REVIEW

Pathogenesis of Parkinsons Disease

Etienne C. Hirsch, PhD,1,2,3 Peter Jenner, PhD, DSc, FRPharmS,4 and Serge Przedborski, MD, PhD5*

1
Universite
Pierre et Marie CurieParis 06, Centre de Recherche de lInstitut du Cerveau et de la Moe lle Epinie`re,
Hopital de la Salpetrie`re, Paris, France
2

et de la Recherche Me
Institut National de la Sante
dicale, Unite
Mixte de Recherche U975, Paris, France
3
Centre National de la Recherche Scientifique, Unite
Mixte de Recherche 7225, Paris, France
4
Neurodegenerative Diseases Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, Kings College,
London, United Kingdom
5
Department of Neurology, Department of Pathology and Cell Biology, and the Center for Motor Neuron Biology and Disease,
Columbia University, New York, New York

A B S T R A C T : Parkinsons disease is a common behavior of misfolded proteins and neuroinflammation.

adult-onset neurodegenerative disorder whose pathoge-
nesis remains essentially unknown. Currently, it is believed
that the neurodegenerative process in Parkinsons disease
is a combination of both cell-autonomous and non-cell-au-
tonomous mechanisms. Proposed cell-autonomous
This suggests that cell death in Parkinsons disease is
caused by a multifactorial cascade of pathogenic events
and argues that effective neuroprotective therapy for Par-
kinsons disease may have to rely on multiple drug interven-
tions. V
C 2012 Movement Disorder Society

mechanisms include alterations in mitochondrial bioener-

getics, dysregulation of calcium homeostasis, and
impaired turnover of mitochondria. As for the proposed Key Words: Dopamine neuron, inflammation, neuro-
non-cell-autonomous mechanisms, they involve prion-like degeneration, mitochndria, misfolded protein

Parkinsons disease (PD) is a common adult-onset
neurodegenerative disease characterized by the rela-
tively selective death of neuronal subtypes, notably
those of the nigrostriatal dopaminergic pathway.1 PD
is usually characterized by the changes that occur in
motor function, such as bradykinesia, rigidity, pos-
tural instability, and rest tremor, although myriad
------------------------------------------------------------
*Correspondence to: Serge Przedborski, Center for Motor Neuron
Biology and Disease, P&S 5-420, Columbia University, 630 West 168th
Street, New York, NY 10032; sp30@columbia.edu
Relevant conflicts of interest/financial disclosures: The authors are
supported by grants from the National Institutes of Health (NS042269,
NS064191, NS38370, NS070276, and NS072182 to S.P.), the U.S.
Department of Defense (W81XWH-08-1-0522, W81XWH-08-1-0465, and
W81XWH-09-1-0245 to S.P.), the Parkinson Disease Foundation, the
Thomas Hartman Foundation For Parkinsons Research, Project A.L.S,
the Wings-over-Wall Street/Muscular Dystrophy Association. INSERM,
CNRS, Universite
Pierre et Marie Curie, Cure Parkinson Foundation,
Rosetrees Trust, Parkinson UK, and National Parkinson Foundation,


Centre national de la recherche scientifique, Institut national de la sante
et de la recherche me
dicale.
Full financial disclosures and author roles may be found in the online
version of this article.
Received: 9 January 2012; Revised: 3 April 2012; Accepted: 8 April
2012
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/mds.25032
nonmotor manifestations are increasingly recognized.2
PD, like many of the prominent adult-onset neurode-
generative disorders such as Alzheimers disease and
amyotrophic lateral sclerosis, is primarily sporadic,
that is, it occurs in the absence of any obvious genetic
linkage.1 However, in rare instances, PD is inherited,
and in these cases, the PD phenotype is transmitted ei-
ther as a recessive or dominant trait.1 Yet the motor
phenotypes of both the sporadic and familial forms of
PD are almost identical, implying that they might
share common underlying mechanisms. Perhaps not
surprisingly, many researchers argue that this pheno-
typic similarity justifies the intense analyses of rare
genetic forms of PD, as these studies could well illumi-
nate the pathogenesis of both sporadic and inherited
disease. Moreover, the familial forms of PD do not
occur because of mutations in a single gene but result
from mutations in multiple distinct genes.3 This
genetic heterogeneity is to be expected because as dis-
cussed elsewhere,4 the taxonomy of neurodegenerative
disorders rests on clinical, biochemical, and neuro-
pathological criteria that serve to lump together ill-
nesses that simply look alike. From a pathogenic point

