Norepinephrine, also known as noradrenaline, is a neurotransmitter found in the sympathetic nervous system and biosynthesized from the amino acid tyrosine, which is sequentially hydroxylated to generate dihydroxyphenylallanine (Dopa), decarboxylated to produce dopamine, and hydroxylated to form NE (
19).
As one of the crucial neurochemical messengers in the CNS, NE plays an important role in human physiology and pathology, and is involved in mood regulation, sleep regulation, expression of behavior and the general degree of alertness and arousal (
20). Norepinephrine also exerts central control over the endocrine system and autonomic nervous system. Outside the CNS and adrenal glands, NE is located in the sympathetic nerve endings, and the NE content of a particular tissue reflects the extent of its sympathetic innervation (
21).
The NET is located in the plasma membrane of noradrenergic neurons, where it functions to take up synaptically released NE. The NET thus serves as the primary mechanism for the inactivation of noradrenergic signaling (
22-
24). Reuptake of NE by the NET protein (also known as uptake 1) is the primary mechanism by which the biological effects of NE in the synapse are terminated (
Fig. 2). The inactivation process through the NET is critical in preventing an excessive increase in the NE concentrations in the synaptic cleft, which regulate adrenergic neurotransmission in the brain, as well as the removal of NE from the heart and other peripheral organs (
21,
25). Reuptake of NE is competitive with a variety of naturally occurring amines and drugs.
Drugs of abuse (
e.g., cocaine) and antidepressants (
e.g., desipramine, venlafaxine, reboxetine, bupropion) block the transport of NE and thereby cause an elevation in the synaptic concentrations of NE and potentiation of the activation of postsynaptic receptors (
21,
26,
27). The above neurobiology of the NE system and other accumulating evidence support the view that NE plays an important role in the CNS