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INTRODUCTION

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5-Hydroxytryptamine (5HT, serotonin) and dopamine (DA) have prominent actions in the CNS and the periphery. Fourteen 5HT receptor subtypes and five DA receptor subtypes have been delineated by pharmacological analyses and cDNA cloning. The availability of cloned receptors has allowed the development of subtype-selective drugs and the elucidation of actions of these neurotransmitters at a molecular level.

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5-HYDROXYTRYPTAMINE

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5HT is found in high concentrations in enterochromaffin cells throughout the GI tract, in storage granules in platelets, and broadly throughout the CNS. 5HT regulates smooth muscle in the cardiovascular system and the GI tract and enhances platelet aggregation.

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SYNTHESIS AND METABOLISM OF 5HT. 5HT is synthesized by a 2-step pathway from the tryptophan (Figure 13-1).

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figure 13–1

Synthesis and inactivation of serotonin. Enzymes are identified in red lettering, and cofactors are shown in blue.

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Tryptophan is actively transported into the brain by a carrier protein. Levels of tryptophan in the brain reflect its plasma concentration and the plasma concentrations of amino acids that compete for the same transporter. Tryptophan hydroxylase, the rate-limiting enzyme in the synthetic pathway, converts tryptophan to l-5-hydroxytryptophan; the enzyme is not regulated by end-product inhibition. Brain tryptophan hydroxylase is not generally saturated with substrate; consequently, the concentration of tryptophan in the brain influences the synthesis of 5HT.

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Aromatic l-amino acid decarboxylase (AADC) converts l-5-hydroxytryptophan to 5HT; it is widely distributed and has broad substrate specificity. The synthesized product, 5HT, is accumulated in secretory granules by a vesicular monoamine transporter (VMAT2); vesicular 5HT is released by exocytosis from serotonergic neurons. In the nervous system, the action of released 5HT is terminated via neuronal uptake by a specific 5HT transporter (SERT), localized in the membrane of serotonergic axon terminals and in the membrane of platelets. This uptake system is the means by which platelets acquire 5HT, since they lack the enzymes required for 5HT synthesis. The amine transporters are distinct from VMAT2, which concentrates amines in intracellular storage vesicles and is a nonspecific amine carrier, whereas the 5HT transporter is specific.

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The principal route of metabolism of 5HT involves oxidative deamination by monoamine oxidase (MAO); the aldehyde intermediate thus formed is converted to 5-hydroxyindole acetic acid (5-HIAA) by aldehyde dehydrogenase (see Figure 13-1). 5-HIAA is actively transported out of the brain by a process that is sensitive to the nonspecific transport inhibitor, probenecid. 5-HIAA from brain and peripheral sites of 5HT storage and metabolism is excreted in the urine along with small amounts of 5-hydroxytryptophol sulfate or glucuronide conjugates. The usual range of urinary excretion of 5-HIAA by a normal adult is 2-10 mg daily. Ingestion of ethanol results in elevated amounts of NADH2 (see Chapter 23), which diverts 5-hydroxyindole acetaldehyde from the oxidative route ...

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