Effects of Specific MAO Inhibitors on Cultured 5-HT Neurons

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Serotonin plays an important role in neurodevelopment by causing changes in forebrain naturation, neurite outgrowth, expression of postsynaptic receptors, and on the apprearance of inhibitory behaviors. This research will focus on the proposition that a component of the action of 5-HT on serotonergic neurons (autoregulation) may be its intracellular metabolism by monoamine oxidase (MAO). The hypothesis is based on the fact that metabolism of 5-HT by MAO generates H202, which is highly toxic to neurons because it can form hydroxy-free radicals. The enzyme MAO exists in two forms, A and B. MAO-A has a higher affinity for 5-HT than MAO-B, but this latter form is localized to serotonergic neurons and astrocytes. Preliminary studies indicate that inhibition of MAO-B is effective in augmenting fetal 5-HT development. The studies are clinically relevant because of the widespread use of monoamine oxidase inhibitors in depressed patients. They may also help understand age-related degenerative processes underlying dementia since MAO-B is increased during aging while serotonergic neurons, important in learning and memory, are reduced.