Serotonin, synthesis

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

Galloway M. Regulation of dopamine and serotonin synthesis by acute administration of cocaine. Synapse. 6 63, 1990. 

The initial hydroxylation of tryptophan, rather than the decarboxylation of 5-HTP, appears to be the rate-limiting step in serotonin synthesis. Therefore, the inhibition of this reaction results in a marked depletion of the content of 5-HT in brain. The enzyme inhibitor most widely used in experiments is parachlorophenylalanine (PCPA). In vivo, PCPA irreversibly inhibits tryptophan hydroxylase, presumably by incorporating itself into the enzyme to produce an inactive protein. This results in a long-lasting reduction of 5-HT levels. Recovery of enzyme activity, and 5-HT biosynthesis, requires the synthesis of new enzyme. Marked increases in mRNA for tryptophan hydroxylase are found in the raphe nuclei 1-3 days after administration of PCPA [6]. 

Boadle-Biber, M. C. Regulation of serotonin synthesis. Prog. Biophys. Mol. Biol. 60 1-15,1993. 

Martin, L. L., and Smith, D. J. (1982) Ketamine inhibits serotonin synthesis and metabolism in vivo. Neuropharmacology, 21 119-125. 

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter. 

Dietary tryptophan is the source of the formation of serotonin. Enzymes and cofactors necessary for serotonin synthesis are present in both the enterochromaf-lin cells of the gastrointestinal tract and neurons in the brain. Tryptophan is initially hydroxylated to form 5-hydroxytryptophan. Decarboxylation of the latter compound results in the formation of serotonin (Fig. 24.2). 

Enhances Serotonin Synthesis Increases Serotonin Release Serotonin agonist Inhibits Serotonin Catabolism Inhibits Serotonin Reuptake... 

Manipulation of the serotonergic system in animal models can be implemented with several strategies inhibition of serotonin synthesis, destruction of serotonin neurons, use of serotonin antagonists, and increase of serotonin function. 

Addition of exogenous tryptophan increases endogenous serotonin synthesis [Barr et al. 1992, 1993]. However, this does not necessarily mean that there is an increase in the activity of the serotonergic system. Charney et al. [1988] have demonstrated a small but significant rise in prolactin in response to an intravenous administration of tryptophan in 21 patients with OCD compared with 21 psychiatrically healthy control subjects. 

Meller E, Goldstein M, Geyer MA Receptor reserve for 5-hydroxytryptamine lA-mediated inhibition of serotonin synthesis possible relationship to anxiolytic properties of 5-hydroxitryptamine lA agonists. Mol Pharmacol 37 231-237, 1990... 

The arylamino acid decarboxylase inhibitory action of DL-a-fluoromethyldopa (4.77) has also been described. By affecting the enzyme through covalent binding, this compound completely inhibits both catecholamine and serotonin synthesis. Unlike 6-hydroxydopamine, a-fluoromethyldopa does not destroy the neurons, and unlike reserpine it does not deplete chromaffin tissue in the adrenal gland. 

Serotonin Receptors Presynaptic Drug Effects 4.5.3.1 Serotonin Synthesis Inhibitors... 

Synthesis inhibitors block tryptophan hydroxylase, the first rate-determining enzyme in serotonin synthesis. Although p-chlorophenylalanine (4.111) can decrease serotonin levels by more than 90%, this agent does not cause the sedation that is seen after catecholamine depletion with reserpine. Therefore, reserpine, although capable of depleting 5-HT vesicles, causes sedation by a catecholaminergic mechanism that inhibits uptake-2. It acts on the membrane of the synaptic vesicle and seems to prevent 5-HT and catecholamine uptake into the granule. 

Hydroxylation at C5 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA fenclonine) and by p-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome but are too toxic for clinical use. 

Serotonin is metabolized by MAO, and the intermediate product, 5-hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests. 

As noted, serotonin synthesis can be inhibited by p-chlorophenylalanine and p-chloroamphetamine. However, these agents are too toxic for general use. Storage of serotonin can be inhibited by the use of reserpine, but the sympatholytic effects of this drug (see Chapter 11) and the high levels of circulating serotonin that result from release prevent its use in carcinoid. Therefore, receptor blockade is the major therapeutic approach to conditions of serotonin excess. 

Serotonin is synthesized via tryptophan and 5-hydroxytryptophan with decarboxylation of the latter (Fig. 25-12). Within the pineal body of the brain and in the retina, serotonin is acetylated to N-acetylseroto-nin,782/783 which is then O-methylated to melatonin, the pineal hormone (Fig. 25-12). A specific inhibitor of serotonin synthesis is p-chlorophenylalanine, and studies with this and other inhibitors suggest that serotonin is required for sleep.784... 

Tohyama, Y., F. Yamane, M. Fikre-Merid, P. Blier, and M. Diksic. Effects of Serotine Receptors Agonists, TFMPP and CGS12066B, on Regional Serotonin Synthesis in the Rat Brain An Autoradiographic Study. Journal of Neurochemistry 80, no. 

Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is an indoleethylamine formed in biologic systems from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16-3). Hydroxylation at C5 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA fenclonine) and by /i-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome. 

Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 2004 305(5681) 217. 

PAH, a nonheme iron-containing enzyme, is a member of a larger BI Independent amino acid hydroxylase family. In addition to PAH, the enzyme family includes tyrosine hydroxylase and tryptophan hydroxylase. The enzymes in this family participate in critical metabolic steps and are tissue specific. PAH catabolizes excess dietary PA and synthesizes tyrosine. In adrenal and nervous tissue, tyrosine hydroxylase catalyzes the initial steps in the synthesis of dihydrox-yphenylalanine. In the brain, tryptophan is converted to 5-hydroxytryptophan as the first step of serotonin synthesis. Consequently, these enzymes are highly regulated not only by their expression in different tissues but also by reversible phosphorylation of a critical serine residue found in regulatory domains of the three enzymes. Since all three enzymes are phosphorylated and dephosphorylated by different kinases and phosphatases in response to the need for the different synthetic products, it is not unexpected that the exact regulatory signal for each member of the enzyme family is unique. 

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