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

Glu
+
Glu +
DA
SNpc
To spinal cord
and brainstem
Cerebral cortex
+
Striatum
D 1
Glu
(stimulatory)
D 2
(inhibitory)
Glu
ACh
– GABA
–
GPe STN
GABA
– GABA
Glu +
GPi/SNpr
Glu
VA/VL
thalamus
GABA
Figure 22–2. Schematic wiring diagram of the basal ganglia.
The striatum is the principal input structure of the basal ganglia
and receives excitatory glutamatergic input from many areas of
cerebral cortex. The striatum contains projection neurons
expressing predominantly D 1
or D 2
dopamine receptors, as well
as interneurons that use ACh as a neurotransmitter. Outflow from
the striatum proceeds along two routes. The direct pathway, from
the striatum to the substantia nigra pars reticulata (SNpr) and
globus pallidus interna (GPi), uses the inhibitory transmitter
GABA. The indirect pathway, from the striatum through the
globus pallidus externa (GPe) and the subthalamic nucleus
(STN) to the SNpr and GPi, consists of two inhibitory
GABAergic links and one excitatory glutamatergic projection
(Glu). The substantia nigra pars compacta (SNpc) provides
dopaminergic innervation to the striatal neurons, giving rise to
both the direct and indirect pathways, and regulates the relative
activity of these two paths. The SNpr and GPi are the output
structures of the basal ganglia and provide feedback to the cerebral
cortex through the ventroanterior and ventrolateral nuclei of
the thalamus (VA/VL).
The key feature of this model of basal ganglia function, which
accounts for the symptoms observed in PD as a result of loss of
dopaminergic neurons, is the differential effect of DA on the direct
and indirect pathways (Figure 22–3). The dopaminergic neurons of
the substantia nigra pars compacta (SNpc) innervate all parts of the
striatum; however, the target striatal neurons express distinct types
of DA receptors. The striatal neurons giving rise to the direct pathway
express primarily the excitatory D 1
dopamine receptor protein,
whereas the striatal neurons forming the indirect pathway express
primarily the inhibitory D 2
type. Thus, DA released in the striatum
tends to increase the activity of the direct pathway and reduce the
activity of the indirect pathway, whereas the depletion that occurs
in PD has the opposite effect. The net effect of the reduced dopaminergic
input in PD is to increase markedly the inhibitory outflow from
the SNpr and GPi to the thalamus and reduce excitation of the motor
cortex.
There are several limitations of this model of basal ganglia
function (Parent and Cicchetti, 1998): The anatomical connections
are considerably more complex than envisioned originally. In addition,
many of the pathways involved use not just one, but several
+
+
–
Glu
+
Glu +
DA
SNpc
To spinal cord
and brainstem
Cerebral cortex
+
Striatum
D 1
Glu
(stimulatory)
–
D 2
(inhibitory)
Glu
ACh
– GABA
–
GPe STN
GABA
GABA
Glu +
GPi/SNpr
Glu
VA/VL
thalamus
GABA
Figure 22–3. The basal ganglia in Parkinson disease. The primary
defect is destruction of the dopaminergic neurons of the
SNpc. The striatal neurons that form the direct pathway from the
striatum to the SNpr and GPi express primarily the excitatory D 1
DA receptor, whereas the striatal neurons that project to the GPe
and form the indirect pathway express the inhibitory D 2
dopamine receptor. Thus, loss of the dopaminergic input to the
striatum has a differential effect on the two outflow pathways;
the direct pathway to the SNpr and GPi is less active (structures
in purple), whereas the activity in the indirect pathway is
increased (structures in red). The net effect is that neurons in the
SNpr and GPi become more active. This leads to increased inhibition
of the VA/VL thalamus and reduced excitatory input to
the cortex. Light blue lines indicate primary pathways with
reduced activity. (See legend to Figure 22–2 for definitions of
anatomical abbreviations.)
neurotransmitters. For example, the neuropeptides substance P and
dynorphin are found predominantly in striatal neurons making up
the direct pathway, whereas most of the indirect pathway neurons
express enkephalin. These transmitters are expected to have slow
modulatory effects on signaling, in contrast to the rapid effects of
glutamate and GABA, but the functional significance of these modulatory
effects remains unclear. Nevertheless, the model is useful
and has important implications for the rational design and use of
pharmacological agents in PD. First, it suggests that to restore the
balance of the system through stimulation of DA receptors, the complementary
effect of actions at both D 1
and D 2
receptors, as well as
the possibility of adverse effects that may be mediated by D 3
, D 4
, or
D 5
receptors, must be considered. Second, it explains why replacement
of DA is not the only approach to the treatment of PD. Drugs
that inhibit cholinergic receptors have long been used for treatment
of parkinsonism. Although their mechanisms of action are not completely
understood, their effect is likely mediated at the level of the
striatal projection neurons, which normally receive cholinergic input
from striatal cholinergic interneurons. Only few clinically useful
drugs for parkinsonism are presently available based on actions
through GABA and glutamate receptors, even though both have
crucial roles in the circuitry of the basal ganglia. However, they represent
a promising avenue for drug development (Hallet and
Standaert, 2004).
+
+
–
613
CHAPTER 22
TREATMENT OF CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS