Serotonin in the Frontal Cortex: A Potential Therapeutic Target for Neurological Disorders.

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter which has broad distribution in the brain. It was discovered by Erspamer and Asero in the 1950s [1]. 5-HT is synthesized in two steps, with Tryptophan Hydroxylase (TPH) as the rate-limiting enzyme [2]. First, tryptophan is converted to 5-hydroxytryptophan (5-HTP) by TPH. Second, the intermediate product, 5-HTP, is converted to 5-HT by aromatic acid decarboxylase (AADC). 5-HT is primarily degraded by the mitochondrial bound protein Monoamine Oxidase A (MAOA), leading to the generation of the metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Importantly, serotonin is also a substrate for melatonin synthesis [3]. 5-HT is released from the axonal terminals of serotoninergic neurons and acts on 14 distinct receptor subtypes that are classified into 7 different families: 5-HT1 (1A, 1B, 1D, 1E, 1F), 5-HT2 (2A, 2B, and 2C), 5-HT3, 5-HT4, 5-HT5 (5A, 5B), 5-HT6, and 5-HT7. Among all these receptors, only 5HT3 receptor is a pentameric ligand-gated ion channel composed of several subunits of which 5 different types have been identified [4]. All other 5-HT receptors are G-protein coupled receptors which regulate the activity of the neurons expressing them [5,6]. Released serotonin is transported to the presynaptic neurons by serotonin transporter (SERT or 5HTT), a type of monoamine transporter protein [7].