Interactions[ edit ] Tryptophan taken as a dietary supplement such as in tablet form has the potential to cause serotonin syndrome when combined with antidepressants of the MAOI or SSRI class or other strongly serotonergic drugs.
Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate :  anthranilate condenses with phosphoribosylpyrophosphate PRPP , generating pyrophosphate as a by-product. The ring of the ribose moiety is opened and subjected to reductive decarboxylation , producing indoleglycerol phosphate; this, in turn, is transformed into indole.
In the last step, tryptophan synthase catalyzes the formation of tryptophan from indole and the amino acid serine. The industrial production of tryptophan is also biosynthetic and is based on the fermentation of serine and indole using either wild-type or genetically modified bacteria such as B. Biosynthetic pathway of serotonin. In amniotes 5-HT neurons are only present in the raphe area of the hind brain whereas in anamniotes, including teleosts, 5-HT cell bodies are also located in pretectal areas and basal forebrain.
Interestingly, TPH2 show a Km for its substrate which is in the range of in vivo brain levels of Trp Consequently, the rate of 5-HT synthesis in cells expressing TPH2 is drastically affected by changes in Trp availability, an effect which is probably not seen in 5-HTergic cells expressing other TPH isoforms Thus, changes in Trp availability may have direct effects on 5-HTergic tone. Coherent to this, Russo et al. Dietary composition as well as stress, physical activity and immune system activation will all have effects on plasma Trp concentrations, and thus on brain Trp availability and raphe 5-HTergic activity Such Trp related changes in 5-HTergic activity could have direct effects on behavior as well as endocrine status through 5-HT projections to telencephalic and hypothalamic areas.
It could be argued that such effects may be less important in teleost fish since they have extra-raphe located 5-HT cell populations expressing the TPH1 isoform, making them less responsive to changes in Trp availability.
However, in teleosts, as well as in other vertebrates, the raphe 5-HTergic cells have a wide projection pattern innervating most brain regions Still, it has to be acknowledged that very little is known about the role of telesost forebrain 5-HT cell population in the control of behavior and endocrine functions Thus, the amount of Trp entering the brain depends on the plasma concentrations of Trp in relation to the other LNAAs [for references see reviews 26 , 27 ].
Hence, ingestion of a normal protein source, usually containing 0. Dietary carbohydrates, on the contrary, increase brain Trp levels. This differential amino acid uptake to skeletal muscles is caused by the fact that Trp in blood plasma is bound to albumin whereas other LNAA are not.
Trp influx to the brain is then promoted by the common LNAA transporter protein in the blood brain barrier having a much higher affinity for Trp compared to albumin Effects of the proteins and carbohydrates on influx of tryptophan Trp to the brain.
Studies in rainbow trout Oncorhynchus myliss show that the amino acid composition of trout albumin differs from that of mammalians and lacks the binding site for indoles 29 , Thus, in rainbow trout, the majority of plasma Trp is in its free non-protein bound state 31 , This assumption is further strengthened by a study by Ruibal et al.
It is not known if the lack of Trp binding by albumin is specific for rainbow trout or if it represents a more general trait of teleost albumin.
However, it is possible that in teleost fishes brain influx of Trp could be more dependent of the dietary amino acid composition than on carbohydrates.
In mammals, the majority of Trp enters the kynurenic pathway and is converted to other bioactive substances than 5-HT, such as kynurenic acid and quinolinic acid Figure 3 [for references see review 11 ]. The first stage of this pathway is catalyzed by the hepatic enzyme tryptophan 2,3-dioxygenase TDO and the extrahepatic enzyme indoleamine 2,3-dioxygenase IDO , enzymes that are induced by glucocorticoids and pro-inflammatory cytokines, respectively Thus, chronic stress and infections can shunt available Trp toward the kynurenic pathway and thereby lowering brain 5-HT synthesis while simultaneously increasing the production of other Trp based bioactive substances.
Major metabolic pathway of tryptophan in mammals. Earlier studies suggested that IDO1 arose by a gene duplication in mammals However, recent phylogenetic analyses show that IDO1 are present in reptiles and in teleosts, indicating that the gene duplication occurred in the common ancestor of vertebrates In mammals, the activation of dendritic cells results in IDO1 induction with the depletion of Trp levels locally or systemically, a mechanism by which interferons inhibit the growth of certain bacteria, intracellular parasites, and viruses Moreover, an elevation of the activity of the kynurenic pathway also inhibits T lymphocyte replication which results in immunosuppression and tolerogenicity.