Movement Disorders, Vol. 000, No. 000, 0000 1

H I R S C H E T A L .
of view, it is possible that the apparent convergence of
the clinical PD phenotype caused by different genes
tells us that the actions of the mutated forms intersect
in common pathways. In this regard, we believe that
despite the genotypic diversity of familial PD, insights
into its pathogenesis that have been gained in the last
decade have begun to reveal some new and interesting
themes, one of which has already started to challenge
our traditional focus on neurons. Indeed, it is increas-
ingly recognized that degenerating neurons in PD,
such as dopaminergic neurons of the nigrostriatal
pathway, do not live in isolation. These neurons
receive a variety of afferents and are surrounded by a
large number of nondopaminergic neurons like
GABAergic and cholinergic neurons and nonneuronal
cells such as astrocytes and microglia. Thus, it is the
current belief that the neurodegeneration in PD occurs
in response to a mixture of deleterious mechanisms
taking place both inside the degenerating neurons (ie,
cell-autonomous processes) and outside the degenerat-
ing neurons (ie, non-cell-autonomous processes). We
now explore this convenient division of cellular and
molecular events occurring in PD to discuss some of
the most recent concepts on its pathogenesis.
Cell-Autonomous Mechanisms
Cell-autonomous mechanisms in PD include oxida-
tive stress, protein aggregation, defects in the ubiqui-
tin-proteasome pathway, and autophagy, but in our
opinion it is alterations in mitochondrial function that
have gained prominence.4 Over the past decade, there
has been an explosion of new information on the neu-
robiology of PD due in part to major advances in mo-
lecular genetics.5 Since the early 2000s, the number of
mutations in apparently disparate genes identified in
PD families has increased exponentially. Importantly,
at least 3 of the products encoded by these genes,
namely, DJ-1, Parkin, and PINK1, have been con-
nected to mitochondria.4 LRRK2 might also plays a
role in modulating the response to mitochondrial inhi-
bition, and mutations in LRRK2 might enhance the
susceptibility of dopaminergic neurons to other insults
occurring in PD.6 Furthermore, in sporadic PD, laser-
capture microdissection showed high levels of deleted
mitochondrial DNA in individual dopaminergic neu-
rons in the substantia nigra.7 The level of mitochon-
drial DNA deletion was greater in cytochrome c
oxidase-deficient neurons than in neurons with normal
cytochrome c oxidase activity.7 This supports the idea
that the observed somatic mitochondrial DNA
mutations cause functional defects in mitochondrial
respiration in nigral dopaminergic neurons. Collec-
tively, these findings in familial and sporadic PD
prompted revisiting the nature of the mitochondrial
2 Movement Disorders, Vol. 000, No. 000, 0000
defect in PD, and this has led to at least 3 recent
breakthroughs.
The Return of Bioenergetics
For years, bioinformatics on small PD cohorts has
been used to try to gain insights into both the etiology
and pathogenesis of PD, but with little success. In a
recent colossal collaborative effort, genomic material
from around the world was combined to perform a
genome-wide meta-analysis of gene sets in 410 sam-
ples from patients with symptomatic and presympto-
matic PD and normal controls.8 The study analyzed
6.8 million raw data points from 9 genome-wide
expression studies, and 185 laser-captured human do-
paminergic neuron and substantia nigra transcrip-
tomes.8 This massive amount of data and analyses led
to the identification of a strong association between
PD and 10 molecular pathways all related to bioener-
getics, including glucose metabolism and mitochon-
drial oxidative phosphorylation.8 Expression of many
of the genes governing mitochondrial bioenergetics
and oxidative metabolism is modulated by the tran-
scriptional coactivator PGC-1a, and in PGC-1a-
knockout mice, expression of the genes responsible for
mitochondrial respiration is reduced and mitochon-
drial respiration decreased.9 Not surprisingly, the
authors inferred from their findings that PGC-1a regu-
lation is perturbed in PD (Fig. 1).
Yet a key question is left unanswered: how does
PGC1a become dysregulated in PD? Perhaps a begin-
ning of the explanation can be found in the work of
Shin et al10 on a new Parkin-interacting substrate
called PARIS. The latter is degraded by a Parkin-de-
pendent mechanism and represses the expression of
PGC1a, among other targets.10 Collectively, these
data allow us to propose the following novel patho-
genic scenario of PD. Following a loss of Parkin func-
tion, because of either genetic mutations or
posttranslational modifications such as oxidative
stress, PARIS accumulates and represses PGC1a,
which, in turn, leads to the downregulation of all the
PGC1a-responsive genes, including those regulating
glucose metabolism and mitochondrial respiration,
hence provoking a defect in bioenergetics and ulti-
mately neuronal degeneration (Fig. 1).
Altered Calcium Conductance
In other recent studies, highly susceptible nigral do-
paminergic neurons were shown to exhibit electro-
physiological characteristics distinct from those of the
more resistant ventral tegmental dopaminergic neu-
rons.11,12 The study by Chan and collaborators11
showed that nigral neurons rely on L-type Cav1.3 cal-
cium channels to drive their rhythmic pacemaking ac-
tivity, which is associated with greater calcium
 P A T H O G E N E S I S O F P A R K I N S O N S D I S E A S E

