Movement Disorders

Vol. 23, Suppl. 3, 2008, pp. S534S547

2008 Movement Disorder Society

Striatal and Extrastriatal Dopamine in the Basal Ganglia:

An Overview of its Anatomical Organization in Normal
and Parkinsonian Brains
Yoland Smith, PhD* and Rosa Villalba, PhD
Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia, USA

Abstract: Degeneration of the nigrostriatal dopaminergic

system is the characteristic neuropathological feature of Parkinsons disease and therapy is primarily based on a dopamine replacement strategy. Dopamine has long been recognized to be a key neuromodulator of basal ganglia function,
essential for normal motor activity. The recent years have
witnessed signicant advances in our knowledge of dopamine function in the basal ganglia. Although the striatum
remains the main functional target of dopamine, it is now
appreciated that there is dopaminergic innervation of the
pallidum, subthalamic nucleus, and substantia nigra. A new
dopaminergic- thalamic system has also been uncovered,
setting the stage for a direct dopamine action on thalamocortical activity. The differential distribution of D1 and D2

receptors on neurons in the direct and indirect striato-pallidal

pathways has been re-emphasized, and cholinergic interneurons are recognized as an intermediary mediator of dopamine-mediated communication between the two pathways.
The importance and specicity of dopamine in regulating
morphological changes in striatal projection neurons provides further evidence for the complex and multifarious
mechanisms through which dopamine mediates its functional
effects in the basal ganglia. In this review, the role of basal
ganglia dopamine and its functional relevance in normal and
pathological conditions will be discussed. 2008 Movement Disorder Society
Key words: Parkinsons disease; substantia nigra; striatum; globus pallidus; subthalamic nucleus; thalamus

The progressive degeneration of midbrain dopaminergic neurons in the substantia nigra pars compacta
(SNc) is a cardinal feature of Parkinsons disease pathology. The original contribution of Ehringer and
Hornykiewicz in 1960 showing the rst direct evidence for a severe loss of dopamine in the caudate
nucleus and putamen of human parkinsonians set the
stage for fty years of extensive research on the role
of dopamine in regulating striatal activity in normal
and pathological conditions. The early studies of Hornykiewicz, Carlson and others have also provided a
solid basis for the development of dopamine replace-

ment therapy in Parkinsons disease (see Refs. 13

for reviews). Since then, a tremendous amount of
work has been devoted towards better understanding
the dopamine regulation of basal ganglia function.411
One of the major steps forward was made in the late
1980s with the introduction of the concept of the
direct and indirect pathways model of basal ganglia
circuitry.12,13 This model has been the cornerstone for
modern research on the basal ganglia and has served
as a critical tool for the revival of neurosurgical
therapies in Parkinsons disease.1416 Obviously, this
model represents an oversimplication of the basal
ganglia organization and its rather simplistic view has
been examined and challenged over the years.1724
These studies have led to renement of the model,
and the development of novel hypotheses for better
understanding how dopamine regulates the basal ganglia and how it contributes to the pathophysiology of
the basal ganglia in Pakinsons disease.9,25,26

*Correspondence to: Yoland Smith, Yerkes Primate Center, 954,

Gatewood Rd NE, Atlanta, GA 30322.
E-mail: ysmit01@emory.edu
Potential conict of interest: Nothing to report.
Received 28 January 2008; Accepted 18 February 2008
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/mds.22027

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DOPAMINE IN THE BASAL GANGLIA

VENTRAL MIDBRAIN DOPAMINERGIC
NEURONS: ANATOMICAL ORGANIZATION
AND DEGENERATION PATTERN IN
PARKINSONS DISEASE
The ventral midbrain dopaminergic neurons are subdivided into three main groups; namely A8 (retrorubral
eld; RRF), A9 (substantia nigra pars compacta; SNc),
and A10 (ventral tegmental area; VTA). Each of these
regions is comprised predominantly of dopaminergic
neurons with small groups of GABAergic interneurons,
except in the VTA where GABAergic projection neurons have also been documented.27 In addition to dopamine, various neuropeptides including enkephalin, substance P, dynorphin, neurotensin and cholecystokinin
have been identied in subsets of neurons in the medial
SNc and VTA. Another main chemical phenotype that
partly contributes to the segregation of these ventral
midbrain regions is the differential expression of the calcium binding protein, calbindin D28K (CB). Although
CB is strongly expressed in neurons of the VTA and
RRF as well as dorsal tier neurons of the SNc (SNc-d),
it is not found in ventral tier SNc neurons (SNc-v).27,28
Interestingly, dopaminergic neurons in the VTA and
SNc-d are signicantly less sensitive to neurodegeneration than SNc-v neurons in Parkinsons disease, suggesting that CB may play a neuroprotective role in PD and
its absence account for the vulnerability of SNc ventral
tier neurons in PD.2934 Another major feature of SNc-v
neurons is the greater expression of dopamine transporter in comparison to other cell groups,35,36 which
presumably accounts for the vulnerability of SNc-v neurons in MPTP-treated mice and monkeys.3739
Tract-tracing studies in the monkey indicate that
these three groups of neurons differ in their projection
patterns to the striatum: (1) the sensorimotor striatum
in the postcommissural putamen is mainly innervated
by dopaminergic cell columns in the SNc-v, (2) the
limbic ventral striatum is targeted preferentially by
VTA and SNc-d neurons, and (3) the associative
striatum in the caudate nucleus is mainly targeted
by dopaminergic neurons in the densocellular part of
SNc-v.27,40,41 The pattern is different in rats; where
SNc-d neurons project predominantly to the dorsal
striatum.42 Two main types of nigrostriatal axons have
been identied based on their origin and pattern of
striatal innervation; thin, varicose and widespread
bers that arise from neurons in the SNc-d, VTA and
RRF and terminate preferentially in the matrix striatal
compartment, and thick more varicose bers which
originate from the SNc-v and terminate mostly in the
patch striatal compartment.27,41

