5-Hydroxytryptamine pathways

Handley, SL (1995) 5-Hydroxytryptamine pathways in anxiety and its treatment. Pharmac. Ther. 66 103-148. 

McQuade, R. Sharp, T. (1997). Functional mapping of dorsal and median raphe 5-hydroxytryptamine pathways in forebrain of the rat using microdialysis. 

Hole, K., Fuxe, K., and Jonsson, G. (1976) Behavioral effects of 5,7-dihydroxytryptamine lesions of ascending 5-hydroxytryptamine pathways. Brain Res., 107 385-399. 

Hole, K., Jonsson, G., and Berge, O. (1977) 5,7-Dihydroxytryptamine lesions of ascending 5-hydroxytryptamine pathways Habituation, motor activity and agonistic behavior. Pharmacol. Biochem. Behav., 7 205-210. 

The reaction of p-toluenesulfonyl chloride (TsCl) with 1-hydroxytryptamines was expected to follow the same reaction pathways as that of MsCl described in Section IV.B. 1. In fact, it is different from the expectation (2000H2487). Thus, 39 reacts with TsCl in THF to provide 49a (42%), 51a (6%), 53a (3%), 60 (0.5%), and... 

Segal, M., and Weinstock, M. (1983) Differential effects of 5-hydroxytryptamine antagonists on behaviors resulting from activation of different pathways arising from the raphe nuclei. Psychopharmacology, 79 72-78. 

Nebigil, C.G., Launay, J.M., Hickel, P., Tournois, C. and Maroteaux, L. (2000) 5-Hydroxytryptamine 2B receptor regulates cell-cycle progression cross-talk with tyrosine kinase pathways. Proceedings of the National Academy of Sciences of the United States of America, 97 (6), 2591-2596. 

Binds to DNA and prevents separation of the helical strands Affects neuronal transmissions Binds to opiate receptors and blocks pain pathway Acts as central nervous system depressant Inhibits Na/K/ATPase, increases intracellular calcium, and increases ventricular contractibility Blocks the actions of histamine on Hi receptor Blocks ai-adrenergic receptor, resulting in decreased blood pressure Inhibits reuptake of 5-hydroxytryptamine (serotonin) into central nervous system neurons Inhibits cyclooxygenase, inhibition of inflammatory mediators Inhibits replication of viruses or tumor cells Inhibits HIV reverse transcriptase and DNA polymerase Antagonizes histamine effects... 

The pathways for synthesis of the monoamine neurotransmitters are not, at least in some neurones, saturated with precursor amino acids (tyrosine for formation of noradrenaline plus dopamine tryptophan for formation of 5-hydroxytryptamine (serotonin)). Marked increases in the blood level of these amino acids can increase their concentrations in neurones which can influence the concentration of the respective neurotransmitters in some neurones in the brain. This may result in changes in behaviour. 

This hypothesis, similarly, proposes that physical activity increases tryptophan transport into the presynaptic neurone, where it is used to synthesise 5-hydroxytryptamine. Hence, when the nerve is stimulated, more 5-hydroxytryptamine is released into the synapse and, if this is another inhibitory transmitter in the motor control pathway, it will inhibit contraction (Figure 13.28). This is one of several effects of 5-hydroxytryptamine in the brain which are probably achieved via different receptors on different neurones. All three hypotheses are summarised in Figure 13.29. 

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.

Figure 2.18. The major pathway leading to the synthesis and metabolism of 5-hydroxytryptamine (5-HT). Metabolism of tryptophan to tryptamine is a minor pathway which may be of functional importance following administration of a monoamine oxidase (MAO) inhibitor. Tryptamine is a trace amine. L-Aromatic amino acid decarboxylase is also known to decarboxylate dopa and therefore the term "L-aromatic amino acid decarboxylase" refers to both "dopa decarboxylase"...

The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) is formed from tryptophan by hydroxylation then decarboxylation, paralleling the tyrosine — dopamine pathway. The non-specific enzyme aromatic amino acid decarboxylase again catalyses the decarboxylation. 

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. 

Serotonin (5-hydroxytryptamine [5-HT]) pathways play an important role in postprandial satiety. Treatments that increase intrasynaptic serotonin or directly activate serotonin receptors tend to reduce food consumption, whereas interventions that dampen serotonergic neurotransmission or block receptor activation reportedly increase food consumption and promote weight gain (Blundell, 1984 Teibowitz, 1986). Moreover, CNS serotonin pathways have been implicated in the modulation of mood, impulse regulation and be-... 