FIG. 1. A scheme illustrating that cell death in Parkinsons disease is a result of a multifactorial cascade of pathogenic events combining cell-auton-
omous and non-cell-autonomous mechanisms. The cell-autonomous mechanisms shown include alterations in mitochondrial bioenergetics, dysre-
gulation of calcium homeostasis, and impaired turnover of mitochondria. Many of the genes governing mitochondrial bioenergetics and oxidative
metabolism are modulated by the transcriptional coactivator PGC-1a, which is dysregulated in Parkinsons disease, possibly because of the accu-
mulation of a Parkin-interacting substrate called PARIS. The proposed non-cell-autonomous mechanisms involve prion-like behavior of misfolded
proteins and neuroinflammation. These combine to initiate neuronal cell death and propagate its progression. The combination illustrates that it is
unlikely that pathogenesis in Parkinsons disease can be stopped or slowed through any single therapeutic intervention.

conductance compared to ventral tegmental dopami-
nergic neurons. In the subsequent study by Guzman
and collaborators,12 it was shown that the greater cal-
cium conductance in nigral dopaminergic neurons is
associated with increased intramitochondrial produc-
tion of reactive oxygen species (ROS). However, we
do not believe the principles of mitochondrial bioener-
getics invoked by the authors to explain how increased
intracellular calcium concentration causes increased
mitochondrial ROS production are correct. Indeed,
bioenergetic principles argue that the faster the elec-
tron flow through the electron transport chain, the
shorter the time the ubiquinone complex is reduced
and the fewer electrons passed to molecular oxygen.
Accordingly, the harder the mitochondria work, the
less (and not the more) ROS is produced. Thus,
should the ROS data be confirmed, the basis between
calcium dyshomeostasis and intramitochondrial ROS
production may lie in some other explanation. None-
theless, even if we disagree with the authors interpre-
tation of their data, it remains true that this work
shows that the singular calcium-dependent pacemak-
ing of nigral neurons is associated with increased mi-
tochondrial ROS.12 If confirmed, the latter findings
may represent one of the molecular underpinnings of
the reported heightened mitochondrial DNA damage
in nigral neurons in PD.7
Parkin and PINK1 Modulate Mitophagy
A third set of investigations brought the concept
that PD pathogenesis might be linked to a defect in
mitochondrial quality-control mechanisms. Although
these have only begun to be recognized in mammals,
it is well established in yeast that when mitochondria
are defective, specific molecular machinery recognizes
and then disposes of these damaged mitochondria
through macroautophagy.4 This quality-control mech-
anism maintains a healthy pool of mitochondria, and
the cell can then withstand the high energy demand of
neurons.4 Several groups, including our own, have
demonstrated that cytoplasmic Parkin can relocate to
the mitochondria following loss of mitochondrial
membrane potential,1317 a well-known indicator of
mitochondrial dysfunction. Parkin translocation is
PINK1 dependent,1317 that is, in the absence of
PINK1, Parkin does not translocate to the mitochon-
dria, even if the membrane potential is lost. Once mi-
tochondria are decorated with Parkin, individual

