5-Hydroxi-Tryptamine

Biogenic amines. A general term usually used to describe endogenous amine-containing compounds such as dopamine, 5-hydroxy-tryptamine, and norepinephrine that function as neurotransmitters. 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Cox, B, Lee, TF and Martin, D (1981) Different hypothalamic receptors mediate 5-hydroxy-tryptamine and tr5 ptamine induced core temperative changes in the rat. Brit. J. Pharmacol. 72 472-482. 

Hydroxy tryptamine, or serotonin, is a neurotransmitter in the central nervous system (CNS). The nerve-cell bodies of the major serotoninergic neurones are in the midline raphe nuclei of the rostral pons, and ascending fibers innervate the basal ganglia, hypothalamus, thalamus, hippocampus, limbic forebrain, and areas of the cerebral cortex. The serotoninergic system plays an important role in the control of mood and behavior, motor activity, hunger, thermoregulation, sleep, certain hallucinatory states, and some neuro-endocrine mechanisms. 

Commissaris, R. L., Lyness, W. H., Moore, K. E., and Rech, R. H. (1981) Central 5-hydroxy-tryptamine and the effects of hallucinogens and phenobarbital on operant responding in rats. Pharmacol Biochem. Behav., 14 595-601. 

Figure 13.28 A possible mechanism by which increased levels of tryptophan and/or tyrosine can occur in neurones and lead to fatigue. The mechanism proposes that physical activity increases the entry of tryptophan or tyrosine into the neurones which increases the concentration of the neurotransmitters, 5-hydroxy-tryptamine or dopamine, respectively. The neurotransmitters are present in vesicles in the presynaptic terminal (Chapter 14). (The pathways for the formation of 5-hydroxytryptamine and dopamine are described in Chapter 14.) This enhances the amount release into the synapses which decreases the excitation of 5-hydroxytryptamine or dopamine neurones in the motor control pathway. It is assumed that they are inhibitory neurotransmitters, they will reduce electrical activity in the motor control pathway and hence nervous stimulation of muscle fibres. This results in fatigue. Mechanisms by which physical activity might result in increased entry of these amino acids into the brain are presented in Appendix 13.5.

MAO is a much less discriminating enzyme in that it will catalyze the removal of an amine group from a variety of substrates. The action of MAO on norepinephrine and epinephrine also is indicated in Figure 9.5. The list of its substrates is very large, including endogenous substances (norepinephrine, epinephrine, dopamine, tyramine, 5-hydroxy-tryptamine) and many drugs that are amines. At least in the brain, two separate forms of MAO have been described MAO type A and MAO type B. The two types are differentiated on the basis of substrate and inhibitor specificity. 

Fig. 1. Influence of substituents in the aromatic ring on the selectivity of 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives as monoamine oxidases (MAO) A or B inhibitors. Ratio of selectivity was calculated from IC50 values of MAO A and B determined by an in vitro assay of mouse brain mitochondria using 5-hydroxy tryptamine (5-HT) and 2-phenylethylamine (PEA) as specific substrates, respectively (see Ref. [9]). Smaller values indicate that inhibitors are MAO A selective [71].

Bel N, Artigas F Fluvoxamine preferentially increases extracellular 5-hydroxy-tryptamine in the raphe nuclei an in vivo microdialysis study. Eur J Pharmacol 229 101-103, 1992... 

Fig. 30-27). The fact that L-tryptophan has some antidepressant activity, but L-dopa does not, was one clue that a low concentration of serotonin (5-hydroxy-tryptamine) might be responsible for depression. Excessive formation of histamine1099 and decreased formation of tyramine and octopamine1100 have also been suggested as causes of depression. 

Neonatal treatment with chlorpromazine or lysergic acid diethylamide (LSD) in rats resulted in lowered brain 5HT (5 Hydroxy Tryptamine) levels in adulthood (ref. 97). Perinatal methadone treatment in rats was shown to decrease not only total brain weight, but also to retard synaptic development of central 5-HT, DA and NA neurons (ref. 98). Early diazepam treatment was found to affect uptake of choline in 60 day old male rats (but not in females) and uptake of GABA (Gamma Amino Butyric Acid) and 5HT in 60 day old females (ref. 99). 