In line with this, IDO1 have been suggested to play an important role in preventing fetal rejection and in facilitating immune escape of tumor cells In addition, some products of the kynrunic pathway may act anti-inflammatory 38 , The Trp catabolizing efficiency of IDO2 and non-mammalian IDO1 seems to be lower than mammalian IDO1, and their function and involvement in the immune response in comparative model species is far less understood However, recently, it has been demonstrated that treatment with bacterial lipopolysaccharide LPS induces and upregulation of IDO expression in rainbow trout, suggesting that this enzyme is involved in the immune response in non-mammalian vertebrates This suggests that systemic infection may decrease Trp influx to the brain of teleost fishes in the same way as in mammals, and result in behavioral and physiological changes see section Kynurenine pathway.
Acute Stress As discussed above chronic stress may result in lowered brain Trp availability as a consequence of a stress-induced activation of the kynurenine pathway. However, acute stress has been reported to have the opposite effect elevating brain Trp levels in both mammals 41 , 42 and teleost fish 3 , This stress-induced increase in brain Trp concentrations appears at least in part related to a sympathetic activation and elevated levels of circulating plasma catecholamines Plasma catecholamines stimulate lipolysis, resulting in elevated plasma levels of non-esterified fatty acids, which in turn could compete with Trp for binding to albumin and thus elevate the plasma pool of free Trp available for uptake into the brain [reviewed by 44 ].
However, as discussed above, rainbow trout albumin appears to lack the Trp binding site, suggesting that mechanisms based on competition between Trp and non-esterified fatty acids are not involved in stress-induced increase in brain Trp in teleosts, at least not in rainbow trout. It has also been suggested that sympathetic activation results in increased permeability of the blood-brain barrier, another mechanism that could increase brain Trp influx Coherent to this, the involvement of 5-HT in the neuroendocrine regulation of the stress response seems to be similar within this linage.
This, mainly through its effects on the release of corticotropin-releasing factor CRF from the hypothalamus 45 , In addition, extra hypothalamic 5-HT appears be involved in appraisal and stress coping mechanisms, modulating behavioral and neuroendocrine responses to stressors 47 , Furthermore, as mentioned in section The Kynurenic pathway and Acute stress, stress by itself can influence the Trp influx to the brain, and thereby affect 5-HT signaling and the stress response.
Thus, the link between Trp and the 5-HT system and how they control behavioral and neuroendocrine stress responses appears complex with 5-HT having context dependent effects 19 , 22 , Effects of Elevated Dietary Trp Long-term effects of Trp dietary manipulations on the neuroendocrine stress response have been observed in both mammals and teleost fishes [for a review see 49 ]. For instance, in pigs, elevated dietary Trp had stress suppressive effects, including elevated hypothalamic 5-HT and lowered post stress plasma cortisol levels, effects that peaked after 5 days of dietary Trp enrichment Similarly, 51 showed that post-stress plasma cortisol levels returned to baseline earlier after social stress in pigs fed Trp enriched feed for 7 days.
Interestingly, a similar time frame for the suppressive effects of dietary Trp supplementation on glucocorticoid release has also been demonstrated in fish for references see Table 1.
For instance, studies in rainbow trout show that suppression of the neuroendocrine stress response is present after 7, but not after 3 or 28 days of treatment with dietary Trp supplementation Furthermore, in the earlier studies showing a suppressive effect of elevated dietary Trp on the neuroendocrine response to an acute stressor the effects were investigated during or directly following a period of dietary Trp supplementation 10 , However, in recent studies in sea water reared Atlantic salmon Salmo salar , the suppressive effect on post-stress plasma cortisol seems to appear between 2 and 8 days after terminating the Trp supplementation.
Moreover, in Atlantic salmon, this suppressive effect was still present at 21 days post Trp supplementation 7 , Basic et al. Moreover, these long-term alternations of HPI axis reactivity was not related to changes in hypothalamic 5-HT neurochemistry. Instead they coincided with changes in dopaminergic neurochemistry in this brain part, effects which may be related to elevated activity of the kynruneric pathway, as discussed in section The Kynurenic pathway.
The latter study also included telencephalon and 5-HT activity followed the same general pattern as cortisol in this brain part. Effects of dietary tryptophan supplementation on the behavioral and endocrine stress response in teleost fishes. Generally, teleost fishes have a remarkable neurogenic and regenerative capacity throughout ontogeny, and it has been suggested that structural changes may underlie long-lasting effects on telencephalic neurochemistry induced by elevated dietary Trp in teleost fishes 7.
This type of brain architectural changes is supported by mammalian studies, showing that the 5-HT system is involved in the organization and development of its own neural projection pattern In addition, a positive relationship between dietary Trp content and neural proliferation markers, such as exogenous 5-bromodeoxyuridine and brain derived neurotrophic factor BDNF has been demonstrated in rats 66 , which lends further support for the suggestion that dietary Trp can induce structural changes in the brain.
There are studies in teleost fishes showing effect of longer Trp treatment periods than 7 days Table 1. For example, Tejpal et al. Moreover, longer Trp treatment periods have also been shown to act stimulatory on plasma cortisol responses. For example, an immune challenge by i. Furthermore, there is a rather high variability in the effect of elevated dietary Trp on baseline cortisol values Table 1. This variability could reflect interspecific differences in Trp metabolism and neuroendocrine mechanisms For example, in the studies performed by Lepage et al.