Movement Disorders, Vol. 000, No. 000, 0000 3

H I R S C H E T A L .
mitochondria quickly form clusters that migrate to the
perinuclear region of the cell.14,17 There, these Parkin-
decorated mitochondria colocalize with markers of
lysosomes,14,17 suggesting that the mitochondrial clus-
ters are degraded by macroautophagy. However, con-
trary to events in yeast, we have recently challenged
the idea that Parkin/PINK1 is part of the machinery of
macroautophagy degrading dysfunctional mitochon-
dria. Instead, based on our findings,18 we propose that
Parkin and PINK1 collaborate to merely facilitate
damaged mitochondria to be preferentially, but not
exclusively, degraded by general macroautophagy.
Nonetheless, whatever the actual molecular process
involved, PD mutations in either Parkin or PINK1
appear to hamper the normal turnover of damaged
mitochondria.14,17 Thus, from the above studies, a
loss of function of Parkin or PINK1 might prevent
damaged mitochondria from being effectively elimi-
nated, and this, in turn, may lead to neuronal dysfunc-
tion and, ultimately, to even neuronal death (see
Conclusions for further discussion on this theme). In
addition, it has been reported that LRRK2 might regu-
late autophagy/lysosomal function,19 but whether this
involves mitophagic pathways in the same way as Par-
kin or PINK1 remains to be established (Fig. 1).
Non-Cell-Autonomous Mechanisms
Diffusion of Parkinsons Disease over Time
and across Brain Regions
Although the symptoms of PD worsen over time,
the mechanisms underlying the progression of the dis-
ease across different brain regions are not fully under-
stood. However, they very likely involve cellular
interactions known as non-cell-autonomous mecha-
nisms. These mechanisms include a spreading of the
pathology (especially of a-synuclein), a progressive
degeneration of dopaminergic and nondopaminergic
neurons and inflammatory processes.
Lewy bodies and Lewy neurites composed of a-syn-
uclein deposits are found in the substantia nigra pars
compacta, where melanized neurons degenerate.20,21
Importantly, these also are present in nondopaminer-
gic brain nuclei that die in PD and even in the periph-
ery.20,21 From analyzing a series of brains at autopsy,
Braak and coworkers22 suggested that a-synuclein
deposition follows a stereotyped progression across
the nervous system. According to Braaks view, the
pathology would start during the preclinical phase of
PD at 2 independent loci, namely, the medulla oblon-
gata and the olfactory structures. Because at this stage
there is no pathology in the substantia nigra, it
remains to be established whether these cases, called
the preclinical phase of PD or PD stage I, are truly a
preclinical form of PD. In the early clinical stages of
PD, inclusions are found in the substantia nigra and
4 Movement Disorders, Vol. 000, No. 000, 0000
the midbrain and rapidly thereafter in the basal fore-
brain, the basal ganglia, and the mesocortex. In the
end stage of the disease, the inclusions invade the
whole neocortex. Yet the distribution of abnormal a-
synuclein deposits does not correlate with disease du-
ration and does not explain the progression of clinical
severity of the disease.23 Furthermore, whether those
a-synuclein deposits truly herald neurodegeneration is
still unknown.
A role for a-synuclein in the progressive nature of
the disease has been revitalized by the discovery of a-
synuclein-immunoreactive Lewy bodies in embryonic
grafted cells in the striata of patients with PD.24,25
This suggests that pathology could spread from one
cell to another and that a-synuclein could be trans-
ferred from an affected neuron to a previously healthy
neuron by a prion-like process. Subsequently,
numerous investigators tried to substantiate this hy-
pothesis using in vitro and in vivo approaches (for a
review, see reference 26). Germane to this new con-
cept are the following 3 observations. First, it has
been demonstrated that a-synuclein is present in the
secretory vesicles of neurons and various biological
fluids, suggesting it might be secreted by exocytosis.26
Second, it has been found that exosomes from neuro-
blastoma cell lines appear to be able to cargo the pro-
tein from one cell to another.27 And third, it has been
shown that preformed fibrils generated from full-
length and truncated recombinant a-synuclein enter
primary neurons, probably by adsorptive-mediated
endocytosis, and promote recruitment of soluble en-
dogenous a-synuclein into insoluble inclusions reminis-
cent of Lewy bodies.28 In the latter study, the authors
demonstrated that the accumulation of pathologic a-
synuclein led to decreases in synaptic proteins, pro-
