Striatal and Extrastriatal Dopamine in the Basal Ganglia: An Overview of its Anatomical Organization in Normal and Parkinsonian Brains

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 dopaminergicsystem is the characteristic neuropathological feature of Par-kinson’s disease and therapy is primarily based on a dopa-mine replacement strategy. Dopamine has long been recog-nized to be a key neuromodulator of basal ganglia function,essential for normal motor activity. The recent years havewitnessed significant advances in our knowledge of dopa-mine function in the basal ganglia. Although the striatumremains the main functional target of dopamine, it is nowappreciated that there is dopaminergic innervation of thepallidum, subthalamic nucleus, and substantia nigra. A newdopaminergic- thalamic system has also been uncovered,setting the stage for a direct dopamine action on thalamo-cortical activity. The differential distribution of D1 and D2

receptors on neurons in the direct and indirect striato-pallidalpathways has been re-emphasized, and cholinergic interneur-ons are recognized as an intermediary mediator of dopa-mine-mediated communication between the two pathways.The importance and specificity of dopamine in regulatingmorphological changes in striatal projection neurons pro-vides further evidence for the complex and multifariousmechanisms through which dopamine mediates its functionaleffects in the basal ganglia. In this review, the role of basalganglia dopamine and its functional relevance in normal andpathological conditions will be discussed. � 2008 Move-ment Disorder SocietyKey words: Parkinson’s disease; substantia nigra; stria-

tum; globus pallidus; subthalamic nucleus; thalamus

The progressive degeneration of midbrain dopami-

nergic neurons in the substantia nigra pars compacta

(SNc) is a cardinal feature of Parkinson’s disease pa-

thology. The original contribution of Ehringer and

Hornykiewicz in 1960 showing the first direct evi-

dence for a severe loss of dopamine in the caudate

nucleus and putamen of human parkinsonians set the

stage for fifty years of extensive research on the role

of dopamine in regulating striatal activity in normal

and pathological conditions. The early studies of Hor-

nykiewicz, Carlson and others have also provided a

solid basis for the development of dopamine replace-

ment therapy in Parkinson’s disease (see Refs. 1–3

for reviews). Since then, a tremendous amount of

work has been devoted towards better understanding

the dopamine regulation of basal ganglia function.4–11

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 Parkinson’s disease.14–16 Obviously, this

model represents an oversimplification of the basal

ganglia organization and its rather simplistic view has

been examined and challenged over the years.17–24

These studies have led to refinement of the model,

and the development of novel hypotheses for better

understanding how dopamine regulates the basal gan-

glia and how it contributes to the pathophysiology of

the basal ganglia in Pakinson’s disease.9,25,26

*Correspondence to: Yoland Smith, Yerkes Primate Center, 954,Gatewood Rd NE, Atlanta, GA 30322.E-mail: [email protected]

Potential conflict of interest: Nothing to report.Received 28 January 2008; Accepted 18 February 2008Published online in Wiley InterScience (www.interscience.wiley.

com). DOI: 10.1002/mds.22027

S534

Movement DisordersVol. 23, Suppl. 3, 2008, pp. S534–S547� 2008 Movement Disorder Society

VENTRAL MIDBRAIN DOPAMINERGIC

NEURONS: ANATOMICAL ORGANIZATION

AND DEGENERATION PATTERN IN

PARKINSON’S DISEASE

The ventral midbrain dopaminergic neurons are sub-

divided into three main groups; namely A8 (retrorubral

field; 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 neu-

rons have also been documented.27 In addition to dopa-

mine, various neuropeptides including enkephalin, sub-

stance P, dynorphin, neurotensin and cholecystokinin

have been identified 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 cal-

cium 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 significantly less sensitive to neurodegenera-

tion than SNc-v neurons in Parkinson’s disease, suggest-

ing that CB may play a neuroprotective role in PD and

its absence account for the vulnerability of SNc ventral

tier neurons in PD.29–34 Another major feature of SNc-v

neurons is the greater expression of dopamine trans-

porter in comparison to other cell groups,35,36 which

presumably accounts for the vulnerability of SNc-v neu-

rons in MPTP-treated mice and monkeys.37–39

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 identified based on their origin and pattern of

