Monoamines are arguably one of the most fascinating groups of chemicals utilized throughout all of nature. The majority of monoamines play vital roles as neurotransmitters and neuromodulators that can lead to a variety of effects on the human body. For example, the monoamine serotonin plays a role in our perception of happiness, while the monoamine epinephrine, or more commonly known as adrenaline not only prepares our bodies for physical stress but also plays a life saving role when it comes to treating anaphylaxis. Anaphylaxis is a severe allergic reaction that can develop when somebody is exposed to certain allergens (ie: food, medication, venom) triggering the immune system to overreact. This leads to the immune system releasing another monoamine known as histamine into the blood-stream, which induces vasodilation (expands blood vessels) that can lead to hurt muscle depression with increased leakage of fluids from the blood vessels. Epinephrine is a physiological antagonist to histamine in the sense that histamine causes the vasodilation while epinephrine causes vasoconstriction (blood vessels constricting), which is able to temporarily mitigate histamines effect on the body.
Their roles throughout nature tend to vary greatly depending on the organism and is somewhat inconsistent. Therefore, this article will focus primarily on human interaction with monoamines. Additionally, any attempt to define a neurotransmitter by a single function is inevitably an over simplification. This is why the following series of articles will try to focus on the more prominent roles of the monoamine within the human body.
Neurotransmitters are essentially molecules that communicate between neurons and their target cells at a chemical synapse. Some neurotransmitters are released by neurons and distributed throughout the body and nervous system, while others are more specific to certain areas. There are hundreds of neurotransmitters present within the human body and at play on a daily basis. Because of this neurotransmitters can generally be categorized in a multitude of ways, one of the more common methods being to categorize them by their chemical structure (peptides, amino acids, monoamines, and others).
Structurally, monoamines are fairly simple and easy to identify as all of them exhibit standard characteristics. Monoamines are organic molecules and always consist of an amino group connected to an aromatic ring by a two carbon chain. Monoamines are deactivated in the body by the enzymes known as monoamine-oxidases which clip off the amine group from the rest of the molecule. The following articles will focus primarily on classical monoamines and the 3 groups of classical monoamines; Indolamines, Imidazoleamines, and Catecholamines. I'm going to be posting 3 articles on each subgroup respectively
Indolamines (part I)
Serotonin (5-hydroxytryptamine / 5-HT)
A lobster with high levels of serotonin and low levels of octopamine is a cocky, strutting sort of shellfish, much less likely to back down when challenged. -Jordan Peterson
Where: Located primarily in the GI tract as a part of the enteric nervous system. In addition it is produced in the CNS, Merkel cells, and taste receptor cells in the tongue. Note: serotonin is also stored in blood platelets and is released during agitation and vasoconstriction where it acts as an agonist to other platelets. 90% of the human body's total serotonin is located within the enterochromaffin cells in the GI tract, where it regulates intestinal movements. About 8% is found in platelets and 1%-2% in the CNS.
- mood and cognition modulation
- mood regulation
- bone mass regulation
While serotonin is used throughout the brain, it is only synthesized by a small number of specific neurons within the brainstem which form the dorsal raphe nucleus. Serotonin is then projected from the raphe nucleus to other regions within the brain, such as the hypocampus, amygdella, spinal cord, and septum. Serotonin levels within the brain are directly influenced by by several genes, such as those which induce the differentiation of the serotonin producing neuron, the enzymes which synthesize serotonin (tryptophan hydroxylase I and tryptophan hydroxylase II), the mechanisms which transport serotonin such as VMAT2 and serotonin re-uptake transporter (SERT), the diverse serotonin receptors that bind serotonin, the serotonin re-uptake protein that transfer serotonin back into the pre-synaptic neuron after usage, and finally monoamine oxydase A which is involved in serotonin breakdown. Variations and mutations in these genes have been associated with a number of behavioral changes such as panic, anxiety, depression, and abnormal reactions in the amygdella, and pre-frontal cortex to fearful stimuli.
In humans, serotonin is used as a neurotransmitter and hormone where it is able to bind to 14 different serotonin receptor variants found on a variety of different cells. Popular media has portrayed serotonin as the happiness chemical and a mood regulator; this is only partially correct. While it is true that lower concentrations of brain serotonin have been linked to depression, the way serotonin impacts our mood is incredibly complex and isn't entirely understood. Simply put, a serotonin deficiency doesn't suddenly result in depression and neither does a surplus of brain serotonin result in excessive joyfulness. Referring to serotonin as a mood regulator is a gross over simplification as this chemical plays equally important roles in our sleep schedule and digestion.
