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Universiteit Leiden

The next big(ger) thing: Metamodulation

Posted on in Pharma
The next big(ger) thing: Metamodulation

Neuromodulation has been a field of great interest, providing valuable insights into the effects of substances on the activity of neurons. However, it appears that neuromodulators are not insensitive to modulation themselves, leading to metamodulation.

Neuromodulation is a phenomenon that has been investigated in a rather extensive way, covering a variety of different neurotransmitters such as serotonin, norepinephrine, dopamine and many others. The effects of many of these neuro-modulators have been and continue to be explored, providing useful insights into how our brain regulates and is regulated. However, still very little attention is paid to the way in which neuromodulatory effects can be affected themselves, by other neuromodulators or even by behavioural states of an organism.

This underexposed type of neuro-modulation is called ‘metamodulation’ and occurs when the effect of for instance dopamine administration is exacerbated or even substantially altered by a ‘third party’ such as another neurotransmitter or even a state an organism is in.

An example of the former type of metamodulation comes from animal research, showing that in the medicinal leech, Hirudo medicinalis, a cocktail of octopamine and serotonin inhibits swimming behaviour, whereas these two transmitters separately lead to increased fictive swimming.

The latter type of metamodulation (i.e. modulation by behavioural states) also is provided by animal research showing that the social status of a crayfish can modulate the serotonergic modulation of neuronal activity responsible for flight behaviour in the animal. As illustrated by the aforementioned examples, studies have thus shown that metamodulation is a meaningful phenomenon with the ability to alter neuromodulatory effects in ways we might not have been aware of previously.

Unfortunately, literature on this subject is scarce and, most importantly, no published studies have addressed possible metamodulation in humans. This is particularly striking when considering that treatments for clinical disorders are regularly based on neuromodulation studies and the lack of research concerning metamodulation could prove to be crucial in explaining why some treatments do not show the desired effect or even no effect at all.

Why scientists have shown so little interest as of yet in exploring metamodulation in general, we do not know. Perhaps its relevance is not yet fully recognized, but hopefully studies that have been done with small animals like crayfish and leeches will lead to more research on metamodulation and an improved understanding of the bigger animal, ourselves. Given time and resources metamodulation could definitely be the next big(ger) thing.

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