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Current Pharmaceutical Design, 2008, 14, 000-000 1
1381-6128/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.
The Endocannabinoid System in Parkinson’s Disease
Massimiliano Di Filippo1,2, Barbara Picconi2, Alessandro Tozzi1,2, Veronica Ghiglieri2,
Aroldo Rossi 1 and Paolo Calabresi1,2,*
1Clinica Neurologica, Universita’degli Studi di Perugia, Perugia, Italy and 2IRCCS, Fondazione Santa Lucia, European
Brain Research Institute, Rome, Italy
Abstract: Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder of largely unknown etiology
caused by a pathological cascade resulting in the degeneration of midbrain dopaminergic neurons of the substantia nigra
pars compacta (SNpc) projecting to the nucleus striatum, the main input station of the basal ganglia neuronal circuit.
The components of the endocannabinoid (ECB) system are highly expressed at different levels in the basal ganglia neural
circuit where they bidirectionally interact with dopaminergic, glutamatergic and GABAergic signaling systems. In par-
ticular, at synapses linking cortical and striatal neurons, endocannabinoids (ECBs) are known to critically modulate syn-
aptic transmission and to mediate the induction of a particular form of synaptic plasticity, the long-term depression.
The evidence that ECBs play a central role in regulating basal ganglia physiology and motor function and the profound
modifications occurring in ECB signaling after dopamine depletion in both experimental models of PD and patients suf-
fering from the disease, provide support for the development of pharmacological compounds targeting the ECB system as
symptomatic and neuroprotectiv e therap eutic strategies for PD.
Key Words: Parkinson’s disease, endocannabinoids, synaptic plasticity, neuroinflammation.
INTRODUCTION
Parkinson's disease (PD) is a chronic and progressive
neurodegenerative disorder of largely unknown etiology
firstly described by James Parkinson more than 180 years
ago and now affecting tens of millions of people worldwide,
with an associated high socioeconomic burden [1,2].
The etiology of PD is still interpreted as a complex puz-
zle of genes, environment, and aging-related processes. In-
deed, only a minority of cases seems to be related to well-
defined genetic or environmental causes, whereas a combina-
tion of mostly unknown genetic and environmental factors is
considered to account for the vast majority of cases [3].
The clinical features of the disease are represented by
poverty of voluntary movements (akinesia), slowness and
impaired scaling of voluntary movement (bradykinesia),
muscle rigidity and limbs tremor at rest [1,2]. These symp-
toms seem to represent the downstream effect of a patho-
logical cascade resulting in the degeneration of midbrain
dopaminergic neurons of the substantia nigra pars compacta
(SNpc) projecting to the nucleus striatum, the main input
station of the basal ganglia neural circuit [1,2].
The discovery of dopamine deficiency in PD and the sub-
sequent introduction of a replacement therapy with the do-
pamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA)
initially revolutionized the treatment of the disease. Unfortu-
nately, motor fluctuations and dyskinesias complicate L-
DOPA treatment in most patients (>90%) within 5–10 years
of treatment initiation. For this reason many other treatments
*Address correspondence to this author at the Clinica Neurologica, Ospeda-
le S. Maria della Misericordia, Universita’ di Perugia, 06156 Perugia, Italy;
Tel: +39 (0)755784230; Fax: +39(0)755784229; E-mail: calabre@unipg.it
targeting non-dopaminergic systems have been proposed
during the years for the management of the disease [4].
The endocannabinoid (ECB) system, among the various
non-dopaminergic neurotransmitter signaling systems, might
represent an interesting potential drug target in PD treatment.
The major components of the ECB system are two en-
dogenous lipids, -N-arachidonoylethanolamine or anan-
damide (AEA) and 2-arachidonoyl-glycerol (2-AG), which
are specific ligands of G protein-coupled receptors named
CB1 and CB2 receptors [5-9]. CB1 receptors are expressed
by neurons and are activated by endocannabinoids (ECBs)
released from postsynaptic target cells in response to synap-
tic depolarization, allowing the regulation of many physio-
logical functions such as memory, cognition and pain per-
ception [10]. Conversely, CB2 receptors are primarily ex-
pressed by immune cells and modulate several aspects of the
immune functions including cytokine production, lympho-
cyte proliferation, and humoral and cell-mediated immune
responses [11,12].