striatal innervation; thin, varicose and widespread

fibers that arise from neurons in the SNc-d, VTA and

RRF and terminate preferentially in the matrix striatal

compartment, and thick more varicose fibers which

originate from the SNc-v and terminate mostly in the

patch striatal compartment.27,41

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 organi-

zation. Three main features characterize the pattern of

nigrostriatal degeneration in PD patients and MPTP-

treated monkeys: (1) Nigrostriatal projections to the

sensorimotor striatal territory (postcommissural 1 lat-

eral precommissural putamen) are more sensitive than

those to the associative (caudate nucleus) and limbic

striata (nucleus accumbens) regions,34,43,44 (2) Nigro-

striatal projections to patches degenerate prior to those

that make up matrix innervation34,45 and (3) VTA pro-

jections to the ventral striatum are selectively spared

and show a far lesser degree of degeneration than other

midbrain dopaminergic neurons33,35,46 (Fig. 1A–C) It is

worth noting that this pattern of nigrostriatal degenera-

tion 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 puta-

men 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-immuno-

reactive neurons28,48 (see Fig. 1) Similar findings 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 neu-

rons in regions that receive strong CB innervation

from the striatum are more resistant than those in CB-

poor pockets called nigrosomes.33 Together, these find-

ings 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

reflected 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 gan-

glia.49,50 A challenge to this model was put forward in

the mid 1990s based on single cell reverse transcrip-

tase-polymerase chain reaction (RT-PCR) studies

showing a much higher incidence of D1 and D2 receptor

S535DOPAMINE IN THE BASAL GANGLIA

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

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 sug-

gested as the main explanation for this discrepancy9,17

(see Fig. 2). In addition, studies of dopaminergic mod-

ulation of ion channels, firing 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 immuno-

reactivity is either largely segregated52,53 or signifi-

cantly 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. 1. Tyrosine hydroxylase (TH, A–C) and calbindin D28k (CB, D–F) immunostaining at three different rostrocaudal levels of the striatumshowing the correspondence between the pattern of distribution of CB immunoreactivity and the regional TH loss in the striatum of an MPTP-treated parkinsonian monkey. Striatal areas poor in CB, like patches (asterisks in A and B) and the caudolateral putamen (B,C) are more severelyaffected 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: Subthala-mic nucleus; Th: Thalamus.

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 reticu-lata; STR: Striatum.

S536 Y. SMITH AND R. VILLALBA


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 re-

ceptor mRNA.56–58 It is noteworthy that the segrega-

tion of D1 and D2 receptor mRNAs is these mice was

confirmed using both immunocytochemistry58 and RT-

PCR 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 fibers being mainly found in the

entopeduncular nucleus (rodent equivalent of the globus

pallidus pars interna) and SNr, while EGFP-D2 fibers

are confined 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 engi-

neered 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 vary-

ing degrees in striatal neurons and other basal ganglia

nuclei.9,27 The potential for colocalization of these re-

ceptor subtypes with D1 and D2 receptors provides a

substrate for direct functional interactions between the

two dopamine receptor families at the level of individ-

ual basal ganglia neurons.9 D3 receptors are particularly

relevant since they display a significant degree of coloc-

alization 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


The loss of striatal dopaminergic innervation results

in neurochemical and morphological changes in striato-

fugal neurons. In both rodent and primate models of

parkinsonism and postmortem brains of PD patients,

there is a significant loss of dendritic spines and a

reduction in the total dendritic length of medium spiny

neurons61–68 (see Fig. 3). This spine loss, which can

reach almost 50% of total spine density in humans and

monkeys, takes several days to develop in animal mod-

els and does not appear to respond favorably to levo-

dopa 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 Significant spine loss was

found in the sensorimotor striatum of MPTP-treated

monkeys that do not display any significant 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 over-

all decrease in glutamatergic excitability of striatofugal

neurons in PD.64,65 Until recently, the mechanism(s)

underlying this spine loss remained unknown. How-

ever, recent rodent data have shed light on this issue

and proposed that D2-containing striatopallidal neu-

rons, 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 quantita-

tive electron microscopic localization of D1-immunore-

active 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.61–68 Furthermore, recent

