Page - (000175) - in Biomedical Chemistry: Current Trends and Developments

neuroinjury has been demonstrated (Miller, 1999). Storing of DA depends on a vesicular transporter protein, the vesicular monoamine transporter (VMAT). If left free on the cytoplasm, DA is rapidly inactivated by the mitochondrial enzyme MAO-A, simultaneously producing H2O2. Serotonin is synthesized from the amino acid tryptophan that is hydroxylated into 5-hydroxytryptophan (5-HTP) by the rate-limiting enzyme tryptophan hydroxylase (TPH). The serotonin precursor, 5-HTP, is decarboxylated by the L-AADC originating the neurotransmitter 5-HT. Synthesis of serotonin depends mainly on the availability of tryptophan, which is present in high levels in the plasma and crosses the blood-brain barrier by active transport. Dietary levels of tryptophan may affect substantially the levels of serotonin in the brain. In the presynaptic terminal, 5-HT is stored in vesicles by a process identical to the one described for dopamine. Interaction of extracellular 5-HT with 5-HT autoreceptors regulates synthesis and release of 5-HT. Inactivation of released 5-HT is mainly attained by 5-HT reuptake through the membrane carrier-protein 5-HT transporter (SERT). Once inside the neuron, 5-HT can be reacumulated into vesicles, or inactivated by the mitochondrial enzyme MAO-B, that metabolizes 5-HT into 5- hydroxyindoleacetic acid (5-HIAA) simultaneously producing H2O2. Inhibition of 5-HT neuron firing activity is mediated through the somatodendritic 5-HT1A autoreceptor, increasing the membrane hyperpolarization (Pineyro, 1999). Serotonin receptors represent the most complex family of neurotransmitter receptors. With the exception of the 5-HT3 receptor, which is a ligand-gated ion channel, all 5-HT receptors belong to the G-protein-coupled receptor superfamily (Hoyer, 2002). Due to its role in antidepressant drug action, 5-HT receptors have been the target of intense research (Pineyro, 1999). These receptors have been divided, according to their primary function, in three main groups. The first group comprises the 5-HT1-like receptors (5-HT1A, 5-HT1B and 5- HT1D), which couple preferentially to Gi/o proteins (pertussis toxin- sensitive) to inhibit cAMP formation (Hoyer, 2002). In the raphe nuclei, 5-HT1A receptors are somatodendritic and act like autoreceptors inhibiting cell firing, while postsynaptic 5-HT1A receptors, are present in