Considering the fact that the 5-HT system is affected by social interaction 3 , 22 , 68 , this type of rearing differences may explain some of the variability in the response to elevated dietary Trp.
Moreover, studies in humans and rats suggest that individual variation in 5-HT neurotransmission underlies differences in the response to dietary Trp manipulationThe caudal group consists of the nucleus raphe magnus B3 , raphe obscurus nucleus B2 , raphe pallidus nucleus B1 , and lateral medullary reticular formation, that project into the brainstem. Only free plasma tryptophan, i. This halts their dopamine release, and thereby serotonin decreases appetite. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord , while the axons of the higher nuclei spread out in the entire brain. Abstract Modulation of tryptophan Trp metabolism may underpin the behavioral effects of androgenic-anabolic steroids AAS and associated image and performance enhancers. Serotonin can also be synthesized, albeit at very low levels, in the bone cells.
Mechanism of action[ edit ] Serotonin is stored in vesicle in the presynaptic neurone, when stimulated by nerve impulses, serotonin is released as a neurotransmitter into the synapse, it reversibly binds to the post synaptic receptor to induce a nerve impulse on the post synaptic neurone. Instead they coincided with changes in dopaminergic neurochemistry in this brain part, effects which may be related to elevated activity of the kynruneric pathway, as discussed in section The Kynurenic pathway. The quantity of tryptophan ingested daily is about 0. The first stage of this pathway is catalyzed by the hepatic enzyme tryptophan 2,3-dioxygenase TDO and the extrahepatic enzyme indoleamine 2,3-dioxygenase IDO , enzymes that are induced by glucocorticoids and pro-inflammatory cytokines, respectively.
Dietary Trp supplementation have also been shown to reduce cannibalism in juvenile grouper Epinephelus coioides 81 and pike perch Sander lucioperca Indeed, in addition to the metabolic pathway leading to serotonin, tryptophan is used in protein synthesis and it is transformed by hepatic tryptophan pyrrolase, generally called tryptophan dioxygenase and by indolaleamine-2,3-dioxygenase, into N-formylkynurenine then into kynurenine, precursor of xanthurenic acid and nicotinic acid. However, further studies are needed to verify this assumption. Likewise, the dietary Trp content have been shown to affect endocrine and behavioral responses to stress in teleost fishes 10 , 19 , Potentially, this may result in poorer stress coping ability trough dietary effects on central 5-HT signaling. AAS and enhancers Androgenic-anabolic steroids are derived from testosterone T.
We also present a hypothesis on how the diet could be used to improve fish stress tolerance through interactions with the Trp metabolic pathways. The impact of exercise and previous biochemical studies is discussed later, followed finally by proposed means of testing the hypothesis. Accordingly, effects of dietary Trp on the neuroendocrine stress response have been reported in a variety of species, spanning from teleosts to humans 4 — It involves two steps: Acetylation of the amine group by N-acetyl transferase leading to N-acetyl-serotonin. Consequently, pathological changes in stress responsiveness, as in depression, have been related to nutritional factors, stress and immune function in humans 14 ,
For instance, in pigs, elevated dietary Trp had stress suppressive effects, including elevated hypothalamic 5-HT and lowered post stress plasma cortisol levels, effects that peaked after 5 days of dietary Trp enrichment Serotonin - Metabolism Biosynthesis Serotonin or 5-hydroxytryptamine is synthesized from L-tryptophan.
Effects of dietary tryptophan supplementation on the behavioral and endocrine stress response in teleost fishes. It mediates its actions on bone cells using three different receptors. Moreover, longer Trp treatment periods have also been shown to act stimulatory on plasma cortisol responses. However, recent phylogenic studies show that IDO paralogues are present within the whole vertebrate linage, however, their involvement in the immune and stress reaction in teleost fishes remains to be investigated. In line with this, human studies show that alterations of the dietary Trp content changes irritability and aggressive behavior [for references see review by Young and Leyton 76 ]. Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate :  anthranilate condenses with phosphoribosylpyrophosphate PRPP , generating pyrophosphate as a by-product.
Indeed, in addition to the metabolic pathway leading to serotonin, tryptophan is used in protein synthesis and it is transformed by hepatic tryptophan pyrrolase, generally called tryptophan dioxygenase and by indolaleamine-2,3-dioxygenase, into N-formylkynurenine then into kynurenine, precursor of xanthurenic acid and nicotinic acid. Earlier studies suggested that IDO1 arose by a gene duplication in mammals However, in recent studies in sea water reared Atlantic salmon Salmo salar , the suppressive effect on post-stress plasma cortisol seems to appear between 2 and 8 days after terminating the Trp supplementation.