The History of Dale’s Law
Is It Still Valid?
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.
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.