5- HTP

The precursor for the synthesis of 5-HT is the amino acid L-tryptophan, which is obtained from dietary protein (Fig. 2.2A). L-tryptophan is converted to 5-hydroxytryptophan (5-HTP) in serotonin neurons by the enzyme tryptophan... 

Serotonergic neurons contain the enzyme L-tryptophan-5-monooxygenase (EC 1.14.16.4), more commonly termed tryptophan hydroxylase, which converts tryptophan to 5-hydroxytryptophan (5-HTP) (Fig. 13-5). Tryptophan hydroxylase contains 444 amino acids, corresponding to a molecular weight of about 51 Da. This enzyme is synthesized in serotonergic cell bodies of the raphe nuclei and is found only in cells that synthesize 5-HT. Therefore its distribution in brain is similar to that of 5-HT itself. The Km of tryptophan hydroxylase for tryptophan is approximately 30-60 pmol/1, a concentration comparable to that of tryptophan in brain. If the concentration of tryptophan in serotonergic neurons is assumed to be comparable to that in whole brain, the enzyme would not be saturated with substrate, and the formation of 5-HT in brain would be expected to rise as the brain concentration of tryptophan increases. This has been found to occur in response to raising the dietary intake of tryptophan specifically. 

The other enzyme involved in the synthesis of 5-HT, aromatic L-amino acid decarboxylase (AADC) (EC 4.1.1.28), is a soluble pyridoxal-5 -phosphate-dependent enzyme, which converts 5-HTP to 5-HT (Fig. 13-5). It has been demonstrated that administration of pyridoxine increases the rate of synthesis of 5-HT in monkey brain, as revealed using position emission tomography (this technique is discussed in Ch. 58). This presumably reflects a regulatory effect of pyridoxine on AADC activity and raises the interesting issue of the use of pyridoxine supplementation in situations associated with 5-HT deficiency. 

AADC is present not only in serotonergic neurons but also in catecholaminergic neurons, where it converts 3,4-dihydroxyphenylalanine (DOPA) to dopamine (see Ch. 12). However, different pH optima or concentrations of substrate or cofactor are required for optimum activity of the enzyme in brain homogenates when using either 5-HTP or DOPA as the substrate. cDNAs encoding AADC... 

Because AADC is not saturated with 5-HTP under physiological conditions, (i.e. the concentration of 5-HTP is much less than the enzyme s Km of 10pmol/l), it is possible to raise the content of 5-HT in brain not only by increasing the dietary intake of tryptophan but also by raising the intake of 5-HTP. This procedure, though,... 

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]. 

The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter. Plasticity is an important concept in neurobiology. In general, this refers to the ability of neuronal systems to conform to either short- or long-term demands placed upon their activity or function (see Plasticity in Ch. 53). One of the processes contributing to neuronal plasticity is the ability to increase the rate of neurotransmitter synthesis and release in response to increased neuronal activity. Serotonergic neurons have this capability the synthesis of 5-HT from tryptophan is increased in a frequency-dependent manner in response to electrical stimulation of serotonergic soma [7]. The increase in synthesis results from the enhanced conversion of tryptophan to 5-HTP and is dependent on extracellular calcium ion. It is likely that the increased 5-HT synthesis results in part from alterations in the kinetic properties of tryptophan hydroxylase, perhaps due to calcium-dependent phosphorylation of the enzyme by calmodulin-dependent protein kinase II or cAMP-dependent protein kinase (PKA see Ch. 23). 

Ortmann, R., Martin, S., Radeke, E., and Delini-Stula, A. (1981) Interaction of beta-adrenoceptor agonists with the serotonergic system in rat brain. A behavioral study using the L-5-HTP syndrome. Naunyn Schmiedebergs Arch. Pharmacol, 316 225-230. 

As with the extension reflex, functional supersensitivity was observed with the flexion reflex, as indicated by increased responsiveness to LSD, 5-HTP, and tryptamine in chronically (2 months) versus acutely (1 day or less) transected rats (136). 

Several compounds affecting various 5-HT functional parameters (uptake inhibition (fluoxetine), metabolism (tranylcypromine) or synthesis (5-OH tryptophan, 5-HTP)) had no effect on subemetic doses of cisplatin [110]. In fact, tranylcypromine and 5-HTP antagonized emesis of cisplatin. Thus these results would favour an inhibitory role of 5-HT instead of emetogenic. It is conceivable that an excess of 5-HT may desensitize 5-HT3 receptors that may result in a reduced sensitivity to emetogenic stimuli. 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

Behavioral and emotional effects In animal studies, ginseng does not prolong pentobarbital-induced sleep, nor does it affect spontaneous locomotion (Mitra et al. 1996). It does potentiate amphetamine-induced locomotion, but it reduces the stereotypy and lethality caused by amphetamine. Ginseng has analgesic effects, which are discussed at greater length in chapter 8. Catalepsy induced by haloperidol is potentiated by ginseng, while the hyperthermic effect of 5-HTP is attenuated. No antiseizure effects have been observed. 

Following the synthesis of 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, the enzyme aromatic amino acid decarboxylase (also known as 5-HTP or dopa decarboxylase) then decarboxylates the amino acid to 5-HT. L-Aromatic amino acid decarboxylase is approximately 60% bound in the nerve terminal and requires pyridoxal phosphate as an essential enzyme. 

Valentino RJ, Foote SL, Page ME (1993) The locus coeruleus as a site for integrating CRF and noradrenergic mediation of stress response. Ann NY Acad Sci 697 173-188 van Vliet IM, Slaap BR, Westenberg HG, Den Boer JA (1996) Behavioral, neuroendocrine and biochemical effects of different doses of 5-HTP in panic disorder. Em- Neuropsych opharmacol 6 103-110... 

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