Dale’s principle is a general rule that a neuron releases the same neurotransmitter or group of neurotransmitters in all its synaptic connections. But what is true about this? Has current neuroscience partially or totally disproved this principle?

In this article we explain what Dale’s principle is and what its validity is today, what the phenomenon of co-transmission consists of and an example of it.

What is the Dale principle?

Dale’s principle or Dale’s law, named after the English physiologist Henry H. Dale, winner of the 1936 Nobel Prize in Physiology and Medicine for his findings on the transmission of nerve impulses, states that a neuron releases the same neurotransmitter (or group of neurotransmitters) in all its synaptic connections .

This principle was initially postulated with some ambiguity; some scientists, including John C. Eccles, interpreted it 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.”

As you can see, there seemed to be two versions of Dale’s principle that claimed something similar, but with nuances. At that time, only two neurotransmitters were known: acetylcholine and noradrenaline (which at the time was thought to be adrenaline); and the possibility of a neuron releasing more than one in a single synapse was not considered at all.

The ambiguity resulting from Dale’s original hypothesis caused some confusion about what the postulated principle meant. In short, it was misinterpreted as denying the possibility that a neuron could release more than one neurotransmitter.

However, the Dale principle, i.e. the hypothesis that a neuron releases only one neurotransmitter in all its synapses, has now been proven to be false. It is established the scientific fact that many neurons release more than one chemical messenger , a phenomenon called cotransmission, which we will talk about next.

The phenomenon of co-transmission

For many years, the scientific community’s understanding of the mechanisms of neurotransmission has been subject to Dale’s law or principle, which, as we have mentioned, postulated that the concept of a neuron releasing only one neurotransmitter. However, from the 1970s onwards new lines of thought and research emerged that challenged these ideas.

The concept of cotransmission was first used 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 amount and variety of substances that are capable of influencing the target cells.

Co-transmission therefore involves the release of various types of neurotransmitters, neuromodulators and substances from a single neuron , allowing more complex effects to be exerted on the post-synaptic receptors and thus generating more complex communication than that which occurs in normal 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 (co-transmitters), such as ATP (an energy source and important neurotransmitter in the nervous system), nitric oxide or neuropeptides (tiny, fast-acting proteins).

There are several examples of neural co-transmission. In the sympathetic nervous system, ATP is colliberated with noradrenaline , and both neurotransmitters exert their action by activating certain receptors, which end up being expressed in the smooth muscle cells. In this way, ATP participates in the contraction of these muscles.

In the parasympathetic nerves, we can also find examples of co-transmission. Acetylcholine, vasoactive intestinal polypeptide (VIP), ATP and nitric oxide are co-transmitters synthesized and released by this type of nerve. For example, nitric oxide acts as the main mediator of neurogenic vasodilation in the brain vessels, while VIP plays an essential role during neurogenic vasodilation in the pancreas.

Studying co-transmission mechanisms: the Aplysia

After Dale’s principle, the study of the impact of cotransmission on the activity of a neuronal circuit has been analysed in detail in invertebrate animal systems, such as that of the Aplysia . Using electrophysiological techniques, the functions of cotransmitters in physiologically identified neurons in well-defined neuronal circuits have been identified and determined.

The Aplysia feeding circuit has provided important insights into the functional role of co-transmission, and how co-transmitters such as cardioactive peptide and myomodulin are able to modulate muscle contractions evoked by another neurotransmitter such as acetylcholine, which is released by motor neurons into the muscles responsible for controlling the animal’s feeding behaviour.

Aplysia can generate two antagonistic eating behaviours, namely: ingestion and egestion. Repetitive stimulation of the IWBC-2 interneuron would activate a central feeding pattern generator in the oral ganglion to progressively produce motor programs for food digestion.

Egging would be activated by repetitive stimulation of the oesophageal nerve, which induces a short-term boost of synaptic transmission between the B20 interneuron and the B8 motor neuron. B20 would have as co-transmitters neurotransmitters such as GABA and dopamine.

Dopamine in this case would act as a fast exciter transmitter , exerting an effect on a receiver similar to 5-HT3. Gaba, on the other hand, would not have any direct effect on these synapses, but could enhance dopaminergic responses by acting on the GABA b receptor and subsequently activating protein kinase C.

The latter is an example where a “conventional” transmitter (such as GABA) would evoke a modulating effect, and the “modulating” transmitter (dopamine) would exert a conventional effect. This effect of GABA is considered as an example of intrinsic modulation by a co-transmitter, since it modulates the circuit to which it belongs.

Bibliographic references:

  • Burnstock, G. (1976). Do some nerve cells release more than one transmitter? Neuroscience, 1(4), 239-248.
  • Osborne, N. N. (1979). Is Dale’s principle valid? Trends in Neurosciences, 2, 73-75.
  • Strata, P., & Harvey, R. (1999). Dale’s principle. Brain research bulletin, 50(5-6), 349-350.
  • Vilim, F. S., Cropper, E. C., Price, D. A., Kupfermann, I., & Weiss, K. R. (1996). Release of peptide cotransmitters in Aplysia: regulation and functional implications. Journal of Neuroscience, 16(24), 8105-8114.