Neurotransmitters: the what, why and how

Neurotransmitters operate as chemical messengers, responsible for the transmission of neuronal signals to target cells, from one cell to another.¹ An imbalance in a neurotransmitter can have major effects on a person’s health and mental wellbeing, making an understanding of the neurotransmitters beneficial. 

GABA (gamma-aminobutyric acid)

GABA is an inhibitory neurotransmitter involved in stress and personality and regulates plasma concentration, protein synthesis and growth hormones in the brain while offering hypotensive, diuretic and insulin regulation.² GABA is produced by the decarboxylation of glutamate catalysed by glutamate decarboxylase.²

GABA administration has been shown to reduce systolic blood pressure, while GABA foods are thought to support memory and learning and reduce cancerous tissue proliferation.² GABA’s inhibitory function occurs when GABA binds to the GABAergic receptor system (involving 3 receptors GABA-A, GABA-B and GABA-C) where it then modulates mood, sleep, temporal and spatial memory and has shown beneficial effects on asthma, epilepsy and depression.³ The hypotension benefits of GABA inhibit peripheral nervous system release of noradrenaline that reduces stimulation of the perivascular nerve, reducing blood pressure.³

GABA can be produced exogenously by microorganisms, mould, yeasts and fungi and is found in fermented foods involving lactic acid bacteria including kimchi, traditional Japanese fermented fish, pecorino cheese.² Gastrointestinal GABA can cross the blood brain barrier through vagus nerve neurotransmission the regulation of gut microbiota.³ Glutamate can be decarboxylated to produce GABA in a reaction dependent on vitamin B6.¹

Serotonin

Production of serotonin requires dietary tryptophan as a precursor occurring peripherally in the enterochromaffin cells of the gut or in the neurons in the raphe of the brain stem.⁴ L-tryptophan must cross the blood brain barrier where it is hydroxylated to 5-hydroxytryptophan by the iron-dependent enzyme tryptophan monoxygenase-fe,¹ then decarboxylated to serotonin (5-hydroxytryptamine by the enzyme 5-hydroxyindoleacetic acid.⁴ Central nervous system production accounts for 5% of total serotonin production, with the majority produced in the gastrointestinal tract and periphery.⁴ Gut microbes are involved in the production and regulation of serotonin levels in the body through the kynurenine pathway.⁴

Serotonin is involved in appetite control, sleep, mood, cognition and temperature, with low serotonin presenting with low mood and depression.⁴ Serotonin is also involved in vasoconstriction and contraction of smooth muscles.¹

Tryptophan is the precursor to serotonin production, with sources available in the diet in milk, tuna, turkey, chicken, oats, cheese, nuts and seeds and bread and endogenously from the liver.⁴ Short chain fatty acids produced by gut microbes can increase serotonin production by enterochromaffin cells.⁴ Vitamin B6 and magnesium are required for the conversion of tryptophan to serotonin.⁵ 

Melatonin

Melatonin is an endocrine and paracrine hormone with the majority of melatonin production centring in the gastrointestinal tract, followed by the pineal gland.⁶ As a lipophilic compound, melatonin is able to cross cellular membranes easily.⁶

Gastrointestinal melatonin is involved in motility, inflammation and pain and may be involved in biological rhythms, metabolism and reproduction.⁶ Gastrointestinal melatonin is found in greater levels near the rectum and colon compared to the ileum and jejunum where it is made by the enterochromaffin cells with L-tryptophan operating as a precursor to melatonin production.⁶ Melatonin from the pineal gland is secreted according to the circadian rhythm, with higher levels secreted in the evening based on light/dark information to promote sleep onset.⁶ 

Tryptophan is converted to serotonin in an iron-dependent reaction, and then converted to melatonin in a reaction involving Acetyl-CoA and S-adenosyl methionine.¹ Low tryptophan levels have been associated with a reduction of REM sleep, demonstrating the relationship between serotonin and melatonin in the pineal gland.⁴