Within the nucleus striatum, the ECB, glutamatergic,
GABAergic and dopaminergic signalling systems profoundly
interact in order to modulate basal ganglia neural network
dynamics and long-term forms of synaptic plasticity. This
strict interaction between ECBs, dopaminergic and glutama-
tergic signals converging onto striatal projecting neurons
represent the basis for the potential usefulness of drugs tar-
geting the ECB system as a therapeutic strategy in PD.
Moreover, since immune mechanisms and neuroinflam-
mation are among the factors that have been implicated in
PD pathogenesis, the CB2-receptor-mediated immunomodu-
latory effects of ECBs might represent another useful target
for drug developing.
2 Current Pharmaceutical Design, 2008, Vol. 14, No. 00 Di Filippo et al.
In this article we will review the physiological basis un-
derlying the potential therapeutic usefulness of pharmacol-
ogical compounds modulating the ECB system in PD. In
particular, in the first part of the work we will discuss the
role of ECBs in modulating synaptic transmission and plas-
ticity within the basal ganglia neuronal circuit while in the
second part of the manuscript we will describe the effects of
dopamine depletion on the ECB system both in experimental
models of PD and in human patients suffering from this dis-
abling neurodegenerative disease.
THE BASAL GANGLIA NEURAL CIRCUIT, PARK-
INSON’S DISEASE AND ENDOCANNABINOID SIG-
NALING
As introduced above, PD core pathological features are
represented by the heterogenous loss of pigmented dopa-
minergic neurons in the SNpc and of their projecting fibers
in the striatum.
The nucleus striatum is the main input nucleus of the
basal ganglia as it receives glutamatergic cortical inputs from
all functional subdivisions of the neocortex and a prominent
input directly from the thalamic nuclei.
Cortical neural signals are processed by a striatal network
comprising GABAergic and cholinergic interneurons and
GABAergic projecting neurons (the so-called ‘medium spiny
neurons’, MSNs) which provide the sole striatal output [13] .
Striatal MSNs project to the output nuclei of the basal
ganglia, either directly (in the so-called “direct pathway”) or
through a series of connections that involves the external
segment of the globus pallidus (GPe) and the subthalamic
nucleus (STN) (in the so-called “indirect pathway”) [14].
The output nuclei (the internal segment of the globus pal-
lidus (GPi) and the substantia nigra pars reticulata (SNpr))
project to the thalamus, which in turn has efferents projec-
tions that complete the cortico-basal ganglia-thalamo-cortical
loop [14] (Fig. 1).
The physiological effect on MSNs of dopamine arising
from the SNpc is complex and still far from being com-
pletely elucidated. Indeed, dopamine receptors stimulation
seems to result in different effects depending on the degree
of membrane depolarization at which the receptor is acti-
vated.
D1 dopamine receptors are known to be positively cou-
pled to adenylyl cyclase, thus causing, when activated, an
increase in cytosolic cA MP levels and several downstream
effects such as the enhancement of NMDA receptor medi-
ated currents, while D2 dopamine receptors are negatively
coupled to adenylyl cyclase and seem to act reducing neu-
ronal excitability and neuronal response to glutamatergic
inputs [15].
According to a classical hypothesis, D1 dopamine recep-
tors are found predominantly in the MSNs of the “direct
pathway”, whereas D2 receptors are mainly expressed by the
MSNs of the “indirect pathway”. The differential effect of
dopamine on these two pathways is thought to result in a
finely regulated balance of output nuclei activity that seems
to be essential for normal motor function. Indeed, when a
subpopulation of striatal neurons is activated, it inhibits a
subpopulation of pallidal neurons and thus indirectly re-
moves the tonic inhibition from a particular target motor
centre, thereby activating its motor program [16].