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Although most midbrain dopaminergic neurons show

a certain degree of degeneration in PD, the pattern of
progressive cell loss is not homogeneous, but rather
displays a complex topographical and regional organization. Three main features characterize the pattern of
nigrostriatal degeneration in PD patients and MPTPtreated monkeys: (1) Nigrostriatal projections to the
sensorimotor striatal territory (postcommissural 1 lateral precommissural putamen) are more sensitive than
those to the associative (caudate nucleus) and limbic
striata (nucleus accumbens) regions,34,43,44 (2) Nigrostriatal projections to patches degenerate prior to those
that make up matrix innervation34,45 and (3) VTA projections to the ventral striatum are selectively spared
and show a far lesser degree of degeneration than other
midbrain dopaminergic neurons33,35,46 (Fig. 1AC) It is
worth noting that this pattern of nigrostriatal degeneration at the striatal and nigral levels is tightly linked
with the level of expression of CB. For instance, at the
striatal level the sensorimotor postcommissural putamen which is particularly affected in human PD, is
devoid of CB-containing neurons.47,48 Similarly,
patches throughout the precommissural putamen and
caudate nucleus are selectively devoid of CB-immunoreactive neurons28,48 (see Fig. 1) Similar ndings are
observed in the nigra where SNc-d and VTA neurons
which are relatively spared in PD are enriched in CB,
whereas more sensitive SNc-v neurons express low
level of CB immunoreactivity.32,35 Finally, SNc neurons in regions that receive strong CB innervation
from the striatum are more resistant than those in CBpoor pockets called nigrosomes.33 Together, these ndings highlight the potential role that CB, or its absence,
may play in PD pathogenesis. As will be discussed
below, the neuroprotective effects of CB are not only
reected by the selective sparing of SNc-d and VTA
neurons, but may also contribute to the differential
degree of spine loss on striatofugal neurons between
the sensorimotor striatum and other striatal territories
(see below).
D1 AND D2 RECEPTORS: ARE THEY
SEGREGATED OR DO THEY CO-LOCALIZE
IN STRIATOFUGAL NEURONS?
The relative segregation of D1 and D2 dopamine
receptors in striatofugal neurons is a key feature of the
direct and indirect pathway model of the basal ganglia.49,50 A challenge to this model was put forward in
the mid 1990s based on single cell reverse transcriptase-polymerase chain reaction (RT-PCR) studies
showing a much higher incidence of D1 and D2 receptor

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Y. SMITH AND R. VILLALBA

FIG. 1. Tyrosine hydroxylase (TH, AC) and calbindin D28k (CB, DF) immunostaining at three different rostrocaudal levels of the striatum
showing the correspondence between the pattern of distribution of CB immunoreactivity and the regional TH loss in the striatum of an MPTPtreated parkinsonian monkey. Striatal areas poor in CB, like patches (asterisks in A and B) and the caudolateral putamen (B,C) are more severely
affected than other striatal regions enriched in CB. Abbreviations: Ac: Anterior commissure; AC: Nucleus accumbens; CD: Caudate nucleus;
GPe: Globus pallidus, external segment; GPi: Globus pallidus, internal segment; IC: Internal capsule; OT: Optic tract; Pu: Putamen; ST: Subthalamic nucleus; Th: Thalamus.