data gathered from chronically treated MPTP monkeys

have shown a relative decrease of both D1-immunore-

active and D1-negative spines in the putamen,68 sug-

gesting 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 expo-

sure remains to be established. In BAC D2 EGFP

transgenic mice, this spine loss can be prevented by

genetic deletion of Cav1.3a1 subunits or pharmacolog-

ical blockade of L-type Cav1.3 channels. Knowing that

D2 dopamine receptor signaling targets only the chan-

nels that contain the Cav1.3a1 subunit, the authors

proposed that a dysregulation of calcium concentra-

tions in specific striatopallidal neurons may ultimately

lead to specific spine loss and pathological basal gan-

glia activity.56 The extent of spine loss was not differ-

ent 1 month after 6-OHDA-induced dopamine deple-

tion indicating that the elimination is completed within



days and is largely dependent on the loss of striatal do-

pamine 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

loss still remain poorly characterized, there is good

evidence that L-type voltage gated calcium channels

(LVGCC) may be involved because the chronic admin-

istration of an LVGCC antagonist completely blocks

spine loss.56

Striatal dopamine denervation also leads to a signifi-

cant increase in the level of calcium calmodulin-

dependent protein kinase II alpha (CAMKIIa)), a change

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 par-kinsonian 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).



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 phenom-

enon.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 specific interactions

between convergent axo-spinous glutamatergic and do-

paminergic 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 dis-

charges in PD.74–76

THE CHOLINERGIC INTERNEURONS: A KEY

MEDIATOR OF DOPAMINE-DEPENDENT

PLASTICITY IN THE STRIATUM

The role of cholinergic interneurons in striatal plas-

ticity and learning is well established.10,77,78 The im-

portance of acetylcholine-dopamine balance in proper

striatal functioning has long been considered to be a

key factor underlying normal basal ganglia func-

tion.10,79–81 Abnormal increased acetylcholine release

in the striatum is a key neurochemical landmark of

Parkinson’s disease.10,79–80 Cholinergic interneurons

are enriched in D2 and D5 dopamine receptors (see

Fig. 2). Recent studies further emphasize the impor-

tance of dopamine-mediated regulation of cholinergic

interneurons in modulating striatal outflow, and influ-

encing the integration, processing and transmission of

information along the dual striatofugal systems. Dopa-

mine-dependent long term depression (LTD) of trans-

mission at glutamatergic synapses is well characterized

in the rat striatum.68,82,83 Pharmacological and molecu-

lar 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 neu-

rons57 even though only neurons in the indirect path-

way express significant numbers of D2 receptors. The

mechanisms by which D2 could mediate LTD in direct

striatofugal neurons is poorly understood and contro-

versial.26,57 Recent evidence suggests a critical role of

cholinergic interneurons in mediating this effect. D2

receptors are, indeed, found on cholinergic interneur-

ons 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

glutamatergic axo-spinous synapses.84,85 Through the

use of BAC transgenic mice with fluorescent reporters

driven by the D1- or D2- receptor promoters, Wang

et al.57 proposed that D2 receptors on cholinergic neu-

rons act to inhibit the release of acetylcholine. This

reduction, then, reduces M1-mediated inhibitory modu-

lation of L-type calcium channels, resulting in

increased intracellular calcium in medium spiny neu-

rons. Under such activation, medium spiny neurons

release endogenous cannabinoids that act presynapti-

cally on CB1 receptors to reduce glutamate release and

mediate LTD.26,57 These findings demonstrate that D2-

mediated 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-medi-

ated communication between direct and indirect stria-

tofugal neurons.

Virtually all cholinergic neurons express high levels

of D5 mRNA and protein in rats and monkeys.9,86–88

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 D1-

and 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 func-

tions 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 func-

tions of dopamine through modulation of striatal activ-

ity 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).



The Nigropallidal Dopaminergic System: A

Substrate for Differential Regulation of

Segregated Pallidofugal Neurons

There are numerous anatomical, immunocytochemi-

cal, and neurochemical studies that support the exis-

tence of nigropallidal dopaminergic projections. Early

retrograde and anterograde tract-tracing studies and

light microscopic immunohistochemical data showing

tyrosine hydroxylase (TH) and dopamine (DA)-immu-

noreactive fibers and varicose processes are discussed

in detail in our previous review of extrastriatal dopa-

mine systems.27 Since then, evidence for functional

dopamine release in the globus pallidus has been gath-

ered. In monkeys, electron microscopic studies have

shown TH-immunoreactive terminals in synaptic con-

tact with dendrites of GPi neurons.27 Perfusion of

D-amphetamine and cocaine into the rat GP produces

concentration-dependent increases in dialysate dopa-

mine.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 pallidosubthala-

mic neurons that are devoid of PPE, but display PV

immunoreactivity (PPE2/PV1) account for 40% and

about 60% of the total GP neuronal population, respec-

tively. 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 filling studies have provided evidence for segre-

