Serotonin synthesis and

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

Earlier, Hemandez-Rodriguez and Chagoya28 reported on the effect of prenatal tryptophan supplementation on serotonin synthesis and the activity of Na+,K+ ATPase in the rat cerebral cortex during postnatal development, from birth up to day 30. Elevated levels of both were observed in comparison to controls. 

In the rat, the most often studied animal species, whose tryptophan metabolism resembles closely that of humans, acute ethanol administration, as described earlier, induces a biphasic effect on serum tryptophan levels, an initial increase followed by a later inhibition. Similarly, acute ethanol administration exerts a biphasic effect on brain serotonin synthesis and turnover, an initial enhancement followed by a later inhibition.111 The initial enhancement is caused by an increase in circulating free tryptophan availability to brain, probably secondary to a catecholamine-dependent lipolysis and a nonesteri-fied fatty acid-mediated displacement of the albumin-bound amino acid, whereas the later inhibition of serotonin synthesis and turnover is the result of a decrease in circulating free and albumin-bound tryptophan availability to the brain secondary to activation of hepatic tryptophan 2,3-dioxygenase (TP) by the earlier increase in free tryptophan to the liver. The activation of hepatic TP by acute ethanol administration, which is substrate (tryptophan) mediated, has been described in rats by Badawy and Evans.111127128... 

Badawy et al.131 attributed the enhanced rat brain serotonin synthesis and turnover by chronic ethanol administration to the increased circulating tryptophan availability to the brain secondary inhibition of hepatic TP activity (NAD(P)H-dependent allosteric inhibition). 

Arevalo, R., Afonso, D., Castro, R., and Rodriguez, M., Fetal brain serotonin synthesis and catabolism is under control by mother intake of tryptophan, Life Sci., 49, 53, 1991. 

Hernandez-Rodriguez, J. and Chagoya, G., Brain serotonin synthesis and Na+,K+-ATPase activity are increased postnatally after prenatal administration of L-tryptophan, Brain Res., 390, 221, 1986. 

Amino acids are involved in many metabolic processes and m protein synthesis. In the central nervous system, they also function as neurotransmitters or neuromodulators (Davidson, 1976 Corradetti et al., 1983 Fonnum, 1981, 1984). Numerous studies have demonstrated the excitatory effects of aspartate and glutamate (Watkins and Evans, 1981) the inhibitory effects of glycine, y-aminobutyric acid (GABA), and taurine (Schaffer et al., 1981 Lloyd et al., 1983 Roberts, 1984), and the precursor roles of tryptophan in serotonin synthesis and of tyrosine and phenylalanine in the biosyntheses of catecholamines (Sved, 1983). It is not surprising, therefore, to see an ever-increasing interest in amino acid analysis in biological samples. 

In this section the emphasis is placed on the serotonergic system in the context of the CNS. The chemical manipulation of the serotonergic system within the CNS can be achieved either directly, for example by the use of S-hTT receptor agonists (e.g. migraine, depression) or antagonists (e.g. emesis), or indirectly by the manipulation of serotonin synthesis and turnover. The latter principle is of particular importance when treating a variety of depressive disorders. 

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. 

Drosophila Ddc is expressed primarily in the CNS and the hypoderm, the epithelial layer of the fly that secretes the cuticle. In the CNS, Ddc is expressed in a small subset of neurons that produce either dopamine or serotonin (Budnik and White, 1988 Valles and White, 1988). In the hypoderm, Ddc expression leads to synthesis of dopamine, which is further metabolized into quinones that have a vital function in the cross-linking, hardening, and pigmentation of the fly cuticle (Wright, 1987). The developmental profile of DDC activity in these two tissues is quite different (Hirsh, 1986). DDC is first detected during late embryo-... 

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

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

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]. 

Glennon, R. A., Liebowitz, S. M., and Leming-Doot, D. (1980) Demethyl analogues of psychoactive methoxyphenalkylamines Synthesis and serotonin receptor affinities. J. Med. Chem., 23 990-994. 

Heinrich, T., Bottcher, H., Gericke, R., Bartoszyk, G.D., Anzali, S Seyfried, C. A., Griner, H.E. and van Amsterdam, C. (2004) Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT]A receptor agonists and serotonin reuptake... 

Several of the neurotransmitters are small-molecule amines such as dopamine, serotonin, epinephrine, and norepinephrine. These neurotransmitters are synthesized in the cytoplasm of the axon terminal and subsequently transported into and stored within the synaptic vesicles. The amino acids glycine and glutamic acid are normal constituents of proteins and are present in abundance in the axons. These are also stored in synaptic vesicles. Each electrical impulse that arrives at the presynaptic side of a synapse will cause only a small minority of the synaptic vesicles to fuse with the plasma membrane and discharge their contents. The remaining synaptic vesicles remain, waiting for subsequent electrical impulses. At the same time, neurotransmitter synthesis continues, as does their storage in synaptic vesicles. This tends to restore the full complement of amine neurotransmitters at the axon terminal. 

When the creation of long-term memories— repeated stimulations interrupted by rest periods—was simulated in this preparation by repeated pulses of serotonin, anatomical changes occurred. Specifically, new synaptic connections were created. It is likely that there are two underlying components to formation of new synaptic connections. One is local protein synthesis in the nerve terminal and the other is CREB (cAMP response element binding) dependent transcription in the neuronal nucleus. Of course, serotoiun pulses also stimulated the release of glutamate. So now the question is how repeated pulses of serotonin are related to protein synthesis and formation of new synapses. 

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. 

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