While the binding of serotonin to appropriate ligand-gated ion channels does have a direct influence on mood and anxiety, other important functions of serotonin are in regulating sleep, appetite, body temperature control, memory and learning, eating behavior, sexual behavior, movements, and even gastrointestinal motility. This lack of specificity is why serotonin is not administered as a drug, that and because serotonin injection is known to cause pain. In nature many insect venoms and plant spines actually contain a high concentration of serotonin to do just that. To compensate for serotonins lack of specificity, many drugs are designed in a way which allows them to only interact with targeted serotonin receptor subtype. Many of these drugs are used therapeutically as antidepressants, these types of drugs are referred to as selective serotonin re-uptake inhibitors (SSRIs), where their effectiveness is dependent on the availability of synaptic serotonin. SSRIs function by blocking the re-uptake of serotonin within the synaptic cleft leading to more serotonin within the synaptic cleft for prolonged periods of time. SSRIs are generally the drug of choice when it comes to treating depression as they're far more specific then serotonin and generally don't impact processes outside the brain much. However they still come with a plethora of side effects as within the brain, serotonin plays a role in many functions which an SSRI will interfere with. A potentially fatal consequences of using SSRIs in combination is "serotonin syndrome" which is generally caused by a combination of two or more drugs used to raise the serotonin levels in the brain.
Non pharmacologic methods have recently shown promise in positive mood induction by attempting to raise brain serotonin levels via more "natural" approaches such as greater exposure to bright light, vigorous physical activity, and tryptophan-rich diets. All monoamines are derived from amino acids and serotonin is derived from the amino acid Tryptophan. Some of you more observant readers might be wondering why not just cut out the middleman and just opt for more serotonin rich diets? This is an excellent question and the reason why we don't is because serotonin is not able to actively cross the blood brain barrier meaning it has no way of reaching the brain after consumption. Tryptophan however is able to cross the blood brain barrier where it can reach raphe nuclei where it can then be used to synthesize serotonin to be projected outward to the rest of the brain. Vigorous physical exercise is also an excellent and incredibly safe way to increase brain serotonin levels. Studies have even shown that these elevated brain serotonin levels are even maintained for severals days post exercise.
Other noteworthy things about serotonin:
- Serotonin has been observed as growth factor for certain types of cells which could possibly make it an important neurotransmitter when it comes to the healing of wounds.
- Serotonin inhibits the release of norepinephrine from certain adrenergic nerves (autonomic neurons that use norepinephrine as their primary neurotransmitter).
I'll sleep when I'm dead. -Warren Zevon
Where: Produced primarily by the pineal gland, but to a lesser degree within the retinas and a several other organs and cells.
- Regulation of sleep–wake cycles
- Synchronization of circadian rhythm
- Blood pressure regulation
- reduction of oxidative stress
Derived from serotonin, melatonin's primary and most well understood function is to help regulate our bodies sleep-wake cycle or circadian rhythm. The pineal gland within the brain is responsible for most of our bodies melatonin synthesis. The impact of melatonin on our circadian rhythms is clear since pineal melatonin synthesis and circulating blood melatonin levels are highest at night. Melatonin is also synthesized in other parts of the body albeit to a much lesser degree. The suprachiasmatic nucleus is responsible for maintaining our brains circadian clock and works by stimulating the production and release of night time melatonin via neural input. Effects associated with the rise of melatonin levels at night include lower blood pressure, body temperature, and an increase in tiredness (shocking I know). The production of melatonin can be inhibited by the exposure of blue light, which is why many experts advise against using electronics before bed (I am guilty of this). Within humans melatonin binds to 2 G-protein coupled melatonin receptors named MT1 and MT2. It is however noteworthy that melatonin likely binds to other sites within the human body, MT1 and MT2 just happen to be the only binding sites identified throughout the body thus far.
In most countries, melatonin is available over the counter (OTC) as a dietary supplement where it is frequently used to treat short-term insomnia (ie: jet lag, work hour shifts) and is usually ingested. However the actual evidence of it's effectiveness for this purpose isn't that strong. A 2017 study found that melatonin use made sleep onset occur 6 minutes faster, but no impact on total time asleep. For the vast majority of individuals, low-doses of melatonin are enough to produce hypnotic effects. While higher doses of melatonin don't appear to create stronger effects, they do however result in increased drowsiness for prolonged periods of time. In general, melatonin can be regarded as a fairly safe supplement as it appears to have minimal short term side effects up to three months at low doses. An imbalance of melatonin within the body has been linked to several neuro-degenerative diseases such as Parkinsons, Huntingtons and Alzheimer's. But don't worry for most people taking melatonin is unlikely to be a slippery slope to Parkinsons disease.
For the most part melatonin is able to produce effects throughout the body via 2 mechanisms, either binding to it's receptors or by acting as an antioxidant. Plants utilize the latter function in order to defend themselves against oxidative stress which is why many foods are naturally rich in melatonin. Generally, melatonin production decreases as a person ages, where infant melatonin levels start to normalize around the third month after birth. A study found that infant melatonin levels were highest between midnight and 8:00 AM. Additionally, the transition between child and teenager tends to result in the release of melatonin being delayed which explains the stereotype of many teenagers being night owls. Other functions of melatonin include acting as an antioxidant / free radical scavenger, neuroprotective agent, modulating immune system activity, and even glucose regulation.
A recent study Harvard study found a correlation between ROS damage and sleep deprivation, it's an excellent read for those who are interested.
Continuation Introduction to monoamines Imidazoleamines (part II)...