gressive impairments in neuronal excitability and con-
nectivity, and, eventually, neuron death.28
Cell-to-cell transfer of a-synuclein can explain the
formation of Lewy bodies and Lewy neurites but
clearly does not account for the full spectrum of PD
and especially not for the degeneration of all neurons.
Indeed, neuronal loss in PD is not restricted to the
substantia nigra or to neurons containing Lewy
bodies. Other neuronal populations also degenerate
such as cholinergic neurons in the basal forebrain and
the midbrain tegmentum, serotonergic neurons in the
raphe nuclei, noradrenergic neurons in the locus
coeruleus (for a review, see reference 29), and even
pyramidal neurons involved in corticocortical connec-
tivity in the presupplementary motor area of the cere-
bral cortex.30 The pathogenic mechanisms taking
place have scarcely been investigated and are pre-
sumed to reflect events in the substantia nigra. Inter-
estingly, the degeneration of some neurons might also
involve non-cell-autonomous mechanisms. Indeed, a
correlation exists between the degree of neuronal
 P A T H O G E N E S I S
degeneration in the substantia nigra pars compacta
and in the pedunculopontine nucleus (PPN),31,32
which sends cholinergic projections directly to nigral
dopaminergic neurons. Interestingly, Toulorge and co-
workers reported that the cholinergic agonist nicotine
can protect dopaminergic neurons in an in vitro model
of spontaneous and selective degeneration.33 However,
protection only occurred when cytosolic calcium was
increased. This rise in calcium was necessary to sensi-
tize dopamine neurons to the action of nicotine
through a mechanism involving a-bungarotoxin-sensi-
tive (presumably a7) nicotinic acetylcholine receptors
and secondarily T-type voltage-gated calcium channels
(Fig. 1). Thus, the degeneration of PPN cholinergic
neurons in PD might exacerbate the loss of nigral do-
paminergic neurons by reducing their stimulatory
inputs. Very similar findings have been made on the
role of noradrenergic input to the substantia nigra and
its effect on dopaminergic cell death. Yet other mecha-
nisms such as loss of trophic support might also
explain neuronal loss in PD. In keeping with this,
decreased concentrations of brain-derived neurotro-
phic factor and nerve growth factor have been
described in the substantia nigra in PD34 whereas glial
cell linederived neurotrophic factor levels were
unchanged.35 Clearly, at this point further studies are
needed to determine if the changes in neurotrophic
factor levels are primary in neuronal degeneration in
PD or merely represent a consequence of neuronal
dysfunction.
NeuroinflammationInstrumental in
Neurodegeneration?
Interactions between neurons and nonneuronal cells
also participate in the cascade of events leading to
neurodegeneration in PD (Fig. 1). Indeed, astrocytosis,
microgliosis, and even lymphocyte infiltration are
found in the substantia nigra in postmortem studies in
PD (for a review, see references 36 and 37). In line
with this, levels of proinflammatory cytokines are
increased in the substantia, the striatum, and the cere-
brospinal fluid of patients with PD.38 Perhaps impor-
tantly, LRRK2 has been found to localize to activated
microglial cells, and the R1441G mutation enhances
the release of cytokines from activated microglia and
increases cell death.39,40 This indicates that both
innate and adaptive immunity are involved in the
pathogenesis of PD. However, postmortem studies do
not allow the determination of whether neuroinflam-
mation participates in neuronal degeneration or
merely represents a consequence of it. To address this
issue, changes occurring in animal models of PD have
been investigated along with the effects of interfering
with such mechanisms on the extent and time course
of neuronal loss.
O F P A R K I N S O N S D I S E A S E
Innate immunity has been studied following initia-
tion of nigral dopaminergic cell loss produced by the
systemic injection of the parkinsonian neurotoxin 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).1
MPTP treatment resulted in extensive microglial acti-
vation in both mice41 and nonhuman primates.42 Fur-
thermore, reduction of microglial activation by
cyclooxygenase-2 inhibitors,43 peroxisome prolifera-
tor-activated receptor-gamma agonists,44 or tumor ne-
crosis factor alpha manipulation45 reduced neuronal
degeneration. Microglial activation was also reported
in rats after viral vectortargeted overexpression of
human a-synuclein in midbrain dopamine neurons.46
Importantly, in vitro studies even suggested that a-syn-
uclein deposition and inflammatory change potentiate
each others pathogenic activity and participate in the