The progressive loss of midbrain dopaminergic neurons
occurring in PD leads to lower striatal levels of dopamine
and thus to the alteration of the equilibrium between the di-
rect and the indirect basal ganglia pathways, leading to GPi
overactivity and thus to an over-inhibition of the motor
thalamus [17]. The inhibition of the motor thalamus, in turn,
acts as a “brake” on the activity of the supplementary motor
cortex resulting in the onset of the parkinsonian syndrome
[17] (Fig. 1).
A series of anatomical, biochemical, and electrophysi-
ological studies have repeatedly demonstrated that the com-
ponents of the ECB system are highly expressed at different
levels in the basal ganglia neural circuit and thus critically
modulate motor function [18,19] (Fig. 2).
CB1 receptors are expressed by MSNs both in their den-
drites and in their presynaptic axon terminals innervating the
external and internal segments of the GP and the SNpr [18-
20] and are also present at the level of corticostriatal excita-
tory glutamatergic terminals and in the excitatory projections
from the STN to the GPi/SNpr and SNpc [18-20] (Fig. 2).
Within the striatum CB1 receptors are also expressed by
parvalbumin immunoreactive interneurons, cholinergic in-
terneurons, and NOS-positive neurons [21].
As introduced above, in contrast to classical neurotrans-
mitters, endogenous cannabinoids can function as retrograde
synaptic messengers, being released from postsynaptic neu-
rons, travelling backward across synapses, activating CB1
receptors on presynaptic axons and thus reducing neuro-
transmitter release [10].
Indeed, activation of presynaptic CB1 receptors on corti-
costriatal terminals reduces glutamate release [18-20]. Simi-
larly, in the output basal ganglia nuclei (GPi and SNpr), CB1
receptors activation inhibit both glutamate release from STN
afferents and GABA release from striatal afferents [18-20].
On the other hand, in the GPe, activation of presynaptic CB1
receptors may increase local GABA levels by reducing
GABA reuptake from striatal afferents to this nucleus
[18,20] (Fig. 2).
ECB signaling is also bi-directionally linked to dopa-
minergic signaling within the basal ganglia. Indeed, in the
striatum, CB1 receptors are coexpressed with D1 and D2
dopamine receptors [18-20]. In particular, it seems that CB1
and D2 dopamine receptors share a common pool of G-
proteins, suggesting the convergence of their signal transduc-
tion mechanisms [22,23] whereas D1-dopamine receptor-
mediated activation of adenylyl cyclase can be completely
blocked by CB1 receptors stimulation [18-20]. It is also
worth noting that D2 dopamine receptor stimulation has been
demonstrated to result in ECBs release in the striatum [24]
and that CB1 receptors activation seems to decrease GABA
release from striatal afferents innervating dopaminergic neu-
rons of the SNpc resulting in an increased firing of these
cells [18-20].
The presence of transient receptor potential vanilloid type
1 (TRPV1) in dopaminergic nigral neurons and a functional
role of these receptors in the modulation of synaptic trans-
mission within the SNpc have also been demonstrated [25].
The Endocannabinoid System in Parkinson’s Disease Current Pharmaceutical Design, 2008, Vol. 14, No. 00 3
According to these evidences it is thought that ECBs may
critically modulate the physiological function of the basal
ganglia neuronal network.
The presence of components of the ECB system in dif-
ferent neural structures and their direct interaction with do-
paminergic, glutamatergic and GABAergic neurotransmitter
signaling systems render these element an ideal target for the
search of non-dopaminergic pharmacological therapies for
PD.
CORTICOSTRIATAL SYNAPTIC PLASTICITY, DO-
PAMINE AND ENDOCANNABINOIDS
It is well accepted that, within the basal ganglia neural
circuit and in particular in the striatum, synapses are able to
Fig. (1). The Basal Ganglia circuit. Physiological connections and effects of dopamine depletion on circuit dynamics.
