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The Endocannabinoid System in Parkinsons Disease

Authors:
  • Università Telematica San Raffaele Roma
  • Università Telematica San Raffaele Roma

Abstract and Figures

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 particular, at synapses linking cortical and striatal neurons, endocannabinoids (ECBs) are known to critically modulate synaptic 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 suffering from the disease, provide support for the development of pharmacological compounds targeting the ECB system as symptomatic and neuroprotective therapeutic strategies for PD.
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 neurons (MSNs) that provide the sole striatal output. According to a classical model, D1 and D2 dopamine receptors are thought to be segregated 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 neurons of the indirect pathway. The output nuclei (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 excessive 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, internal segment of the globus pallidus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleus.
… 
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 corticostriatal excitatory glutamatergic terminals and in excitatory 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. Conversely , in the GPe, activation of presynaptic CB1 receptors may increase local GABA levels by reducing GABA reuptake from striatal afferents 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 Gproteins , suggesting the convergence of their signal transduction mechanisms. CB1 receptors activation seems also to decrease GABA release 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.
… 
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 ++ ) elevation , 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, dopamine; 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.
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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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10.
... During demonstration on both experimental and patient models of PD, it has been observed that neuroinflammation is a ubiquitous process. Besides the enormous loss of dopaminergic neuronal cells, it also manifests a prominent reaction of glial cells along with the neuroinflammatory responses shown by upgraded levels of cytokine and inflammatory-associated factors, considering here the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as it is depicted in Figure 3 [127]. . Probable mechanisms to demonstrate the neuroprotective action of cannabinoids in PD independent of CB-1R. ...
... Thus, it is persuadable that CBs may affect the survival of neurons and conserve various regulatory synaptic functions during PD acting through CB1 receptor at "immune" CB2 receptor and "neuronal" receptors, delineating the strong pharmacological action to effect simultaneously, both synaptic and immune functions within CNS borders [127]. Altogether, the past and latest data encouraged the concept of the significant role of the endocannabinoid signalling in the motor control system [128,129]. ...
... In general, several studies indicate parkinsonism to be correlated with ECS signalling overactivity in the striatum, potentially delineating an endogenous compensatory mechanism that reflects a possible effort to stabilize striatal function subsequent to DA depletion. Afterwards, it was shown that ECS modulation could enhance parkinsonian symptoms in rodents as well as in primate PD experimental models [127]. In fact, in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) marmoset PD model, there is an increase in the number of striatal CB1 receptors along with enhanced CB1 receptor G-protein coupling [150]. ...
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Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.
... The primary target of therapies in management of the disease include replacement of dopamine for symptomatic control and no treatments are available that directly slow down the progression of degeneration in the nigral region. The pathology of Parkinson's disease includes hyper functionality of the cannabinoid receptors [104]. The levels of anandamide were detected to be almost double in the cerebrospinal fluid of an untreated patient with Parkinson's disease in comparison to healthy individuals, independent of the stage of disease, concentration of drug, or range of symptoms experienced by the patient [105]. ...
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Over the last 25 years, the human endocannabinoid system (ECS) has come into the limelight as an imperative neuro-modulatory system. It is mainly comprised of endogenous cannabinoid (endocannabinoid), cannabinoid receptors and the associated enzymes accountable for its synthesis and deterioration. The ECS plays a proven role in the management of several neurological, cardio-vascular, immunological, and other relevant chronic conditions. Endocannabinoid or endogenous cannabinoid are endogenous lipid molecules which connect with cannabinoid receptors and impose a fashionable impact on the behavior and physiological processes of the individual. Arachidonoyl ethanolamide or Anandamide and 2-arachidonoyl glycerol or 2-AG were the endocannabinoid molecules that were first characterized and discovered. The presence of lipid membranes in the precursor molecules is the characteristic feature of endocannabinoids. The endocannabinoids are released upon rapid enzymatic reactions into the extracellular space via activation through G-protein coupled receptors, which is contradictory to other neurotransmitter that are synthesized beforehand, and stock up into the synaptic vesicles. The current review highlights the functioning, synthesis, and degradation of endocannabinoid, and explains its functioning in biological systems.