Disease in which symptoms are due to a 5-hydroxy-tryptamine secreting tumour, usually located in the gastrointestinal tract. 

Arvidsson LE, Hacksell U, Glennon RA. Recent advances in central 5-hydroxy-tryptamine receptor agonists and antagonists. In Jucker E, ed., Progress in Drag Research. Basel Birkhauser Verlag, 1986 365-471. 

Fozard JR. The development and early clinical evaluation of serotonin 5-HT3 receptor antagonists. In Fozard JR, ed., The Peripheral Actions of 5-Hydroxy-tryptamine. Oxford Oxford University Press, 1989 355-376. 

Fayolle C, Fillion MP, Barone P, Oudar P, Rousselle JC, Fillion G. 5-Hydroxy-tryptamine stimulates two distinct adenylate cyclase activities in rat brain ... 

Berg KA, Clarke WP, Chen Y, Ebersole BJ, McKay RD, Maayani S. 5-Hydroxy-tryptamine type 2A receptors regulate cyclic AMP accumulation in a neuronal cell line by protein kinase C-dependent and calcium/caknodulin-dependent mechanisms. Mol Pharmacol 1994 45 826-836. 

Cox DA, Watts SW, Cohen ML. Neomycin selectively inhibits 5-hydroxy-tryptamine-induced contraction in the guinea pig trachea. J Pharmacol Exp Ther 1996 277 954-959. 

Nebigil CG, Launay JM, Hickel P, Tournois C, Maroteaux L. 5-Hydroxy-tryptamine 2B receptor regulates cell-cycle progression cross-talk with tyrosine kinase pathways. Proc Natl Acad Sci USA 2000 97 2591-2596. 

Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. A 5-hydroxy-tryptamine receptor in human atrium. Br J Pharmacol 1990 100 879-885. 

Hirst WD, Price GW, Rattray M, Wilkin GP. Identification of 5-hydroxy-tryptamine receptors positively coupled to adenylyl cyclase in rat cultured astrocytes. Br J Pharmacol 1997 120 509-515. 

Kurrasch-Orbaugh DM, Watts VJ, Barker EL, Nichols DE. Serotonin 5-hydroxy-tryptamine(2A) receptor-coupled phospholipase C and phospholipase A(2) signaling pathways have different receptor reserves. J Pharmacol Exp Ther 2003 304 229-237. 

Launay JM, Herve P, Peoc h K, et al. Function of the serotonin 5-hydroxy-tryptamine 2B receptor in pulmonary hypertension. Nat Med 2002 8 1129-1135. 

Willins DL, Berry SA, Alsayegh L, et al. Clozapine and other 5-hydroxy-tryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytiyptamine-2A receptors in vitro and in vivo. Neuroscience 1999 91 599-606. 

Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J. A nonclassical 5-hydroxy-tryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol 1988 34 880-887. 

Boess FG, Riemer C, Bos M, Bentley J, Bourson A, Sleight AJ. The 5-hydroxy -tryptamine, receptor-selective radioligand H-3 Ro 63-0563 labels 5-hydroxy-tryptamine receptor binding sites in rat and porcine striatum. Mol Pharmacol 1998 54 577-583. 

Bonaventure P, Nepomuceno D, Kwok A, et al. Reconsideration of 5-hydroxy-tryptamine (5-HT)(7) receptor distribution using [(3)H]5-carboxamidotiyptamine and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline analysis in brain of 5-HT(lA) knockout and 5-HT(lA/lB) double-knockout mice. J Pharmacol Exp Ther 2002 302 240-248. 

Spier AD, Lummis SC. The role of tryptophan residues in the 5-Hydroxy-tryptamine(3) receptor ligand binding domain. J Biol Chem, 2000 275(8) ... 

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