mRNA coexpression in striatofugal neurons than had

been predicted by in situ hybridization methods.9,17,51
The higher sensitivity of the RT-PCR method was suggested as the main explanation for this discrepancy9,17
(see Fig. 2). In addition, studies of dopaminergic modulation of ion channels, ring properties and synaptic
transmission have all shown that individual striatal
neurons can respond to both D1 and D2 agonists.17,26

Immunocytochemical studies also led to controversial

data, suggesting that D1 and D2 receptors immunoreactivity is either largely segregated52,53 or signicantly coexpressed24,54 in individual striatal neurons.
However, strong support for the segregation hypothesis
has recently been put forward through the development
of BAC transgenic mice in which cellular EGFP
expression was driven by a D1 or D2 receptor pro-

FIG. 2. Box diagram that summarizes the localization of various subtypes of dopamine receptors in the basal ganglia. Abbreviations: GPe, GPi:
see Figure 1; MSN: Medium spiny neurons; STN: Subthalamic nucleus; SNc: Substantia nigra pars compacta; SNr: Substantia nigra pars reticulata; STR: Striatum.

Movement Disorders, Vol. 23, Suppl. 3, 2008

DOPAMINE IN THE BASAL GANGLIA

moter.55 In these transgenic animals, EGFP-labeled
striatal neurons from BAC D1-EGFP mice express
exclusively D1 receptor mRNA, while medium spiny
neurons in BAC D2-EGFP mice contain only D2 receptor mRNA.5658 It is noteworthy that the segregation of D1 and D2 receptor mRNAs is these mice was
conrmed using both immunocytochemistry58 and RTPCR methods.56,57 In addition, Gerfen58 has shown
that EGFP in the two strains of mice is differentially
distributed between the direct and indirect striatofugal
pathways; EGFP-D1 bers being mainly found in the
entopeduncular nucleus (rodent equivalent of the globus
pallidus pars interna) and SNr, while EGFP-D2 bers
are conned to the globus pallidus (rodent equivalent of
the globus pallidus pars externa). The segregation of D1
and D2 receptors along direct and indirect striatofugal
pathways therefore appears to remain a key hallmark of
the functional circuitry of the basal ganglia in these
transgenic animals. On the other hand, caution must
be taken in translating data in these genetically engineered BAC D1/D2 mice to normal animals. Based on
RT-PCR data, it appears that the chemical phenotype of
striatofugal neurons in BAC mice is different from that
previously described by the same authors in normal
rats.9,17,56,57 It is also important to keep in mind that
other members of the D1- and D2-like family receptors
(D3, D4, and D5 receptors) are also expressed to varying degrees in striatal neurons and other basal ganglia
nuclei.9,27 The potential for colocalization of these receptor subtypes with D1 and D2 receptors provides a
substrate for direct functional interactions between the
two dopamine receptor families at the level of individual basal ganglia neurons.9 D3 receptors are particularly
relevant since they display a signicant degree of colocalization within D1- or D2-containing neurons,9,59 and
have been proposed to contribute to the pathogenesis of
L-DOPA-induced dyskinesia.60
SELECTIVE ELIMINATION OF SPINES
IN THE DOPAMINE-DEPLETED STRIATUM:
POTENTIAL IMPLICATIONS FOR ABNORMAL
BASAL GANGLIA DISCHARGES IN
PARKINSONS DISEASE
The loss of striatal dopaminergic innervation results
in neurochemical and morphological changes in striatofugal neurons. In both rodent and primate models of
parkinsonism and postmortem brains of PD patients,
there is a signicant loss of dendritic spines and a
reduction in the total dendritic length of medium spiny
neurons6168 (see Fig. 3). This spine loss, which can
reach almost 50% of total spine density in humans and

