Figure 1.

Overview of the actions of NE in neural synapses. Noradrenergic neurons originate from the locus coeruleus and project to regions of the forebrain, including the cortex and hypothalamus. NE is synthesized from the amino acids TYR and PHL and converted first to DOPA, DA, and further to NE by the enzymes TYR-H, AADC, and DA β-H, respectively, after which NE is stored in presynaptic vesicles. Following its release into the synaptic cleft, NE exerts its effects through binding to the adrenergic receptors (ARs): α_1A, α_1B, and α_1D; α_2A, α_2B, and α_2C; or β₁, β₂, and β₃. α₁- and β-ARs have a stimulatory effect on cell signaling, whereas α₂-ARs inhibit signaling. Also, while ARs are mainly located post-synaptically, α₂- and β₂-AR subtypes can also be localized pre-synaptically. NE is removed from the synaptic cleft by either reuptake via NET (expressed on the presynaptic terminals of NE neurons and glial cells), inactivation through the catabolic enzyme COMT to NM, or metabolism by MAO into several transitional metabolites, including its principal brain metabolite, MHPG. AADC, l-aromatic amino acid decarboxylase; cAMP, cyclic adenosine monophosphate; COMT, catechol O-methyltransferase; DA, dopamine; DA β-H, dopamine β-hydroxylase; DHPG, dihydroxyphenylglycol; DOPA, 3,4-dihydroxyphenylalanine; MAO, monoamine oxidase; MHPG, 3-methoxy-4-hydroxyphenylglycol; NE, norepinephrine; NET, NE transporter; NM, normetanephrine; PHL, phenylalanine; PHL-H, phenylalanine hydroxylase; PLC, phospholipase C; TYR, tyrosine; TYR-H, tyrosine hydroxylase.