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Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.
This work examined the influence of the pineal gland and its hormone melatonin on the metabolism of serotonin (5-HT) in discrete areas of the forebrain, such as the Striatum and the nucleus accumbens, and the midbrain raphe. The content of 5-HT and its major oxidative metabolite, the 5-hydroxyindoleacetic acid (5-HIAA), as well as the in-vivo tryptophan hydroxylation rate were examined after long-term pinealectomy (one month) and daily melatonin treatment (500 μg/kg; twice daily for ten days) in pinealectomized rats. Pinealectomy did not alter 5-HT content in any of these brain areas, but it significantly increased the content of 5-HIAA in Striatum and the 5-HIAA/5-HT ratio in nucleus accumbens. The normal values of these parameters were recuperated after administration of exogenous melatonin, but it also increased the rate of tryptophan hydroxylation in both areas. In addition, melatonin treatment decreased the levels of 5-HIAA in dorsal raphe nucleus. These data suggest that the pineal gland, through the secretion of melatonin, modulates the local metabolism of 5-HT in forebrain areas by acting on the oxidative deamination. Moreover, melatonin injected in pinealectomized rats derives in a more extended effect than pinealectomy and induces a stimulation of 5-HT synthesis in the striatum, probably due to a pharmacological effect. These results point to the striatum as a target area for the interaction between pineal melatonin and the serotonergic function, and suggest a differential effect of the melatonin injected on areas containing serotonergic terminals and cell bodies, which may relevant for the mode of action of melatonin and its behavioral effects.
The half life of melatonin is roughly 20 minutes in the bloodstream, so it is released immediately rather than stored. TPOH enzyme activity does increase at night, while the AAAD and HIOMT run continuously, however it is AANAT that is significantly regulated by circadian rhythms. This is in part because serotonin is a branch point for multiple other neurotransmitters synthetic pathways, and ASMT performs the O-methylation step for all of these as well. In rats, the concentration of melatonin increases by a factor of 10 in the pineal gland from day to night time, and by a factor of 5-10 in blood plasma. (4)
Structure and function of the brain serotonin system .
SCI and neurodegenerative diseases like PD result in a loss of monoamines, like 5-HT and DA, that are critical for motor function. One long-standing therapeutic strategy has thus been to replace monoamines by giving their precursors, such as 5-HTP or -DOPA (; ; ; ; ; ; ; ). However, the mechanism by which precursors are converted to monoamines has remained uncertain, especially with SCI, considering that the enzymes for synthesis of monoamines, including AADC, are normally mostly confined to monoamine fibers and these fibers are almost entirely lost with a complete spinal transection (; ). Our results demonstrate that an upregulation of AADC in spinal cord blood vessels, pericytes, and neurons after SCI compensates for a loss of AADC in descending monoamine fibers after SCI. AADC in both spinal vessels and neurons is capable of generating 5-HT when the precursor 5-HTP is exogenously applied, thus explaining the therapeutic action of precursors like 5-HTP. In the brain of normal rats, AADC activity has previously been seen in vessel endothelial cells and pericytes, although in this case the monoamines produced from precursors by AADC are quickly metabolized by MAO (within minutes) () and thus do not accumulate substantially unless MAO is blocked (), unlike what we see after injury.
Considering that we have previously reported 5-HT itself to increase the LLR at a very low nanomolar EC50 dose of ~10 nM (), our present finding that 5-HTP acts at an EC50 dose 1,000 times higher (10 μM) indicates that there is a 1,000-fold loss of functional 5-HT during synthesis of 5-HT by AADC. We suspected that this could be partly due to metabolism of 5-HT in AADC cells and thus tested this by blocking metabolism of 5-HT. Monoamine oxidase A (MAO-A) is the key enzyme that metabolizes 5-HT into 5-HIAA and is located intracellularly on the mitochondrial membrane (; ). When we applied clorgyline, a MAO-A inhibitor (), 5-HTP still increased LLRs with an efficacy (peak response) similar to 5-HTP alone (), but the EC50 of 5-HTP was markedly decreased to ~1 μM, and thus there is indeed a 10-fold metabolism (loss) of 5-HT after it is synthesized (, E and G). Application of 5-HT itself increased the LLR similarly to 5-HTP, and again the MAO inhibitor did not affect the efficacy of this increase (peak amplitude, ) but did produce a significant reduction in the EC50 of exogenously applied 5-HT (by a factor of 2; ), although this effect was significantly smaller than that of 5-HTP. Thus, roughly speaking, in AADC cells (vessels and neurons) MAO causes an eightfold loss in 5-HT made from applied 5-HTP, and after the 5-HT leaves these cells there is an additional twofold loss to MAO metabolism before the 5-HT diffuses to 5-HT receptors where it increases the LLR (see for mechanism).