Neuronal systems that contain one of the monoamines—norepinephrine, dopamine, or 5-hydroxytryptamine (serotonin)— provide examples in this category. Certain other pathways emanating from the reticular formation and possibly some peptide-containing pathways also fall into this category. These systems differ in fundamental ways from the hierarchical systems, and the noradrenergic systems serve to illustrate the differences. 

Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine. Although these compounds are present in very small amounts in the CNS, they can be localized using extremely sensitive histochemical methods. These pathways are the site of action of many drugs for example, the CNS stimulants cocaine and amphetamine appear to act primarily at catecholamine synapses. Cocaine blocks the reuptake of dopamine and norepinephrine, whereas amphetamines cause presynaptic terminals to release these transmitters. 

Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate from neurons in the raphe or midline regions of the pons and upper brain stem. 5-HT is contained in unmyelinated fibers that diffusely innervate most regions of the CNS, but the density of the innervation varies. 5-HT acts on more than a dozen receptor subtypes. Except for the 5-HT3 receptor, all of these... 

FIGURE 18.4 Pharmacologist s view of emetic stimuli. Myriad signaling pathways lead from the periphery to the emetic center. Stimulants of these pathways are noted in italics. These pathways involve specific neurotransmitters and their receptors (bold text). Receptors are shown for dopamine, D acetylcholine (muscarinic), M histamine, H and 5-hydroxytryptamine, 5-HT. Some of these receptor types also may mediate signaling in the emetic center. This knowledge offers a rationale for current antiemetic therapy. 

Consolo S, Wu CF, Fusi R (1987) Di receptor-linked mechanism modulates cholinergic neurotransmission in rat striatum. J Pharmacol Exp Ther 242 300-5 Consolo S, Arnaboldi S, Giorgi S, Russi G, Ladinsky H (1994) 5-HT4 receptor stimulation facilitates acetylcholine release in rat frontal cortex. Neuroreport 5 1230-2 Cooper AJ, Stanford IM (2001) Dopamine D2 receptor mediated presynaptic inhibition of stri-atopallidal GABAa IPSCs in vitro. Neuropharmacol 41 62-71 Cox B, Kerwin RW, Lee TF, Pycock CJ (1980) A dopamine-5-hydroxytryptamine link in the hypothalamic pathways which mediate heat loss in the rat. J Physiol 303 9-21 Dailly E, Chenu F, Renard CE, Bourin M (2004) Dopamine, depression and antidepressants. Fun-dam Clin Pharmacol 18 601-7... 

Carcinoid is a tumor of the enterochromaffin cells that normally synthesize 5-hydroxytrytophan and 5-hydroxytryptamine. The carcinoid syndrome is seen when there are significant metastases of the primary tumor in the liver. It is characterized by increased gastrointestinal motility and diarrhea, as well as by regular periodic flushing. These symptoms can be attributed to systemic release of large amounts of serotonin and can be controlled with inhibitors of tryptophan hydroxylase, such as p-chlorophenylalanine. The synthesis of 5-hydroxytryptamine in advanced carcinoid syndrome may be so great that as much as 60% of the body s tryptophan metabolism proceeds by this pathway, compared with about 1% under normal conditions. A significant number of... 

Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new protein synthesis, essentially the whole of the dietary intake of tryptophan is metabolized by way of the oxidative pathway shown in Figures 8.4 and 9.4, which provides both a mechanism for total catabolism by way of acetyl coenzyme A and a pathway for synthesis of the nicotinamide nucleotide coenzymes (Section 8.3). 

As shown in Figure 8.2, NAD(P) can be synthesized from the tryptophan metabolite quinolinic acid. The oxidative pathway of tryptophan metabolism is shown in Figure 8.4. Under normed conditions, almost aU of the dietary intake of tryptophan, apart from the smedl amount that is used for net new protein synthesis, is metabolized by this pathway, and hence is potentially available for NAD synthesis. About 1% of tryptophan metabolism is byway of 5-hydroxylation and decarboxylation to 5-hydroxytryptamine (serotonin), which is excreted mainly as 5-hydroxyindoleacetic acid. 

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