S537

monkeys, takes several days to develop in animal models and does not appear to respond favorably to levodopa therapy.68,69 In PD patients and MPTP-treated
monkeys, neurons in the sensorimotor postcommissural
putamen, the most severely dopamine-depleted striatal
territory, are more strongly affected than other striatal
regions.67,68 However, striatal spine loss is an early
pathogenic feature of parkinsonism that develops in
parallel with the degree of dopamine denervation in
MPTP-treated monkeys.68 Signicant spine loss was
found in the sensorimotor striatum of MPTP-treated
monkeys that do not display any signicant motor
impairments.68 In 6-OHDA-treated rats, the degree of
spine loss correlates with the reduction in the total
number of glutamatergic synapses suggesting an overall decrease in glutamatergic excitability of striatofugal
neurons in PD.64,65 Until recently, the mechanism(s)
underlying this spine loss remained unknown. However, recent rodent data have shed light on this issue
and proposed that D2-containing striatopallidal neurons, but not D1-immunoreactive striatonigral neurons,
are selectively affected following dopamine depletion
in rats.56 These observations were gathered directly
using multiphoton imaging in corticostriatal slices of
17- to 25-day-old BAC D1 and BAC D2 EGFP mice
treated with reserpine, and indirectly through quantitative electron microscopic localization of D1-immunoreactive spines in 6-OHDA-treated adult rats.56 These
observations are at odds with previous Golgi studies
in both human parkinsonians and animal models of
parkinsonism showing a rather homogeneous loss of
spines across large populations of Golgi-impregnated
striatal medium spiny neurons.6168 Furthermore, recent
data gathered from chronically treated MPTP monkeys
have shown a relative decrease of both D1-immunoreactive and D1-negative spines in the putamen,68 suggesting the spine pathogenesis affects both direct and
indirect pathway striatofugal neurons in this animal
model.68 Whether these apparent discrepancies rely on
species differences or chronic versus acute toxin exposure remains to be established. In BAC D2 EGFP
transgenic mice, this spine loss can be prevented by
genetic deletion of Cav1.3a1 subunits or pharmacological blockade of L-type Cav1.3 channels. Knowing that
D2 dopamine receptor signaling targets only the channels that contain the Cav1.3a1 subunit, the authors
proposed that a dysregulation of calcium concentrations in specic striatopallidal neurons may ultimately
lead to specic spine loss and pathological basal ganglia activity.56 The extent of spine loss was not different 1 month after 6-OHDA-induced dopamine depletion indicating that the elimination is completed within

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Y. SMITH AND R. VILLALBA

FIG. 3. Golgi-impregnated MSNs in the caudate nucleus (A,A0 -B,B0 ) and putamen (C,C0 -D,D0 ) of a normal (A,A0 ,C,C0 ) and a MPTP-treated parkinsonian monkey (B,B0 ;D,D0 ). Note the severe spine loss on dendrites of the MPTP-treated monkey compared to control. Scale bars: A,C: 25 lm
(valid for B and D); B0 ,D0 : 5 lm (valid for A0 and C0 ).

days and is largely dependent on the loss of striatal dopamine rather than the death of midbrain dopaminergic
neurons, per se.56 The selectivity for D2-containing
spines is consistent with previous studies showing that
chronic treatment with D2 receptor antagonists such as
haloperidol also causes dystrophic changes in dendrites
of medium spiny neurons.70 Although the intracellular
biochemical mechanisms that underlie striatal spine

Movement Disorders, Vol. 23, Suppl. 3, 2008

loss still remain poorly characterized, there is good

evidence that L-type voltage gated calcium channels
(LVGCC) may be involved because the chronic administration of an LVGCC antagonist completely blocks
spine loss.56
Striatal dopamine denervation also leads to a signicant increase in the level of calcium calmodulindependent protein kinase II alpha (CAMKIIa)), a change

DOPAMINE IN THE BASAL GANGLIA

that results in increased phosphorylation of the GluR1
AMPA glutamate receptors, but only in animals with
sustained nigrostriatal dopamine depletion for more
than a year, suggesting an age or time-related phenomenon.71 Although the broad implications of striatal
spine loss in PD remain to be established, the fact that
spines are the main targets of glutamatergic inputs
from the cerebral cortex and thalamus,72 combined
with functional evidence for highly specic interactions
between convergent axo-spinous glutamatergic and dopaminergic afferents in the rat striatum,73 indicate that
this change in synaptic connectivity likely results in
ineffectively timed and patterned striatofugal activity,
thereby leading to pathological basal ganglia discharges in PD.7476

THE CHOLINERGIC INTERNEURONS: A KEY

MEDIATOR OF DOPAMINE-DEPENDENT
PLASTICITY IN THE STRIATUM
The role of cholinergic interneurons in striatal plasticity and learning is well established.10,77,78 The importance of acetylcholine-dopamine balance in proper
striatal functioning has long been considered to be a
key factor underlying normal basal ganglia function.10,7981 Abnormal increased acetylcholine release
in the striatum is a key neurochemical landmark of
Parkinsons disease.10,7980 Cholinergic interneurons
are enriched in D2 and D5 dopamine receptors (see
Fig. 2). Recent studies further emphasize the importance of dopamine-mediated regulation of cholinergic
interneurons in modulating striatal outow, and inuencing the integration, processing and transmission of
information along the dual striatofugal systems. Dopamine-dependent long term depression (LTD) of transmission at glutamatergic synapses is well characterized
in the rat striatum.68,82,83 Pharmacological and molecular evidence support a role of D2 receptors in the
induction of striatal LTD,6 although LTD can be
induced in both direct and indirect striatofugal neurons57 even though only neurons in the indirect pathway express signicant numbers of D2 receptors. The
mechanisms by which D2 could mediate LTD in direct
striatofugal neurons is poorly understood and controversial.26,57 Recent evidence suggests a critical role of
cholinergic interneurons in mediating this effect. D2
receptors are, indeed, found on cholinergic interneurons whose activation reduces acetylcholine release
which, in turn, has a dramatic impact on direct and
indirect striatofugal activity, mainly through activation
of M1 muscarinic receptors strongly expressed at

