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

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SECTION II
PRESYNAPTIC TERMINAL
Dietary
phenylalanine
Hepatic
PH
Tyrosine
HVA
DOPA
TH
Tyr
AADC
COMT
HVA DOPAC
MAO
ALDH
DA
DA
DA
VMAT2
Depolarization
(Na + and
Ca 2+ entry)
NEUROPHARMACOLOGY
Neuronal reuptake
(DAT, NET), then storage
(VMAT2), or metabolism
DA
Synaptic DA
D1/D2 family
of receptors
D 2
autoreceptor
Postsynaptic uptake
[(OCT1, OCT2,
ENT (OCT3)]
POSTSYNAPTIC CELL
Effector
response
DA
COMT
HVA
HVA
ALDH
MAO
3MT
Figure 22–1. 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 22-4. PH, phenylalanine hydroxylase.
subgroup of striatal neurons consists of interneurons that connect neurons
within the striatum but do not project beyond its borders.
Acetylcholine (ACh) and neuropeptides are used as transmitters by
these striatal interneurons.
The outflow of the striatum proceeds along two distinct routes,
termed the direct and indirect pathways. The direct pathway is formed
by neurons in the striatum that project directly to the output stages of
the basal ganglia, the substantia nigra pars reticulata (SNpr) and the
globus pallidus interna (GPi); these, in turn, relay to the ventroanterior
and ventrolateral thalamus, which provides excitatory input to
the cortex. The neurotransmitter of both links of the direct pathway is
γ-aminobutyric acid (GABA), which is inhibitory, so that the net effect
of stimulation of the direct pathway at the level of the striatum is to
increase the excitatory outflow from the thalamus to the cortex. The
indirect pathway is composed of striatal neurons that project to
the globus pallidus externa (GPe). This structure, in turn, innervates the
subthalamic nucleus (STN), which provides outflow to the SNpr and
GPi output stage. As in the direct pathway, the first two links—the
projections from striatum to GPe and GPe to STN—use the
inhibitory transmitter GABA; however, the final link—the projection
from STN to SNpr and GPi—is an excitatory glutamatergic
pathway. Thus, the net effect of stimulating the indirect pathway at
the level of the striatum is to reduce the excitatory outflow from the
thalamus to the cerebral cortex.