Clinical chemistry of serotonin and metabolites .
In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation.
To assess the effects of external administration of L- tryptophan on the synthesis of serotonin and melatonin as well as on the immune function of Wistar rats, 300 mg of the amino acid were administered either during daylight (08:00) or at night (20:00) for 5 days.
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Amino Acid Synthesis and Metabolism
Even if one knows the serotonin level in the blood, this serotonin level may fluctuate throughout the day and basing treatment for depression on the serotonin level in the blood is not practical and probably not effective.
Serotonin, depression, and aggression: The problem of brain energy
Short of spinal fluid analysis - for the neurotransmitters serotonin, norepinephrine, dopamine, and others - which is not practical, it is difficult to know the brain chemicals that are involved in a particular person's depression.
Melatonin Effects on Serotonin Synthesis and Metabolism …
There are always potential side effects when serotonin or other brain chemical levels are manipulated, especially with high doses of supplements, but when do in a gradual low dose way, it is much safer.
Melatonin Supports CYP2D-Mediated Serotonin Synthesis …
monoamines, such as serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine, play a powerful role in modulating the excitability of motoneurons in the spinal cord (; ; ; ; ; ; ). 5-HT, in particular, increases motoneurons' resting membrane potential and facilitates low-voltage-gated persistent inward currents composed of sodium (Na PIC) and calcium (Ca PIC), allowing motoneurons to depolarize more easily and therefore generate appropriate muscle contractions (; ). In normal rats, spinal monoamines are primarily produced in the terminals of descending brain stem fibers (; ), which contain the necessary biosynthesis enzymes, including tryptophan hydroxylase (TPH) that converts tryptophan to 5-hydroxytryptophan (5-HTP), tyrosine hydroxylase (TH) that converts tyrosine to -dihydroxyphenylalanine (-DOPA), and aromatic -amino acid decarboxylase (AADC) that converts 5-HTP to 5-HT and -DOPA to dopamine (DA); they also contain monoamine oxidase (MAO) that metabolizes monoamines (; ; ; ). Transection of the spinal cord destroys all supraspinal innervation of the spinal cord, leading to the loss of most monoamine fibers caudal to the lesion site (; ) together with a dramatic loss of monoamines and some of the key enzymes involved in monoamine synthesis, including TPH and TH (; ; ).
33. Serotonin, Tryptophan Metabolism and the Brain …
While both peripheral and central AADC produce 5-HT from exogenously applied 5-HTP, this AADC is unlikely to endogenously produce 5-HT that can affect the spinal cord after spinal transection, for several reasons. First, peripherally synthesized 5-HT is mostly transported, stored in vesicles, or metabolized before it gets into the circulation; what little 5-HT does enter the circulation (from gut) is avidly transported into platelets, leaving serum 5-HT levels very low (; ), and this remaining 5-HT does not easily cross the BBB (). Second, while 5-HTP does easily cross the BBB (by the amino acid L-transport system) (; ), very little if any is normally detected in serum (; ; ; ), and thus AADC-containing cells in the spinal cord (D cells and vessels) are unlikely to receive adequate endogenous 5-HTP to make 5-HT. Finally, there is not likely a significant source of 5-HTP intrinsic to the spinal cord after transection, considering that most TPH is lost with injury, along with the associated descending 5-HT fibers (; ).
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