S539

glutamatergic axo-spinous synapses.84,85 Through the

use of BAC transgenic mice with uorescent reporters
driven by the D1- or D2- receptor promoters, Wang
et al.57 proposed that D2 receptors on cholinergic neurons act to inhibit the release of acetylcholine. This
reduction, then, reduces M1-mediated inhibitory modulation of L-type calcium channels, resulting in
increased intracellular calcium in medium spiny neurons. Under such activation, medium spiny neurons
release endogenous cannabinoids that act presynaptically on CB1 receptors to reduce glutamate release and
mediate LTD.26,57 These ndings demonstrate that D2mediated dopaminergic transmission in cholinergic
interneurons may play a key role in striatal processing
of extrinsic inputs, learning, and synaptic plasticity.
They also emphasize the important role of cholinergic
cells as an intermediary mediator of dopamine-mediated communication between direct and indirect striatofugal neurons.
Virtually all cholinergic neurons express high levels
of D5 mRNA and protein in rats and monkeys.9,8688
Activation of D5 receptors potentiates acetylcholine
release, while D2 stimulation has the opposite effect
on cholinergic transmission in the striatum.89,90 The
cholinergic neurons, therefore, represent a strategic
location where dopamine could mediate postsynaptic
effects that rely on functional interactions between D1and D2-like receptor families. In rats, D5 receptors are
necessary for the induction of long term potentiation
(LTP) in cholinergic neurons.91 They also mediate
changes in GABAergic signaling through enhancement
of Zn12-sensitive component of GABA-A currents.92
Although much remains to be known about the functions of D5 receptors, their widespread distribution
suggests that they may mediate dopaminergic functions
at various levels of the basal ganglia circuitry.

EXTRASTRIATAL DOPAMINE IN THE BASAL

GANGLIA: ANATOMICAL AND FUNCTIONAL
EVIDENCE IN NORMAL AND
PATHOLOGICAL CONDITIONS
The striatum is by far the main basal ganglia target
of midbrain dopaminergic neurons. Albeit complex and
enigmatic, the important basal ganglia regulatory functions of dopamine through modulation of striatal activity is well established and heavily studied. Over the
past 10 years, considerable evidence for extrastriatal
dopamine function has been put forward to explain
some of the paradoxical changes observed in basal
ganglia circuitry27 (see Fig. 4).

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Y. SMITH AND R. VILLALBA

FIG. 4. Diagram showing the extent of striatal and extrastriatal dopaminergic projections top the basal ganglia and thalamus. The SNc
projects most strongly to the striatum, but also innervates all other
basal ganglia nuclei and provides a signicant input to various
thalamic nuclei.

The Nigropallidal Dopaminergic System: A

Substrate for Differential Regulation of
Segregated Pallidofugal Neurons
There are numerous anatomical, immunocytochemical, and neurochemical studies that support the existence of nigropallidal dopaminergic projections. Early
retrograde and anterograde tract-tracing studies and
light microscopic immunohistochemical data showing
tyrosine hydroxylase (TH) and dopamine (DA)-immunoreactive bers and varicose processes are discussed
in detail in our previous review of extrastriatal dopamine systems.27 Since then, evidence for functional
dopamine release in the globus pallidus has been gathered. In monkeys, electron microscopic studies have
shown TH-immunoreactive terminals in synaptic contact with dendrites of GPi neurons.27 Perfusion of
D-amphetamine and cocaine into the rat GP produces
concentration-dependent increases in dialysate dopamine.93 In both rats and primates, the GP is made up
of two segregated populations of projection neurons.
Pallidostriatal neurons that express pre-proenkephalin
but not parvalbumin (PPE1/PV2) and pallidosubthalamic neurons that are devoid of PPE, but display PV
immunoreactivity (PPE2/PV1) account for 40% and
about 60% of the total GP neuronal population, respectively. The pallidosubthalamic neurons also provide
inputs to GPi and SNr, though pallidostriatal neurons
are directed almost exclusively to the striatum.94
Although the chemical phenotype of pallidal neurons
has not been as well characterized in primates, single
cell lling studies have provided evidence for segregated pallidosubthalamic and pallidostriatal neurons in
squirrel monkeys.95