gated pallidosubthalamic and pallidostriatal neurons in

squirrel monkeys.95

The two main populations of GP neurons respond

differently to systemic or local application of dopamine

receptor-related compounds in rats. For instance, sys-

temic administration of D2 antagonist induces c-fos

expression mainly in PPE1/PV2 pallidostriatal neu-

rons, 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 regula-

tion of DA upon PV-positive and PV-negative GP neu-

rons 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 significantly 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 influenced by

dopaminergic perturbations, though they exhibit differ-

ential degrees of regulation by dopamine and down-

stream basal ganglia nuclei.98

Two major targets likely mediate local dopamine

effects in the GP, presynaptic D2 receptors on striatofu-

gal GABAergic axons and terminals and/or postsynap-

tic D2 receptors on GP neurons.99 Although presynaptic

D2 receptors on striatopallidal projections have long

been recognized, postsynaptic expression of D2 recep-

tor mRNA in rat GP neurons have just been uncov-

ered.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 pallidosubtha-

lamic 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 co-

express both D2 and D3 receptors mRNA, most neu-

rons 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 findings provide a solid

substrate through which local intrapallidal release of

FIG. 4. Diagram showing the extent of striatal and extrastriatal do-paminergic projections top the basal ganglia and thalamus. The SNcprojects most strongly to the striatum, but also innervates all otherbasal ganglia nuclei and provides a significant input to variousthalamic nuclei.



dopamine can bypass the striatofugal system and modu-

late directly GP neuronal activity through stimulation

of pre- and post-synaptic D2 family receptors.

There is some evidence that the nigropallidal dopa-

minergic 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

outflow in early, asymptomatic, stages of Parkinson’s

disease.102 The nigropallidal system also plays an im-

portant role in mediating the beneficial behavioral

effects of intranigral glial derived nerve factor (GDNF)

in primate models of parkinsonism.103

THE NIGROSUBTHALAMIC DOPAMINERGIC

SYSTEM: A CRITICAL ROLE FOR

D5 RECEPTORS

The subthalamic nucleus receives light dopaminergic

innervation from collaterals of SNc nigrostriatal neu-

rons.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 firing rate and reg-

ulates postsynaptic GABA A-mediated transmission in

subthalamic neurons.104 Various D1 and D2 family do-

pamine 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 significant change in D1 receptor

in the ipsilateral STN of 6-OHDA-treated rats.105

Recent studies highlighted the importance of D5 recep-

tors 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 administra-

tion 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 reg-

ulating activity of the indirect pathway of the basal gan-

glia 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 elec-

trical activity in a subset of STN neurons endowed with

burst-firing capacity, resulting in longer discharges of

spontaneous or evoked bursts. These effects specifically

involve D5 since they remain intact in D1 receptor

knock-out mice and because burst-competent STN neu-

rons only express D5 receptors mRNA and protein

immunoreactivity.107 Together, these data provide a

strong basis for D5-mediated functional dopamine regu-

latory effects in the STN. Its potential role in regulating

burst firing, makes D5 receptor an interesting target

for the development of novel pharmacotherapeutic

approaches in Parkinson’s disease.

DENDRITIC RELEASE OF DOPAMINE IN THE

SUBSTANTIA NIGRA: A UNIQUE SOURCE OF

LOCAL DOPAMINE REGULATION OF SNc

AND SNr NEURONS

Local dendritic release of dopamine in the substantia

nigra has long been established, though the exact mech-

anisms that underlie the release, regulation, and func-

tion 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-reg-

ulator of its own release through activation of D2 and

D3 receptors in dendrites and cell bodies of SNc neu-

rons. The physiological significance of this regulation

remains controversial; some studies showing significant

D2-mediated effects on nigral dopamine release,108–110

while others demonstrated a rather weak auto-inhibitory

effect of D2 receptor activation on dopamine

release.111–114 On the other hand, data mainly gathered

from in vitro studies, show that dopamine may also act

through pre-synaptic D1 receptors on GABAergic stria-

tal terminals to facilitate GABA release in the SNr (but

see Ref. 115), thereby increases firing of GABAergic

SNr neurons and raises GABA outflow in target tha-

lamic nuclei.27 These in vitro observations are sup-

ported 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.116–118 D5 and D4

receptors are also expressed in SNc and SNr neurons,

respectively, but the physiological significance 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

