Depiction of the monoamine-deficiency hypothesis at the synaptic level Depiction of the monoamine-deficiency hypothesis at the synaptic level. Monoaminergic neurotransmission is mediated by serotonin or norepinephrine released from presynaptic neurons. Serotonin is synthesized from tryptophan by tryptophan hydroxylase (TPH); norepinephrine is synthesized from tyrosine, catalyzed by tyrosine hydroxylase. Monoamine transmitters are stored in presynaptic vesicles and released into the synaptic cleft. Cessation of the synaptic action of the neurotransmitters occurs through both reuptake transporters as well as feedback control of release through presynaptic 5-HT1A and 5-HT1B regulatory autoreceptors for serotonin and alpha2-noradrenergic receptors for norepinephrine. Monoamine oxidase A (MAO-A) catabolizes monoamines presynaptically. Protein p11 interacts with 5-HT1B receptors and increases their function. Postsyntactically, both serotonin and norepinephrine bind to G-protein-coupled receptors: cyclic AMP (cAMP)-coupled receptors activate adenylate cyclase (AC) to generate cAMP, while phosphatidylinositol (PI)-coupled receptors activate phospholipase C (PLC). PLC generates inositol triphosphate (IP3) and diacylglycerol (DAG). cAMP activates protein kinase A (PKA), while IP3 and DAG activate protein kinase C (PKC). These two protein kinases affect the cAMP response element–binding-protein (CREB). Findings that support the monoamine-deficiency hypothesis include a relapse of depression with inhibition of tyrosine hydroxylase or depletion of dietary tryptophan, an increased frequency of mutations affecting the brain-specific form of TPH-2, increased specific ligand binding to MAO-A, subsensitive 5-HT1A receptors, 5-HT1B receptor malfunction, decreased p11 levels, polymorphisms in the serotonin-reuptake transporter associated with depression, an inadequate G-protein response to neurotransmitters, and reduced levels of cAMP, inositol and CREB in postmortem brain. (Reproduced with permission from Belmaker RH, Agam G. Major depressive disorder. N Engl J Med. 2008;358(1):55–68.) Source: The Neurobiology of Depression: An Integrated Systems-Level, Cellular–Molecular and Genetic Overview, Depression in Medical Illness Citation: Barsky AJ, Silbersweig DA, Boland RJ. Depression in Medical Illness; 2016 Available at: http://neurology.mhmedical.com/DownloadImage.aspx?image=/data/books/1891/bar19084_c02_11.png&sec=148706715&BookID=1891&ChapterSecID=138744296&imagename= Accessed: November 11, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved