, a group of neurotransmitters in all the synaptic connections it possesses. However, recent studies have cast a cloud of doubt on this principle, and it is important to review its validity and veracity in the biology of the nervous system in living beings.

Henry Dale

Sir Henry Hallett Dale, OM, GBE, PRS, after whom Dale's Law got its name
Dale’s law owes its name to the researcher Henry Dale, who dedicated a great part of his academic life to studying the effect of substances such as histamine and adrenaline, their presence and function in living beings. Some of his contributions were the terms “cholinergic” and “adrenergic” in medical terminology. These terms are used to designate those nerves that release acetylcholine or adrenaline in their synaptic endings. With these major discoveries, important advances were made in the study of the autonomic nervous system. The researcher was awarded the Nobel Prize for Medicine in 1936, which he shared with Otto Loewi, thanks to his research on excitation and chemical transmission of nerve impulses.

The History of Dale’s Law

Serotonin and Dopamine are the most commonly known neurotransmitters
When neurotransmitters come up in conversation, most people think of the most commonly known ones: dopamine, serotonin, etc. And it is known that they serve as a means of communication between neurons and between other cells in the body that are involved in the proper functioning of the whole organism. In the early 20th century, the researcher Sir Henry Dale thought that individual neurons are limited to secrete the same neurotransmitter in all the synaptic terminations of their axons, which are branches of the spindle that leave the main cell body. On the other hand, another of the most important scientists of that time, Sir John Eccles, corroborated Dale’s law but, in other terms, establishing that neurons only emit one neurotransmitter. From that moment on and for many years since, the idea of “nerve cell and a single neurotransmitter” was widely accepted.

Is It Still Valid?

Dale's Law was misinterpreted
This law was first postulated with a degree of ambiguity, some researchers, such as John C. Eccles, understood the law as follows: “neurons release the same group of neurotransmitters at all their synapses”; while others interpreted the original statement in this other way: “neurons release only one neurotransmitter at all their synapses.” This is why there were two versions of Dale’s law that supported similar things but not the same, that is to say, with nuances. It is important to mention that in those years, when the law was postulated, only two neurotransmitters were known: acetylcholine and noradrenaline (which at that time was believed to be adrenaline); and the idea of a neuron releasing not only one but several neurotransmitters in a single synaptic connection was not even considered. 

This aforementioned ambiguity in the hypothesis Dale formulated resulted in confusion about what the postulated principle actually meant. We now know for sure that the law was misinterpreted as denying the possibility that a neuron could release more than one neurotransmitter. However, Dale’s principle, i.e., the hypothesis that a neuron releases only one neurotransmitter at all its synapses, has now been proven to be false. It is an established scientific fact that many neurons release more than one chemical messenger, a phenomenon called cotransmission.

Cotransmission

The words nitric oxide spelt out with childrens letters on a wooden table, beside a stethoscope
For a long time, the understanding of the mechanisms of neurotransmission by the academic and research community has been based on Dale’s law, which, as already mentioned, postulated that a neuron could only release a single neurotransmitter from its synaptic terminals. However, it was in the 1970s that new lines and areas of research emerged that challenged these ideas. The concept of cotransmission came into use in the mid-1970s by, among other scientists, Geoffrey Burnstock. This concept introduces the idea that individual neurons, both in the central nervous system and in the peripheral system, contain and can release a large number and variety of substances that are capable of influencing target cells. It is then that cotransmission involves the release of various types of neurotransmitters, neuromodulators, and substances in a single neuron, which allows the complex effects of postsynaptic receptors to take place, and thus, creates the generation of complex and functional communication that takes place in normal nerve transmission. 

Today we know that, contrary to what Dale’s principle postulated, it is not exceptional for neurons to release neurotransmitters in the company of other substances (cotransmitters), such as ATP (energy source and important neurotransmitter of the nervous system), nitric oxide, or neuropeptides (tiny fast-acting proteins). Today, it is known that Dale’s law is not what actually occurs in neurons. It is not extraordinary that neurons release neurotransmitters together with other chemical compounds (cotransmitters). A clear and common example is ATP (the energy currency of the cell and an important neurotransmitter in the nervous system), nitric oxide, and neuropeptides (small, fast-acting protein molecules).

There are several examples of neuronal cotransmission. In the sympathetic nervous system, ATP is released with noradrenaline, and both neurotransmitters exert their action by activating certain receptors, which end up being expressed in smooth muscle cells. In this way, ATP participates in the contraction of these muscles. In parasympathetic nerves, we can also find examples of cotransmission. Acetylcholine, vasoactive intestinal polypeptide (VIP), ATP, and nitric oxide are cotransmitters synthesized and released by this type of nerves. For example, nitric oxide acts as the main mediator of neurogenic vasodilation in cerebral vessels, whereas VIP plays an essential role during neurogenic vasodilation in the pancreas.

In modern neuroscience, neurons are often classified by their cotransmitter, e.g., GABAergic neurons in the striatum use opioid peptide or substance P as their primary cotransmitter. Some neurons may release at least two neurotransmitters at the same time – one is the primary, and the other is a cotransmitter – in order to provide the negative feedback necessary for significant coding stabilization in the absence of inhibitory interneurons. 

Examples of cotransmitters include:

  • GABA with Glycine colliberation.
  • Dopamine with Glutamate colliberation.
  • Acetylcholine with Glutamate colliberation.
  • Acetylcholine with vasoactive intestinal peptide colliberation.
  • Acetylcholine with calcitonin gene-related peptide (CGRP) colliberation.
  • Glutamate with dynorphin (in the hippocampus) colliberation.
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