Cortical neural signals are processed by a striatal neuronal network comprising interneurons and GABAergic projecting medium spiny neu-
rons (MSNs) that provide the sole striatal output. According to a classical model, D1 and D2 dopamine receptors are thought to be segre-
gated in two subpopulations of MSNs, forming two large efferent streams that differ in their axonal targets, respectively named the “direct”
and “indirect” pathways. The physiological effect of dopamine receptor stimulation on D1- and D2- receptor expressing MSNs is far from
being elucidated. Although still controversial, dopamine arising from the substantia nigra pars compacta (SNpc) is thought to activate (+)
D1 expressing striatal neurons of the direct pathway and to inhibit (-) D2 expressing striatal neuron s of the indirect pathway. The output nu-
clei (the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNpr)) project to the thalamus, which in turn
has efferents that complete the cortico-basal ganglia-thalamo-cortical loop.
According to this model during Parkinson’s disease dopamine deficiency causes overactivity of the indirect pathway, resulting in excessiv e
glutamatergic drive to the GPi and SNpr and reduced activity of the inhibitory GABAergic direct pathway, further disinhibiting the activity of
the same output nuclei. Because these structures use the inhibitory neurotransmitter GABA, the increased output of the basal ganglia leads to
excessive inhibition of the motor thalamus, in turn, acts as a “brake” on the activity of the supplementary motor cortex resulting in the onset
of the parkinsonian syndrome
Please note that in the Figure inhibitory GABAergic connections are represented in red while excitatory glutamatergic connections are in
green.
Abbreviations: DA, dopamine; GABA, gamma-aminobutyric acid; Glu, glutamate; GPe, external segment of the globus pallidus; GPi, inter-
nal segment of the globus pallidus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleu s.
4 Current Pharmaceutical Design, 2008, Vol. 14, No. 00 Di Filippo et al.
undergo long-lasting functional and morphological modifica-
tions following the repeated activation of neuronal pathways
[26].
This fascinating capacity, named synaptic plasticity, is
thought to underlie, at corticostriatal synapses, neuronal cir-
cuit dynamics and development, several key cognitive proc-
esses and, notably, motor learning.
Both a long-term depression (LTD) and a long-term po-
tentiation (LTP) of the efficacy of synaptic transmission
have been demonstrated to occur at striatal synapses onto
MSNs following the repeated stimulation of the corticostri-
atal pathway. The induction of both LTD and LTP at corti-
costriatal synapses requires dopamine receptors stimulation
[26] and is impaired in PD experimental models and in PD
Fig. (2). Expression and physiological function of the CB1 receptor within the Basal Ganglia neural circuit.
CB1 receptors are expressed by striatal MSNs both in their dendrites and in their presynaptic axon terminals innervating the external and
internal segments of the GP and the SNpr and are also present at the level of co rticostriatal excitatory glutamatergic terminals and in excita-
tory projections from the STN to the GPi/SNpr and SNpc.
Activation of presynaptic CB1 receptors on corticostriatal terminals reduces glutamate release. Similarly, in the output basal ganglia nuclei
(GPi and SNpr) CB1 receptors activation inhibit both glutamate release from STN afferents and GABA release from striatal afferents. Con-
versely, in the GPe, activation of presynaptic CB1 receptors may increase local GABA levels by reducing GABA reuptake from striatal af-
ferents to this nucleus.
In the striatum, CB1 receptors are co-expressed with D1 and D2 dopamine receptors and share with these receptors a common pool of G-
proteins, suggesting the convergence of their signal transduction mechanisms. CB1 receptors activation seems also to decrease GABA re-
lease from striatal afferents innervating dopaminergic neurons of the SNpc resulting in increased firing of these cells (not shown).
Abbreviations: DA, dopamine; GABA, gamma-aminobutyric acid; Glu, glutamate; GPe, external segment of the globus pallidus; GP, globus
pallidus; GPi, internal segment of the globus pallidus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; STN,
subthalamic nucleus.
The Endocannabinoid System in Parkinson’s Disease Current Pharmaceutical Design, 2008, Vol. 14, No. 00 5
patients, both in the striatum and in the motor cortex [27,28].