Catecholamines - Dopamine, Norepinephrine and Epinephrine

Catecholamine production requires tyrosine and the iron dependent enzyme monooxygenase to hydroxylate tyrosine to form L-dopa which then undergoes further reactions to produce dopamine, epinephrine and norepinephrine.¹ 

Tyrosine can be produced endogenously from the conversion of phenylalanine and from dietary sources.⁷

Catecholamines have a role in metabolism and operate as hormones, while norepinephrine regulates sleep and alertness, epinephrine in circulation to support the catabolism of nutrients.¹

Dopamine has been shown to stimulate motivation and learning and coordination.^1,8

Acetylcholine

Choline is found in foods generally in the form of phosphatidylcholine in eggs, meat, liver, salmon, wheat germ and legumes as lecithin. Adequate pancreatic enzymes are required to free choline from its bound form lecithin.¹ Acetylcholine production requires choline to cross the blood brain barrier to the cerebral cells where in the neuronal presynaptic terminal acetylcholine is produced by combining choline with acetyl-CoA which is provided from glucose metabolism.¹

Histamine

Histamine is produced from histidine in a dicarboxylic reaction involving vitamin B6.¹ Histamine operates as a neurotransmitter and can stimulate hydrochloric acid in the stomach, stimulate vasoconstriction when released from mast cells in an immunologic response in the respiratory tract and epithelial cells, promoting bronchoconstriction of the lungs and increasing capillary permeability to allow the transport of white blood cells and phagocytes.¹ 

References

1. Gropper, S. S., & Smith, J. L. (2012). Advanced nutrition and human metabolism. Cengage Learning.
2. Dhakal, R., Bajpai, V. K., & Baek, K. H. (2012). Production of GABA (γ-aminobutyric acid) by microorganisms: A review. Brazilian Journal of Microbiology, 43(4), 1230–1241. https://doi.org/10.1590/S1517-83822012000400001 
3. Diez-Gutiérrez, L., San Vicente, L., Luis, L. J., Villarán, M. del C., & Chávarri, M. (2020). Gamma-aminobutyric acid and probiotics: Multiple health benefits and their future in the global functional food and nutraceuticals market. Journal of Functional Foods, 64(October 2019), 103669. https://doi.org/10.1016/j.jff.2019.103669 
4. Jenkins, T. A., Nguyen, J. C. D., Polglaze, K. E., & Bertrand, P. P. (2016). Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients, 8(1), 1–15. https://doi.org/10.3390/nu8010056 
5. Makkar, R., Behl, T., Bungau, S., Zengin, G., Mehta, V., Kumar, A., Uddin, M. S., Ashraf, G. M., Abdel-Daim, M. M., Arora, S., & Oancea, R. (2020). Nutraceuticals in neurological disorders. International Journal of Molecular Sciences, 21(12), 1–19. https://doi.org/10.3390/ijms21124424 
6. Chen, C. Q., Fichna, J., Bashashati, M., Li, Y. Y., & Storr, M. (2011). Distribution, function and physiological role of melatonin in the lower gut. World Journal of Gastroenterology, 17(34), 3888–3898. https://doi.org/10.3748/wjg.v17.i34.3888 
7. Parker, G., & Brotchie, H. (2011). Mood effects of the amino acids tryptophan and tyrosine: “Food for Thought” III Parker and Brotchie Mood effects of amino acids. Acta Psychiatrica Scandinavica, 124(6), 417–426. https://doi.org/10.1111/j.1600-0447.2011.01706.x 
8. Berke, J. D. (2018). What does dopamine mean? Nature Neuroscience, 21(6), 787–793. https://doi.org/10.1038/s41593-018-0152-y 
9. A Simple Guide to Neurotransmitters [Internet]. Compound Interest. 2022 [cited 13 October 2022]. Available from: https://www.compoundchem.com/2015/07/30/neurotransmitters/ 

Appendix

Figure 1. The structure of neurotransmitters.

Figure 2. The connection between nutraceuticals and neurotransmitters⁵

‍