Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 7Neurotransmitters & Neuromodulators 139

dopamine β hydroxylase that is not membrane-bound are
released with norepinephrine and epinephrine. The half-life of
circulating dopamine β-hydroxylase is much longer than that
of the catecholamines, and circulating levels of this substance
are affected by genetic and other factors in addition to the rate
of sympathetic activity.

Catabolism of Catecholamines

Norepinephrine, like other amine and amino acid transmit-
ters, is removed from the synaptic cleft by binding to postsyn-
aptic receptors, binding to presynaptic receptors (Figure 7–3),
reuptake into the presynaptic neurons, or catabolism. Reup-
take is a major mechanism in the case of norepinephrine, and
the hypersensitivity of sympathetically denervated structures
is explained in part on this basis. After the noradrenergic
neurons are cut, their endings degenerate with loss of reup-
take in them. Consequently, more norepinephrine from oth-
er sources is available to stimulate the receptors on the
autonomic effectors.
Epinephrine and norepinephrine are metabolized to biologi-
cally inactive products by oxidation and methylation. The
former reaction is catalyzed by MAO and the latter by cate-
chol-O-methyltransferase (COMT). MAO is located on the
outer surface of the mitochondria. It has two isoforms, MAO-A
and MAO-B, which differ in substrate specificity and sensitivity
to drugs. Both are found in neurons. MAO is widely distrib-
uted, being particularly plentiful in the nerve endings at which
catecholamines are secreted. COMT is also widely distributed,
particularly in the liver, kidneys, and smooth muscles. In the
brain, it is present in glial cells, and small amounts are found in
postsynaptic neurons, but none is found in presynaptic norad-
renergic neurons. Consequently, catecholamine metabolism
has two different patterns.
Extracellular epinephrine and norepinephrine are for the
most part O-methylated, and measurement of the concentra-
tions of the O-methylated derivatives normetanephrine and
metanephrine in the urine is a good index of the rate of
secretion of norepinephrine and epinephrine. The O-methyl-
ated derivatives that are not excreted are largely oxidized, and
3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid,
VMA) is the most plentiful catecholamine metabolite in the
urine. Small amounts of the O-methylated derivatives are also
conjugated to sulfate and glucuronide.
In the noradrenergic nerve terminals, on the other hand,
some of the norepinephrine is constantly being converted by
intracellular MAO (Figure 7–7) to the physiologically inactive
deaminated derivatives, 3,4-dihydroxymandelic acid (DOMA)
and its corresponding glycol (DHPG). These are subsequently
converted to their corresponding O-methyl derivatives, VMA
and 3-methoxy-4-hydroxyphenylglycol (MHPG).

α & β Receptors

Epinephrine and norepinephrine both act on α and β receptors,
with norepinephrine having a greater affinity for α-adrenergic

receptors and epinephrine for β-adrenergic receptors. As noted

previously, the α and β receptors are typical G protein-coupled

receptors, and each has multiple forms. They are closely related

to the cloned receptors for dopamine and serotonin and to mus-

carinic acetylcholine receptors.

Clonidine lowers blood pressure when administered centrally.

It is an α 2 agonist and was initially thought to act on presynaptic

α 2 receptors, reducing central norepinephrine discharge. How-

ever, its structure resembles that of imidazoline, and it binds to

imidazoline receptors with higher affinity than to α 2 adrenergic

receptors. A subsequent search led to the discovery that imidazo-

line receptors occur in the nucleus tractus solitarius and the vent-

rolateral medulla. Administration of imidazolines lowers blood

pressure and has a depressive effect. However, the full signifi-

cance of these observations remains to be explored.

Dopamine

In certain parts of the brain, catecholamine synthesis stops at

dopamine (Figure 7–1) which can then be secreted into the

synaptic cleft. Active reuptake of dopamine occurs via a Na+-

and Cl–-dependent dopamine transporter. Dopamine is me-

tabolized to inactive compounds by MAO and COMT in a

manner analogous to the inactivation of norepinephrine. 3,4-

Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid

(HVA) are conjugated, primarily to sulfate.

Dopaminergic neurons are located in several brain

regions including the nigrostriatal system, which projects

from the substantia nigra to the striatum and is involved in

FIGURE 7–7 Biochemical events at noradrenergic endings.

NE, norepinephrine; COMT, catechol-O-methyltransferase; MAO,

monoamine oxidase; X, receptor. For clarity, the presynaptic receptors

have been omitted. Note that MAO is intracellular, so that norepineph-

rine is being constantly deaminated in noradrenergic endings. COMT

acts primarily on secreted norepinephrine.

Noradrenergic

neuron

Postsynaptic

tissue

Dopamine

Dopa

NE

NE

COMT

MAO

Reuptake

Tyrosine

Deaminated

derivatives

Normetanephrine