Movement Disorders, Vol. 23, Suppl. 3, 2008

The two main populations of GP neurons respond

differently to systemic or local application of dopamine
receptor-related compounds in rats. For instance, systemic administration of D2 antagonist induces c-fos
expression mainly in PPE1/PV2 pallidostriatal neurons, whereas systemic administration of D1 1 D2
agonists results in increased c-fos expression in PPE-/
PV1 pallidosubthalamic neurons.96 On the other hand,
local intra-GP application of D2 agonist induces c-fos
in PV-negative neurons only.97 The long-term regulation of DA upon PV-positive and PV-negative GP neurons has recently been examined in 6-OHDA-treated
rats or animals chronically treated with systemic D2
antagonists. Following either treatment, there is an
overall increase in pallidal expression of glutamic acid
decarboxylase mRNA (GAD67) in both populations of
GP neurons. However, the magnitude of the increase
was found to be signicantly higher in PV-negative
neurons.98 STN lesion completely blocked 6OHDA- or
D2 antagonist-induced GAD67 mRNA increases in
PV1 cells, but only partly offset GAD67 mRNA
increase in PV-negative pallidal neurons, suggesting
that PV1 and PV-negative neurons are inuenced by
dopaminergic perturbations, though they exhibit differential degrees of regulation by dopamine and downstream basal ganglia nuclei.98
Two major targets likely mediate local dopamine
effects in the GP, presynaptic D2 receptors on striatofugal GABAergic axons and terminals and/or postsynaptic D2 receptors on GP neurons.99 Although presynaptic
D2 receptors on striatopallidal projections have long
been recognized, postsynaptic expression of D2 receptor mRNA in rat GP neurons have just been uncovered.99 In rat, D2 mRNA-containing neurons are found
throughout the full extent of GP, but are most dense
within a dorsoventral band along its lateral border. In
contrast, the ventromedial GP contains fewer D2
mRNA-positive neurons than in other pallidal regions.
Although almost half PV1 or PV-negative neurons
express D2 mRNA, pallidostriatal PV- neurons have a
greater density of D2 mRNA than PV1 pallidosubthalamic neurons.99 D3 and D4 receptors are also
expressed postsynaptically in the rat and primate globus
pallidus.27 In humans, D3 receptor mRNA and binding
are strongly expressed in both GPe and GPi, whereas
D2 is mainly found in GPe. Although some neurons coexpress both D2 and D3 receptors mRNA, most neurons contain only one receptor subtype.100 In the rat
GP, activation of postsynaptic D4 receptors reduces
GABAergic currents through the suppression of protein
kinase A activity.101 These ndings provide a solid
substrate through which local intrapallidal release of

DOPAMINE IN THE BASAL GANGLIA

S541

dopamine can bypass the striatofugal system and modulate directly GP neuronal activity through stimulation
of pre- and post-synaptic D2 family receptors.
There is some evidence that the nigropallidal dopaminergic projection may not be as severely affected as
the nigrostriatal system in PD and animal models of
parkinsonism,27 In addition, enhanced function of the
nigropallidal system to GPi may be involved in
compensatory mechanisms to maintain normal pallidal
outow in early, asymptomatic, stages of Parkinsons
disease.102 The nigropallidal system also plays an important role in mediating the benecial behavioral
effects of intranigral glial derived nerve factor (GDNF)
in primate models of parkinsonism.103

spontaneous or evoked bursts. These effects specically

involve D5 since they remain intact in D1 receptor
knock-out mice and because burst-competent STN neurons only express D5 receptors mRNA and protein
immunoreactivity.107 Together, these data provide a
strong basis for D5-mediated functional dopamine regulatory effects in the STN. Its potential role in regulating
burst ring, makes D5 receptor an interesting target
for the development of novel pharmacotherapeutic
approaches in Parkinsons disease.

THE NIGROSUBTHALAMIC DOPAMINERGIC

SYSTEM: A CRITICAL ROLE FOR
D5 RECEPTORS
The subthalamic nucleus receives light dopaminergic
innervation from collaterals of SNc nigrostriatal neurons.27,41 Unicellular injection of SNc neurons label
TH-immunoreactive terminals that form en passant type
symmetric synapses on dendrites of STN neurons in
rats104 and monkeys.27 Albeit far less prominent than in
the striatum, local electrical stimulation evokes synaptic
dopamine release in the rat STN.104 Local dopamine
application in the STN increases the ring rate and regulates postsynaptic GABA A-mediated transmission in
subthalamic neurons.104 Various D1 and D2 family dopamine receptors are expressed in the STN, but the
exact pre- or post-synaptic target sites remain a matter
of debate.27 Dopaminergic lesion results in increased
levels of D2 receptors mRNA, decreased expression of
D3 receptors, but no signicant change in D1 receptor
in the ipsilateral STN of 6-OHDA-treated rats.105
Recent studies highlighted the importance of D5 receptors in mediating postsynaptic dopamine effects in the
rat STN. The expression of D5 receptor mRNA is far
stronger than that of D1, D2, and D3 receptors in rat
STN.106 Systemic administration of D1 family receptor
agonist induces c-fos expression, whereas administration of D2 family receptor agonist has no effect in the
rat STN.106 Post-synaptic D5 receptors may therefore
play a more critical role than previously thought in regulating activity of the indirect pathway of the basal ganglia circuitry. Further recent evidence that supports
functional D5 receptors in STN comes from a patch
clamp recording study in brain slices.107 It was found
that D5 dopamine receptors activation strengthens electrical activity in a subset of STN neurons endowed with
burst-ring capacity, resulting in longer discharges of