progressive nature of neurodegeneration.47 Yet there is
still a debate about whether microglial activation is
harmful. Indeed, microglial cells also produce anti-
inflammatory cytokines and exert phagocytic activities
that could prevent the extension of neuronal degenera-
tion. In this context, trying to switch the phenotype of
microglial cells from a proinflammatory M1 to an
immunomodulatory M2 phenotype might represent an
interesting therapeutic strategy.48
Experimental studies have also shown that adaptive
immunity is involved in animal models of PD (Fig. 1).
T lymphocytes (CD4 and CD8 lymphocytes) but not B
lymphocytes infiltrate the substantia nigra and the
striatum of MPTP-intoxicated mice.4951 In this
model, ablation of CD4 but not of CD8 lymphocytes
provided protection against MPTP toxicity to dopami-
nergic neurons by a Fas/Fas ligand-mediated pathway.
The specific antigens that trigger the lymphocytic
response have not been identified but are likely include
nitrated a-synuclein released from dying neurons.52,53
Conclusions
The growing consensus in PD research is that the
demise of selective subsets of neurons that characterize
this adult-onset neurodegenerative disorder results
from a combination of cell-autonomous mechanisms
(that is, mechanisms that take place inside dying neu-
rons) and non-cell-autonomous mechanisms (that is,
mechanisms that originate from outside the dying neu-
rons). It is also important to stress that although the
lions share of attention is given to dopaminergic neu-
rons, many other neuronal subtypes degenerate in PD.
There is as yet no evidence that different neuronal
populations die by distinct pathogenic mechanisms, so
currently studying dopaminergic neurons is perfectly
appropriate, but this may need to be reviewed once
events occurring outside the substantia nigra have
received similar attention.
Movement Disorders, Vol. 000, No. 000, 0000 5
H I R S C H E T A L .
Among the cell-autonomous mechanisms, there is a
resurgence of interest in the idea that mitochondrial
dysfunction may be a key pathogenic mechanism of
PD. However, all recent studies have pointed toward
damaged mitochondria in PD occurring as a conse-
quence of upstream molecular defects and not, as was
thought for many years, as a primary pathogenic
event. Significantly, above we discussed some of such
potential primary defects that may lead to the accu-
mulation of dysfunctional mitochondria in dopaminer-
gic neurons, either because of enhanced damage or of
decreased elimination, or both. Based on the new
body of information discussed here, the following
pathogenic scenario of PD emerges. In dopaminergic
neurons, increased calcium conductance and the ensu-
ing greater mitochondrial ROS production lead to
higher levels of damaged mitochondria. In normal
individuals, Parkin and PINK1 function to eliminate
damaged mitochondria by macroautophagy allowing
nigral dopaminergic neurons to retain a normal pool
of healthy mitochondria. In contrast, in PD a loss of
Parkin function leads to a progressive buildup of dam-
aged mitochondria because of a concerted effect to
reduce PGC1a activity and a defect in Parkin/PINK1-
dependent mitochondrial turnover. Thus, over time,
the burden caused by mitochondrial dysfunction will
rise and eventually reach a pathological threshold,
provoking neuronal dysfunction and ultimately cell
death.
To this equation must be added the contribution of
non-cell-autonomous mechanisms. In aggregate, the
data reviewed here on non-cell-autonomous mecha-
nisms of neuronal degeneration in PD indicate our
vision of the disease involving only nigral dopaminer-
gic neurons was much too simplistic. It is now well
established that the disease expands overtime to other
neuronal populations and that nonneuronal cells par-
ticipate in this propagation. The consequences of these
complex cell interactions are that the pathophysiology
of the disease needs to be revisited in a cell-specific
manner. Indeed, a modified expression of a gene or
protein might have different consequences in different
cell types. This has recently been exemplified for the
anti-inflammatory action of glucocorticoids. Indeed,
stimulation of glucocorticoid receptors on microglial
cells is neuroprotective in MPTP-intoxicated mice, but
this is not the case for the stimulation of glucocorti-
coid receptors on dopaminergic neurons.54 These cell-
specific properties will render any therapeutic interven-
tion extremely difficult because the pharmacological
agents will not only have to cross the bloodbrain bar-
rier but also to reach a specific cell type.
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