According to these latter evidence, the presence of an im-
pairment of synaptic plasticity in the basal ganglia neuronal
circuit has been proposed as a key component of several
theories explaining basal ganglia network abnormalities dur-
ing this neurodegenerative disease [29,30].
ECBs have been demonstrated to critically participate in
the induction of a form of LTD expressed at synapses linking
cortical and striatal neurons and thus to exert a critical role in
the regulation of striatal neural circuit dynamics.
ECBs, such as AEA, have been demonstrated to be re-
leased by striatal MSNs following membrane depolarization,
intracellular calcium elevation and D2 dopamine receptor
stimulation [24,31].
Thus, the hypothesized scenario in the striatum is that
AEA, released by the postsynaptic neurons after depolariza-
tion and D2 dopamine receptor stimulation, might act as ret-
rograde messenger activating presynaptic CB1 receptors and
thus inducing a long-lasting depression of excitatory gluta-
matergic transmission [32-34] (Fig. 3).
It is worth to note that it has been recently proposed that
striatal MSNs of the direct and indirect pathways might ex-
press different synaptic properties [35]. In particular, it has
been suggested that ECBs release sufficient to trigger ECBs-
mediated LTD, is restricted to indirect-pathway MSNs [35]
(Fig. 3).
ECBs-dependent LTD is lost at indirect-pathway MSNs
synapses in experimental models of PD, but, interestingly, it
can be rescued either in the presence of a D2 dopamine re-
ceptor agonist, such as quinpirole, or by the application of
URB597, an inhibitor of fatty acid amide hydrolase (FAAH),
the degradative enzyme for the endogenous cannabinoid
AEA [35].
Notably, the administration of the same pharmacological
compounds (URB597 and quinpirole) has been demonstrated
to markedly decrease catalepsy and to increase locomotor
activity in the same experimental PD models [35], suggest-
ing a direct correlation between the rescue of an ECBs-
mediated form of synaptic plasticity at corticostriatal syn-
apses and the improvement of PD motor symptoms.
The loss of ECBs-dependent striatal LTD at corticostri-
atal synapses onto indirect-pathway MSNs might thus be
considered a critical event leading to the alteration of the
balance between the direct and the indirect basal ganglia
pathways.
In particular, it might contribute to the abnormal poten-
tiation of this specific neuronal circuit resulting in the over-
activation of the GPi, the subsequent over-inhibition of the
supplementary motor cortex and thus leading to the onset of
the parkinsonian syndrome (Fig. 1).
Endocannabinoids, Neuroprotection and Neuroinflam-
mation
As the degeneration of dopaminergic neurons of the
SNpc and the subsequent striatal dopamine deficiency lead
to most of the motor features of PD, the aim of neuroprotec-
tive strategies in PD is to prevent further dopaminergic cell
death, thereby slowing the disease progression [36]. A num-
ber of factors have been implicated in the pathogenesis of
cell death in PD including oxidative stress, mitochondrial
dysfunction, inflammation, excitotoxicity, and apoptosis
[1,2,37].
It is worth to note that ECBs, in addition to their recog-
nized effects on synaptic transmission and plasticity in the
basal ganglia circuit, might also exert a neuroprotective role
in PD, preventing dopaminergic cell loss in the SNpc [38,39]
Indeed, there is a solid evidence that the ECB system
becomes activated in response to different stimuli that may
damage neurons. For example, AEA levels are increased
after neuronal damage of different etiology and CB1 recep-
tors are up-regulated in brain cells in response to injury
and/or inflammation [39].
Several molecular mechanisms seem to underlie the neu-
roprotectant properties of ECBs. For example, cannabinoid
receptor agonists inhibit glutamatergic synaptic transmission
and reduce the production of tumour necrosis factor- and
reactive oxygen intermediates, which are all factors involved
in neuronal damage during PD [38,39].
In particular, ECBs seem to play a role in prevent excito-
toxic cell damage and death [40,41], an event that is thought
to mediate, at least in part, the cascade leading to SNpc neu-
ronal death during PD.
