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

PRESYNAPTIC TERMINAL
Dietary
phenylalanine
Hepatic
PH
Tyrosine
HVA
DOPA
AADC
COMT
HVA DOPAC
MAO
ALDH
DA
Neuronal reuptake
(DAT, NET), then storage
(VMAT2), or metabolism
POSTSYNAPTIC CELL
HVA
HVA
TH
Tyr
DA
Synaptic DA
D1/D2 family
of receptors
Effector
response
ALDH
MAO
DA
DA
VMAT2
Depolarization
(Na + and
Ca 2+ entry)
D 2
autoreceptor
Postsynaptic uptake
[(OCT1, OCT2,
ENT (OCT3)]
Figure 13–7. Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential
actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules
and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA
may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters.
Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron,
and by catechol-O-methyl tranferase (COMT) and MAO/ALDH in non-neuronal cells; the final metabolic product is homovanillic
acid (HVA). See structures in Figure 13-6. PH, phenylalanine hydroxylase.
DA
3MT
COMT
353
CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE
the periphery also metabolizes L-DOPA to 3-O-methyldopa, which
then competes with L-DOPA for uptake into the CNS. Consequently,
L-DOPA given in the treatment of Parkinson disease must be coadministered
with peripheral COMT inhibitors to preserve L-DOPA
and allow sufficient entry into the CNS (Chapter 22).
PHYSIOLOGICAL FUNCTIONS
OF DOPAMINE
Multiple DA Receptors
Five distinct GPCRs have been cloned and determined
to mediate the actions of DA (Figure 13–8). Though the
cloning and classification of these receptors was initially
based on mammalian studies, subsequent experimentation
has revealed similar DA receptor groups in
both vertebrate and invertebrate systems. The DA
receptors are distinct from one another in pharmacology,
amino acid sequence, distribution, and physiological
function. They have been organized into two
families—the D1-like and D2-like receptors—based
upon their effector-coupling profile (for a recent review
of DA receptors, see Rankin et al., 2009).
History of DA Receptor Subtypes. In 1971, Kebabian and
Greengard determined that DA caused an increase in neostriatal
cyclic AMP production, presumably by activating a DA-sensitive
adenylyl cyclase enzyme. Subsequently, the DA-induced increase in
cyclic AMP was attributed to a D1 receptor while a second category
of DA receptors that did not raise cyclic AMP levels was termed the
D2 receptor. Differences in pharmacological responsiveness gave
rise to the hypothesis that there were multiple subtypes of DA