DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

352 O
by AADC, the same enzyme that generates 5-HT from
OH L-Phenylalanine
L-5-hydroxytryptophan. In the CNS and periphery,
NH 2
AADC activity is very high, and basal levels of L-DOPA
cannot be readily measured. Unlike DA, L-DOPA readily
O 2
tetrahydrobiopterin
crosses the blood-brain barrier and is converted to
DA in the brain, which explains its utility in therapy
for Parkinson disease (Chapter 22).
SECTION II
NEUROPHARMACOLOGY
HO
tetrahydrobiopterin
HO
HO
HO
HO
HO
HO
Dopamine
MAO
DOPAC
Phenylalanine
hydroxylase
O
NH 2
OH
Tyrosine
hydroxylase
O
NH 2
NH 2
COOH
OH
L-aromatic
amino acid
decarboxylase
COMT
COMT
L-Tyrosine
L-DOPA
H 3 CO
HO
3-Methoxytyramine
H 3 CO
HO
MAO
AD
NH 2
COOH
HVA
Figure 13–6. Synthesis and inactivation of dopamine. Enzymes
are identified in blue lettering, and co-factors are shown in black
letters.
(Chapter 8). Four alternatively spliced isoforms of
tyrosine hydroxylase have been identified in humans,
which is in contrast to many non-human primates (two
isoforms) and rat (one isoform). At present, it is
unclear if these various isoforms play different roles.
Once generated, L-DOPA is rapidly converted to DA
The neurochemical events that underlie DA neurotransmission
are summarized in Figure 13–7. In dopaminergic neurons,
synthesized DA is packaged into secretory vesicles (or into granules
within adrenal chromaffin cells) by the vesicular monoamine
transporter, VMAT2. This packaging allows DA to be stored in
readily releasable aliquots and protects the transmitter from further
anabolism or catabolism. By contrast, in adrenergic or noradrenergic
cells, the DA is not packaged; instead, it is converted to
NE by DA β-hydroxylase and, in adrenergic cells, further altered
to epinephrine in cells expressing phenylethanolamine N-methyltransferase
(Chapter 8). Synaptically released DA is subject to both
transporter clearance and metabolism. The DA transporter (DAT)
is not selective for DA; moreover, DA can also be cleared from the
synapse by the NE transporter, NET. Reuptake of DA by the DA
transporter is the primary mechanism for termination of DA action,
and allows for either vesicular repackaging of transmitter or metabolism.
The DA transporter is regulated by phosphorylation, offering
the potential for DA to regulate its own uptake.
The DA transporter is predominantly localized perisynaptically
so that DA is cleared at a distance from its release site, suggesting
that high concentrations of DA are released into the synapse,
thus necessitating a spatially distant transporter. In addition to clearing
synaptic neurotransmitter, the DA transporter is a site of action for
cocaine and methamphetamine, which have distinct mechanisms to
increase extracellular DA. The DA transporter is also the molecular
target for some neurotoxins, including 6-hydroxydopamine and
1-methyl-4-phenylpyridium (MPP+), the neurotoxic metabolite of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following
uptake into dopaminergic neurons, MPP+ and 6-hydroxydopamine
elicit intra- and extracellular DA release, ultimately resulting in neuronal
death. This selective dopaminergic degeneration mimics
Parkinson disease, and serves as an animal model for this disorder.
Metabolism of DA occurs primarily by the cellular
MAO enzymes localized on both pre- and postsynaptic
elements. MAO acts on DA to generate an inactive aldehyde
derivative by oxidative deamination (Figures 13–6
and 13-7), which is subsequently metabolized by aldehyde
dehydrogenase to form 3,4-dihydroxyphenylacetic
acid (DOPAC).
DOPAC can be further metabolized by catechol-Omethyltransferase
(COMT) to form homovanillic acid (HVA). Both
DOPAC and HVA, as well as DA, are excreted in the urine. Levels
of DOPAC and HVA are reliable indicators of DA turnover; ratios of
these metabolites to DA in cerebral spinal fluid serve as accurate
representations of brain dopaminergic activity. In addition to metabolizing
DOPAC, COMT also utilizes DA as a substrate to generate
3-methoxytyramine, which is subsequently converted to HVA by
MAO. In humans, HVA is the principal metabolite of DA. COMT in