In addition to the neuroprotective effects mediated by the
modulation of CB1 receptors, some potential beneficial ef-
fects might also be exerted by ECBs via their effects on im-
mune system cells such as B cells, NK cells, monocytes,
neutrophil granulocytes and T cells [12,42].
Indeed, it has been repeatedly demonstrated that in both
patients and experimental models of PD, neuroinflammation
is an ubiquitous finding [43] and, apart from the massive loss
of dopaminergic neurons, PD brains also show a conspicu-
ous glial reaction together with signs of a neuroinflammatory
reaction, manifested by elevated cytokine levels and upregu-
lation of inflammatory-associated factors such as cyclooxy-
genase-2 and inducible nitric oxide synthase [44,45].
Notably, immune reactions and proinflammatory immune
diffusible mediators may be involved in PD pathogenesis not
only by directly contributing to neuronal cells damage and
loss [46] but also causing an impairment in synaptic trans-
mission and plasticity, two physiological events that are
known to be deeply influenced by glial cells [47].
It is thus conceivable that ECBs might influence neuron
survival and preserve physiological synaptic function during
PD acting both at “neuronal” CB1 receptors and at “im-
mune” CB2 receptors, representing a potential pharmacol-
ogical tool to affect, at the same time, both immune and syn-
aptic functions within CNS boundaries.
The Endocannabinoid System in PD and L-DOPA In-
duced Diskinesia: Evidence from Experimental Models
Evidence from experimental models of PD in rodents and
primates suggest that profound changes occur in ECB signal-
ing in the basal ganglia both in the setting of dopamine de-
pletion and following a replacement therapy with L-DOPA
[18-20]. In particular, many studies suggest that parkin-
sonism is associated with over-activity of the ECB signaling
6 Current Pharmaceutical Design, 2008, Vol. 14, No. 00 Di Filippo et al.
system in the striatum, potentially representing an endoge-
nous compensatory mechanism reflecting an attempt to nor-
malize striatal function following dopamine depletion.
Within the striatum, an elevation of AEA levels accom-
panies dopamine loss in the 6-hydroxydopamine (6-OHDA)
experimental model of PD, together with a reduction of
FAAH activity [48], two events which would be expected to
enhance striatal CB1 receptor stimulation. Remarkably, the
anomalies in the ECB system observed in this model have
been demonstrated to be completely reversed by chronic
treatment of parkinsonian rats with L-DOPA [49].
Evidence from non-human primates seems to support the
hypothesis of an increased striatal ECB signaling during PD.
Indeed, in the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-
Fig. (3). Endocannabinoids-dependent long-term depression (LTD) at cortico-striatal synapses onto “indirect pathway” D2-
expressing projecting spiny neurons.
In experimental conditions the high-frequency stimulation (HFS) of corticostriatal fibers using a train of pulses at 100 Hz, in association with
postsynaptic neuronal firing, is able to induce a long-term depression (LTD) of corticostriatal transmission onto striatal projecting medium
spiny neurons. This form of synaptic plasticity is thought to be critical for the control of the intrastriatal circuit dynamics, cognitive functions
and motor learning.
Endocannabinoids, such as AEA, are released by striatal MSNs following membrane depolarization (+), intracellular calcium (Ca++) eleva-
tion, D2 dopamine receptor stimulation and metabotropic glutamate receptor (mGluR) activation.
After being released by the postsynaptic neurons, endocannabinoids might act as retrograde messengers activating presynaptic CB1 receptors
and thus inducing a long-lasting depression of excitatory glutamatergic transmission. In the case of intracellular recordings, this long-lasting
depression is observed as a depression of the evoked excitatory post-synaptic potential amplitude (EPSP) (lower part of the figure).
Abbreviations: AMPARs, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors; Ca++, calcium ions; DA, dopamin e;
GABA, gamma-aminobutyric acid; Glu, glutamate; GPe, external segment of the globus pallidus; GP, globus pallidus; GPi, internal segment
of the globus pallidus; mGluRs, metabotropic glutamate receptors; NMDARs, N-methyl-d-aspartate receptors; SNpc, substantia nigra pars
compacta; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleus; +, membrane depolarization.