... Cannabinoids are transported to the synaptic gap and bind to CB1 receptors on the presynaptic membrane, leading to depolarization-induced de-excitation, which then induces eCB-LTD (Cerovic et al., 2013; Figure 2A). In support of the above, the LTD between MSN synapses in the indirect pathway was abolished in the experimental model of PD (Di Filippo et al., 2008;Pisani et al., 2011). This deficit can be restored using D2 dopamine receptor agonists such as quinpirole or URB597, an inhibitor of FAAH (Kreitzer and Malenka, 2007). ...
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Parkinson’s disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.
... b. the Fatty-Acids-Amino-Hydrolase (FAAH) C385A polymorphism (rs324420) responsible for endocannabinoids (eCBs) degradation is not significantly different between hypnotizability groups but the polymorphism frequencies indicate a trend to higher degradation efficiency from lows to highs (Presciuttini et al., 2020). We may hypothesize that small differences in the eCBs content could be amplified by the eCBs interactions with nor-adrenegic (Scavone et al., 2013) and dopaminergic pathways (Di Filippo et al., 2008). Thus, a contribution of the FAAH polymorphism to the highs' ability to control pain by suggestions for analgesia should not be excluded. ...
... Components of the ECS are abundantly expressed in the basal ganglia and interact with glutamatergic, γ-aminobutyric acid-ergic (GABAergic), and dopaminergic neurotransmitter systems, suggesting therapeutic potential in PD [185,[218][219][220][221][222][223][224][225][226][227][228]. Endocannabinoid receptors are particularly vital in PD because both CB1R and D1/D2-like receptors are colocalized in striatal neurons [229]. ...
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Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
... The main biochemical pathology is the significant degeneration and loss of dopaminergic neurons in the substantia nigra and a significant decrease in the dopamine concentration in the striatum accompanied by dysfunction of the basal ganglia [68], a region that is a crucial regulator of motor activity affected by PD. CB1 receptors are highly distributed in the basal ganglia [69] and exert complex regulatory effects on some important neurotransmitters, playing a role in anti-excitatory neural toxicity [70] and neuroprotection. Clinical observations have reported that the degeneration of dopaminergic neurons is accompanied by increased endocannabinoid system activity, and endocannabinoid system dysfunction is observed in both PD patients and experimental animal models. ...
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The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.
... In fact, noradrenergic and eCBs pathways converge onto several brain regionsthe nucleus accumbens, the locus coeruleus, the nucleus of solitary tract, and the medial prefrontal cortexand the modulation of the activity of eCBs receptors CB1 alters the indices of nor-adrenergic activity (Scavone, Sterling, & Van Bockstaele, 2013). Moreover, in the basal ganglia circuits eCBs interact with dopaminergic pathways (Di Filippo et al., 2008). Another candidate to account for suggestion-induced analgesia is the oxytocin (OXT) released in the brain and possibly modulating the sensory and emotional components of pain (Poisbeau, Grinevich, & Charlet, 2018). ...
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Fatty acid amide hydrolase (FAAH) degrades the endogenous endocannabinoid (eCB) anandamide and might be involved in the response to suggestions of analgesia in subjects with high hypnotizability scores (highs). Since the A allele of the FAAH C385A polymorphism (rs324420) is associated with lower FAAH activity, it was studied in 21 highs, 66 low hypnotizable individuals (lows), and 172 individuals not selected for hypnotizability (controls) representing the general population. No significant difference was observed among groups, but the A allele frequency showed a significant trend to increase from lows to controls and from controls to highs. Since eCB small differences can be amplified by eCB interactions with other neurotransmitters, a contribution of the FAAH polymorphism to the highs’ analgesia should not be excluded.
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l-Dopa-induced dyskinesias (LIDs) are a frequent complication in l-dopa-treated patients affected by Parkinson's disease (PD). In the last years, several progresses in the knowledge of LIDs mechanisms have led to the identification of several molecular and electrophysiologic events. A complex cascade of intracellular events underlies the pathophysiology of LIDs, and, among these, aberrant plasticity in the cortico-basal ganglia system, at striatal and cortical level, plays a key role. Furthermore, several recent studies have investigated genetic susceptibility and epigenetic modifications in LIDs pathophysiology that might have future relevance in clinical practice and pharmacologic research. These progresses might lead to the development of specific strategies not only to treat, but also to prevent or delay the development of LIDs in PD.