flow along dopaminergic fibers with g-butyrolactonereduces dendritic dopamine release, while it can be

enhanced by the depolarizing agent veratridine, high

potassium concentrations and amphetamine.123–127 To-

gether, these findings demonstrate the importance of



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.128–131 Various dopamine re-

lease mechanisms have been suggested in the rat sub-

stantia 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 synaptosome-

associated protein SNAP-25 (25kDA synaptosome-

associated protein).136 Another line of evidence sup-

ports a role for dopamine transporter (DAT) reversal in

nigral dopamine release,137 but this effect remains con-

troversial since other published studies have shown that

DAT inhibition increases nigral dopamine levels.124,138

The dendritic release of dopamine provides SNc neu-

rons with unique capabilities in self-regulating their

own activity at the cell body and terminal levels. The

abundance of pre- and post-synaptic dopamine recep-

tors in SNc and SNr provide multiple targets whereby

dendritic dopamine release can mediate its functional

effects on nigral outflow.

INTRASTRIATAL DOPAMINERGIC NEURONS:

A COMPENSATORY MECHANISM FOR

DOPAMINE DEPLETION IN

PARKINSON’S 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 significantly after neurotoxic dopamine deple-

tion in animal model or in humans with Parkinson’s

disease suggesting that it may act as a compensatory

mechanism for the progressive dopamine loss in parkin-

sonism.27,139–141 Their number is significantly 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 fea-

tures of interneurons ie they have smooth aspiny den-

drites and a deeply invaginated nucleus.140–143 How-

ever, their cell body is on average significantly smaller

than any other types of striatal interneurons. In fact,

except for a small subset (about 10–15%) that co-local-

izes 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

population of neurons that appears in response to dopa-

mine depletion, though direct evidence for such neuro-

genesis in the adult striatum remains controver-

sial.140,144 In MPTP-treated monkeys, these neurons are

mainly concentrated along the lateral border of the cau-

date nucleus and the pre-commissural putamen, indicat-

ing 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 termi-

nals 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 neu-

rons 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 deple-

tion in Parkinson’s disease.146,147

THE THALAMIC DOPAMINERGIC SYSTEM:

AN UNRECOGNIZED DOPAMINERGIC

SYSTEM THAT DEGENERATES IN


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 significant com-

ponent 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 significant dopaminergic inner-

vation of midline, associative and ventral motor nuclei

(see Fig. 4). In contrast, the intralaminar and relay sen-

sory 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 nigrostri-

atal dopaminergic pathway and degenerates in MPTP-

treated 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 evi-

dence showed that dendrites of thalamic interneurons are

the main targets of dopamine terminals in the monkey

thalamus.153 These findings concur with biochemical



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.101,156–158 Strong peri-

karyal D5 immunolabeling is found throughout the

human thalamus.119 Although much work remains to

be done to unravel the functional significance of dopa-

mine at the thalamic level, these anatomical data

provide a solid foundation for a robust and complex

thalamic dopamine system that likely mediates broad

influences on neuronal activity in various cortical and

subcortical regions through thalamofugal connections.

Its possible degeneration in the monkey model of Par-

kinson’s disease provides further evidence for a critical

extrastriatal site whereby dopamine depletion could

induce significant pathologic changes in neuronal activ-

ity and behavior.

CONCLUDING REMARKS

Exciting developments have been made in our

understanding of dopamine function in the basal gan-

glia. The potential role of dopamine at both striatal

and extrastriatal levels, the importance of dopamine in

regulating spine plasticity in specific subsets of striato-

fugal neurons and the recognition of cholinergic inter-

neurons 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 specific functions of various mem-

bers of the D1 and D2 dopamine receptor families has

hampered considerably our progress in understanding

the functional significance 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 func-

tional interactions between the two receptor families.

Acknowledgments: This work was supported by grantsfrom the NIH, National Parkinson Foundation, Tourette Syn-drome Association to YS and the NIH base grant of theYerkes Primate Center (RR00165).

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Striatal and Extrastriatal Dopamine in the Basal Ganglia: An Overview of its Anatomical Organization in Normal and Parkinsonian Brains