The Endocannabinoid System in Parkinson’s Disease Current Pharmaceutical Design, 2008, Vol. 14, No. 00 7
marmoset model of PD the number of striatal CB1 receptors
is increased and CB1-receptor-G-Protein coupling is en-
hanced [50].
According to the evidence of a putative compensatory
up-regulation of the ECB system components in the striatum
following dopamine depletion, it has been demonstrated that
the modulation of ECB signaling might improve parkin-
sonian symptoms both in rodent and primate experimental
models of PD [35,51,52]. With regard to this evidence, en-
hanced CB1 receptor signaling seems thus to represent an
attempt to compensate the downstream striatal effects of
dopaminergic denervation.
There are several effects of CB1 receptor activation that
might potentially explain the “ben eficial” effects of its up-
regulation during PD. As detailed above indeed, CB1 recep-
tor-mediated effects result in the modulation of both dopa-
minergic and glutamatergic signaling converging on striatal
MSNs.
With regard to the modulation of dopaminergic signaling,
CB1 receptors activation is tough to increase the firing rate
of dopaminergic neurons of the SNpc and to activate the
pool of G-proteins normally activated by D2 receptors [18-
20].
As far as it concerns the modulation of the glutamatergic
signaling system, an enhanced CB1 receptor signaling could
reduce glutamate release and facilitate the induction of spe-
cific forms of synaptic plasticity at cortico striatal synapses
[18-20,35], two events that might respectively counteract
glutamatergic over-activity and the loss of LTD that have
been demonstrated to occur in PD experimental models
[35,53,54].
On the other hand, some of the CB1-receptor-mediated
effects might also result in the worsening of PD motor symp-
toms. For example, some studies have shown the presence of
increased concentrations of 2-AG in the GPe in experimental
PD models, an event which may potentially result in PD
symptoms worsening [18,20].
As introduced above, involuntary movements, or dyski-
nesias, represent a debilitating complication of L-DOPA
therapy for PD that is experienced by most patients [1 ;2].
The molecular mechanisms underlying L-DOPA-induced
dyskinesia (LID) in PD are far from being elucidated, al-
though important advances have been made in recent years
[17]. LID development has been associated with several
events including pulsatile stimulation of dopamine receptors
[55], abnormalities in non-dopaminergic neurotransmitter
systems [56], changes in proteins and genes expression and
abnormalities in synaptic plasticity at corticostriatal synapses
[28,29].
In particular, with regard to this latter point, it has been
demonstrated that in the 6-OHDA model of PD the devel-
opment of LID is associated with the D1-dopamine receptor-
dependent loss of a particular form of neuroplasticity, named
“depotentiation” which is thought to be essential to re-
normalize synaptic weights after a synaptic potentiation and
to allow the deletion of unessential memory traces [28,29].
All these pathogenetic events result in a complex altera-
tion of the basal ganglia neuronal network, whose net result
would be the reduced inhibition of thalamocortical neurons
and the subsequent overactivation of cortical motor areas
[17].
Although studies on the status of CB1 receptors during
L-DOPA-induced dyskinesia have provided contrasting re-
sults [50,57], the weight of evidence seems to suggest that
LID, compared to dopamine depletion alone, is associated
with a reduction in CB1 receptor signaling in the striatum
[18].
In this case, it is possible to hypothesize that such altera-
tion in CB1-receptor signaling might actively contribute to
LID pathogenesis by enhancing both striatal glutamatergic
transmission and D1-dopamine-receptor signaling [18,20].
Moreover, the presence of a reduced CB1 receptor sig-
naling might be directly responsible of the loss of both corti-
costriatal ECB-dependent LTD and synaptic “depotentia-
tion” that have been described in experimental PD models
and that are thought to underlie neuronal network abnormali-
ties during this neurodegenerative disease [26,29,35,53].
