FIGURE 1–5. The noradrenergic system.
This figure depicts the
noradrenergic projections throughout the brain (A)
the various regulatory processes involved in norepinephrine (NE)
NE neurons innervate
nearly all parts of the neuroaxis, with neurons in the locus coeruleus
being responsible for most of the NE in the brain (90% of
NE in the forebrain and 70% of total NE in the brain).
The amino acid l
-tyrosine is actively
transported into presynaptic NE nerve terminals, where it is ultimately
converted into NE. The rate-limiting step is conversion of l
by the enzyme tyrosine hydroxylase (TH).
(AMPT) is a competitive inhibitor of tyrosine hydroxylase and has
been used to assess the impact of reduced catecholaminergic function
in clinical studies. Aromatic amino acid decarboxylase (AADC) converts l
to dopamine (DA). l
-dopa then becomes
decarboxylated by decarboxylase to form dopamine (DA). DA is then
taken up from the cytoplasm into vesicles, by vesicle monoamine
transporters (VMATs), and hydroxylated by dopamine
(DBH) in the presence of O2
to form NE. Normetanephrine (NM), which is formed by the action
of COMT (catechol-O
on NE, can be further metabolized by monoamine oxidase (MAO) and
aldehyde reductase to 3-methoxy-4-hydroxyphenylglycol (MHPG). Reserpine
causes a depletion of NE in vesicles by interfering with uptake
and storage mechanisms (depressive-like symptoms have been reported
with this hypertension). Once released from the presynaptic terminal, NE
can interact with a variety of presynaptic and postsynaptic receptors.
Presynaptic regulation of NE neuron firing activity and release
occurs through somatodendritic (not shown) and nerve-terminal 2
respectively. Yohimbine potentiates NE neuronal firing and NE release by
blocking these 2
thereby disinhibiting these neurons from a negative feedback influence.
Conversely, clonidine attenuates NE neuron firing and release by
activating these receptors. Idazoxan is a relatively selective 2
antagonist primarily used for pharmacological purposes. The binding
of NE to G protein receptors (Go
etc.) that are coupled to adenylyl cyclase (AC) and phospholipase
(PLC-b) produces a
cascade of second-messenger and cellular effects (see diagram and
later sections of the text). NE has its action terminated in the
synapse by rapidly being taken back into the presynaptic neuron
via NE transporters (NETs). Once inside the neuron, it can either
be repackaged into vesicles for reuse or undergo enzymatic degradation.
The selective NE reuptake inhibitor and antidepressant reboxetine
and older-generation tricyclic antidepressant desipramine are able
to interfere/block the reuptake of NE. On the other hand,
amphetamine is able to facilitate NE release by altering NET function.
Green spheres represent DA neurotransmitters; blue spheres represent
NE neurotransmitters. DAG = diacylglycerol; IP3
from Cooper JR, Bloom FE, Roth RH: The Biochemical
Basis of Neuropharmacology,
7th Edition. New York,
Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982,
1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by
permission of Oxford University Press, Inc. Modified from Nestler et al. 2001.