Local dendritic release of dopamine in the substantia

nigra has long been established, though the exact mechanisms that underlie the release, regulation, and function of intranigral dopamine are relatively complex and
remain poorly understood. Two main physiological
effects of dopamine have been reported on SNc and
SNr neurons. On one hand, dopamine acts as a self-regulator of its own release through activation of D2 and
D3 receptors in dendrites and cell bodies of SNc neurons. The physiological signicance of this regulation
remains controversial; some studies showing signicant
D2-mediated effects on nigral dopamine release,108110
while others demonstrated a rather weak auto-inhibitory
effect of D2 receptor activation on dopamine
release.111114 On the other hand, data mainly gathered
from in vitro studies, show that dopamine may also act
through pre-synaptic D1 receptors on GABAergic striatal terminals to facilitate GABA release in the SNr (but
see Ref. 115), thereby increases ring of GABAergic
SNr neurons and raises GABA outow in target thalamic nuclei.27 These in vitro observations are supported by recent in vivo data showing increased SNr
neuronal activity that can be blocked by a selective D1
antagonist following local application of amphetamine
or D1 agonist in rat and monkey SNr.116118 D5 and D4
receptors are also expressed in SNc and SNr neurons,
respectively, but the physiological signicance of these
receptor subtypes remains poorly understood.119,120
Dendrites of SNc neurons can generate action potentials
which may trigger dopamine release.121,122 Blockade of
sodium channels with TTX, or reduction of impulse
ow along dopaminergic bers with g-butyrolactone
reduces dendritic dopamine release, while it can be
enhanced by the depolarizing agent veratridine, high
potassium concentrations and amphetamine.123127 Together, these ndings demonstrate the importance of

DENDRITIC RELEASE OF DOPAMINE IN THE

SUBSTANTIA NIGRA: A UNIQUE SOURCE OF
LOCAL DOPAMINE REGULATION OF SNc
AND SNr NEURONS

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Y. SMITH AND R. VILLALBA

electrical impulse to modulate dendritic dopamine

release in the substantia nigra, but this does not rule out
the contribution of extrinsic inputs to the regulation of
nigral dopamine release.128131 Various dopamine release mechanisms have been suggested in the rat substantia nigra. Conventional vesicular dopamine release
is supported by electron microscopic evidence for
vesicle aggregates and synaptic specializations along
dendrites of SNc neurons132,133 (but see Ref. 134),
expression of VMAT2 135 and inhibition of release by
botulinum toxin A, known to cleave the synaptosomeassociated protein SNAP-25 (25kDA synaptosomeassociated protein).136 Another line of evidence supports a role for dopamine transporter (DAT) reversal in
nigral dopamine release,137 but this effect remains controversial since other published studies have shown that
DAT inhibition increases nigral dopamine levels.124,138
The dendritic release of dopamine provides SNc neurons with unique capabilities in self-regulating their
own activity at the cell body and terminal levels. The
abundance of pre- and post-synaptic dopamine receptors in SNc and SNr provide multiple targets whereby
dendritic dopamine release can mediate its functional
effects on nigral outow.
INTRASTRIATAL DOPAMINERGIC NEURONS:
A COMPENSATORY MECHANISM FOR
DOPAMINE DEPLETION IN
PARKINSONS DISEASE?
Intrastriatal dopaminergic neurons have been
described in rat, monkey and human striatum using TH
and DAT immunostaining.27 The density of these cells
increases signicantly after neurotoxic dopamine depletion in animal model or in humans with Parkinsons
disease suggesting that it may act as a compensatory
mechanism for the progressive dopamine loss in parkinsonism.27,139141 Their number is signicantly increased
following viral vector delivery of glial cell line-derived
neurotrophic factor (GDNF) into the putamen of
MPTP-treated monkeys.142 More than 99% of these
neurons display morphological and ultrastructural features of interneurons ie they have smooth aspiny dendrites and a deeply invaginated nucleus.140143 However, their cell body is on average signicantly smaller
than any other types of striatal interneurons. In fact,
except for a small subset (about 1015%) that co-localizes with calretinin, none of the known markers of striatal
interneurons (parvalbumin, somatostatin, neuropeptide
Y, nitric oxide synthase and choline acetyltransferase)
is expressed in striatal dopaminergic neurons,141,144
suggesting that they represent a newly generated