According to this view, studies on the symptomatic ef-
fects of CB1 receptors agonists in rodent [58] and primate
[59] models have demonstrated beneficial effects of these
pharmacological compounds on LID [58,59].
The Endocannabinoid System in PD: Evidence from PD
Patients
The results of studies on the status of the ECB system in
PD patients seem to follow the same general trend observed
in animal models of the disease. Indeed, an increase in CB1
receptor binding has been found in the striatum of patients
suffering from PD as well as an increased efficacy of activa-
tion of the same receptor [50].
Moreover, in the cerebrospinal fluid of untreated PD pa-
tients increased levels of the endogenous cannabinoid AEA
have been demonstrated [60].
The results of a survey on frequency and patterns of can-
nabis use in PD patients have shown that, of 399 responders,
25 % had taken cannabis and 45.9 % of these patients re-
ported some benefits [61]. In particular, bradykinesia was the
symptom most commonly improved by cannabinoids, fol-
lowed by muscle rigidity and tremor [61]. In addition, 14%
of the patients reported alleviation of dyskinesias with can-
nabis use [61].
However, although in a pilot trial the cannabinoid recep-
tor agonist nabilone significantly reduced LID in PD patients
[62], a larger, randomized, double-blind, placebo-controlled
crossover trial showed that orally administered cannabis ex-
tract did not result in objective or subjective improvement in
dyskinesias or parkinsonism in PD patients [63].
An exploratory randomized, double-blind, placebo-
controlled study also analyzed the potential effects of CB1
receptor blockade in PD patients without showing an im-
provement in motor function or a reduction in LID [64].
The disappointing results of studies investigating the po-
tential therapeutic effects of compounds modulating the ECB
system in PD patients suggest the need for further research in
this field.
8 Current Pharmaceutical Design, 2008, Vol. 14, No. 00 Di Filippo et al.
The causes underlying the relative “failure” of these stud-
ies are probably different and might be related to the com-
plex neuroanatomy of the basal ganglia neuronal circuit.
It is possible to hypothesize, for example, that some of the
observed changes in ECBs and CB1 receptor levels could be
interpreted as beneficial, compensatory mechanisms, while
others might represent part of the pathogenetic process and,
in this context, the effect of a chronic dopamine replacement
therapy with L-DOPA further complicates the issue.
CONCLUSIONS AND FUTURE PERSPECTIVES
Many years ago L-DOPA, still the most effective therapy
for PD, was introduced. L-DOPA works optimally early in
the treatment of the disease, in the so-called “honeymoon
period” but, as the progression of PD advances (in ~5–10
years), the efficiency of the drug decreases over time and
many patients develop motor fluctuations (‘wearing-off’ and
‘on–off’ phenomena) and dyskinesias.
For this reason, th e research of a pharmacological com-
pound able to improve PD symptoms without directly modu-
lating the dopaminergic system is receiving increasing inter-
est from neurologists and neuroscientists.
Several neurotransmitter systems have been proposed as
potential targets for drug developing such as the glutamater-
gic, the serotoninergic or the opioid transmitter systems [4].
The ECB system could represent an ideal candidate as
therapeutic target in basal ganglia disorders and particularly
in PD. Indeed, its components are highly expressed in the
basal ganglia neural circuit and have been demonstrated to
control motor function during physiological conditions.
Moreover, the profound modifications occurring in ECB
signaling after dopamine depletion in PD experimental mod-
els and in PD patients suggest that the system is somehow
influenced by the PD-related pathological process.
Finally, the expression of CB2 receptors on immune cells
might allow the modulation of the neuroinflammatory proc-
esses that are known to accompany neuronal cell loss during
PD and for which a certain pathogenetic role has been sug-
gested.
The ideal pharmacological compound in the scenario
should be selective enough, to modulate, in the striatum, the
“ménage à trois” between ECBs, dopamine and glutamate,
allowing a physiological synaptic transmission and plasticity
onto MSNs without unbalancing the interaction between the
same signaling systems in other structures of the basal gan-
glia neural circuit.
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