Movement Disorders, Vol. 23, Suppl. 3, 2008

population of neurons that appears in response to dopamine depletion, though direct evidence for such neurogenesis in the adult striatum remains controversial.140,144 In MPTP-treated monkeys, these neurons are
mainly concentrated along the lateral border of the caudate nucleus and the pre-commissural putamen, indicating a preferential distribution in the associative striatal
territory.141 They display GAD-67 immunoreactivity,
receive very scarce synaptic innervation from extrinsic
inputs and give rise to GABA-containing axon terminals that rarely form clear synaptic contacts.141,143 They
also express AMPA GluR1 and NMDAR1 glutamate
receptor subunits but are non-immunoreactive for the
AMPA GluR2 and GluR3 subunits as well as group I
metabotropic glutamate receptors.27,145 In brief, the
striatum is endowed with intrinsic dopaminergic neurons that co-express GABA and up-regulate following
dopamine depletion. The preferential localization of
these neurons in the associative territory of the striatum
suggests regional differences in the development of
compensatory mechanisms following dopamine depletion in Parkinsons disease.146,147
THE THALAMIC DOPAMINERGIC SYSTEM:
AN UNRECOGNIZED DOPAMINERGIC
SYSTEM THAT DEGENERATES IN
PARKINSONS DISEASE
The nigrothalamic GABAergic projection from the
SNr has long been known as a major output pathway
of the basal ganglia,148,149 but such is not the case for
the nigrothalamic dopaminergic tract, which, until
recently had not been recognized as a signicant component of the basal ganglia thalamocortical system.
Three recent studies in monkeys150,151 and humans152
emphasized the existence of this system in primates.
All studies revealed a signicant dopaminergic innervation of midline, associative and ventral motor nuclei
(see Fig. 4). In contrast, the intralaminar and relay sensory nuclei contain the lowest amount of dopamine
axons. However, there is some controversy between
the two monkey studies regarding the source(s) of this
innervation. On one hand, some authors reported that it
originates mainly from axon collaterals of the nigrostriatal dopaminergic pathway and degenerates in MPTPtreated monkeys,150 while others demonstrated a more
diverse origin from various hypothalamic, brainstem
and mesencephalic dopaminergic neuronal groups,151
with a limited contribution from the SNc. Recent evidence showed that dendrites of thalamic interneurons are
the main targets of dopamine terminals in the monkey
thalamus.153 These ndings concur with biochemical

DOPAMINE IN THE BASAL GANGLIA

studies showing the presence of dopamine in the
human and monkey thalamus.154,155 Moreover D2-like
dopamine receptor binding sites have been shown in
the human thalamus with a distribution that resembles
that of the dopamine innervation.101,156158 Strong perikaryal D5 immunolabeling is found throughout the
human thalamus.119 Although much work remains to
be done to unravel the functional signicance of dopamine at the thalamic level, these anatomical data
provide a solid foundation for a robust and complex
thalamic dopamine system that likely mediates broad
inuences on neuronal activity in various cortical and
subcortical regions through thalamofugal connections.
Its possible degeneration in the monkey model of Parkinsons disease provides further evidence for a critical
extrastriatal site whereby dopamine depletion could
induce signicant pathologic changes in neuronal activity and behavior.
CONCLUDING REMARKS
Exciting developments have been made in our
understanding of dopamine function in the basal ganglia. The potential role of dopamine at both striatal
and extrastriatal levels, the importance of dopamine in
regulating spine plasticity in specic subsets of striatofugal neurons and the recognition of cholinergic interneurons as the intermediary mediator for cross-talks
between the direct and indirect striatofugal pathways
uncover novel mechanisms by which dopamine can
mediate its regulatory function at various levels of the
basal ganglia circuitry. The lack of pharmacological
tools to dissect out specic functions of various members of the D1 and D2 dopamine receptor families has
hampered considerably our progress in understanding
the functional signicance of these diverse receptor
subtypes. However, the widespread expression of D3,
D4, and D5 receptors in striatal and extrastriatal basal
ganglia nuclei highlight the potential importance of
these dopaminergic receptors, and set the stage for
multifarious dopamine-mediated effects through functional interactions between the two receptor families.
Acknowledgments: This work was supported by grants
from the NIH, National Parkinson Foundation, Tourette Syndrome Association to YS and the NIH base grant of the
Yerkes Primate Center (RR00165).

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