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Parkinson’s Disease (PD) is currently the most rapid growing neurodegenerative disease and over the past generation, its global burden has more than doubled. The onset of PD can arise due to environmental, sporadic or genetic factors. Nevertheless, most PD cases have an unknown etiology. Chemicals, such as the anthropogenic pollutant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amphetamine-type stimulants, have been associated with the onset of PD. Conversely, cannabinoids have been associated with the treatment of the symptoms’. PD and medical cannabis is currently under the spotlight, and research to find its benefits on PD is on-going worldwide. However, the described clinical applications and safety of pharmacotherapy with cannabis products are yet to be fully supported by scientific evidence. Furthermore, the novel psychoactive substances are currently a popular alternative to classical drugs of abuse, representing an unknown health hazard for young adults who may develop PD later in their lifetime. This review addresses the neurotoxic and neuroprotective impact of illicit substance consumption in PD, presenting clinical evidence and molecular and cellular mechanisms of this association. This research area is utterly important for contemporary society since illicit drugs’ legalization is under discussion which may have consequences both for the onset of PD and for the treatment of its symptoms.
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The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
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The effect of tetanic activation of corticostriatal glutamatergic fibers was studied in striatal slices by utilizing extracellular and intracellular recording techniques. Tetanic stimulation produced a long-term synaptic depression (LTD) (> 2 h) of both extracellularly recorded field potentials and intracellularly recorded EPSPs. LTD was not coupled with changes of intrinsic membrane properties of the recorded neurons. In some neurons, repetitive cortical activation produced a short-term posttetanic potentiation (1-3 min). Subthreshold tetanic stimulation, which under control condition did not cause LTD, induced LTD when associated with membrane depolarization. Moreover, LTD was not expressed in cells in which the conditioning tetanus was coupled with hyperpolarization of the membrane. Bath application of aminophosphonovalerate (30-50 microM), an antagonist of NMDA receptors, did not affect the amplitude of the synaptic potentials and the expression of LTD. Striatal LTD was significantly reduced by the pretreatment of the slices with 30 microM 2-amino-3-phosphonopropionic acid, an antagonist of glutamate metabotropic receptors. LTD was not blocked by bicuculline (30 microM), a GABA(A) receptor antagonist. Scopolamine (3 microM), an antagonist of muscarinic receptors, induced a slight, but significant, increase of the amplitude of LTD. Both SCH 23390 (3 microM), an antagonist of D1 dopamine (DA) receptors, and I-sulpiride (1 microM), an antagonist of D2 DA receptors, blocked LTD. LTD was also absent in slices obtained from rats in which the nigrostriatal DA system was lesioned by unilateral nigral injection of 6-hydroxydopamine. In DA-depleted slices, LTD could be restored by applying exogenous DA (30 microM) before the conditioning tetanus. In DA-depleted slices, LTD could also be restored by coadministration of SKF 38393 (3-10 microM), a D1 receptor agonist, and of LY 171555 (1-3 microM), a D2 receptor agonist. Application of a single class of DA receptor agonists failed to restore LTD. These data show that striatal LTD requires three main physiological and pharmacological conditions: (1) membrane depolarization and action potential discharge of the postsynaptic cell during the conditioning tetanus, (2) activation of glutamate metabotropic receptors, and (3) coactivation of D1 and D2 DA receptors. Striatal LTD may alter the output signals from the striatum to the other structures of the basal ganglia. This form of synaptic plasticity can influence the striatal control of motor activity.
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Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
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ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors1–4, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phos-phodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others5,6indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger.
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An anonymous questionnaire sent to all patients attending the Prague Movement Disorder Centre revealed that 25% of 339 respondents had taken cannabis and 45.9% of these described some form of benefit. © 2004 Movement Disorder Society
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
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Two proteins with seven transmembrane-spanning domains typical of guanosine-nucleotide-binding-protein-coupled receptors have been identified as cannabinoid receptors; the central cannabinoid receptor, CB1, and the peripheral cannabinoid receptor, CB2, initially described in rat brain and spleen, respectively. Here, we report the distribution patterns for both CB1 and CB2 transcripts in human immune cells and in several human tissues, as analysed using a highly sensitive and quantitative PCR-based method. CB1 was mainly expressed in the central nervous system and, to a lower extent, in several peripheral tissues such as adrenal gland, heart, lung, prostate, uterus, ovary, testis, bone marrow, thymus and tonsils. In contrast, the CB2 gene, which is not expressed in the brain, was particularly abundant in immune tissues, with an expression level 10-100-fold higher than that of CB1. Although CB2 mRNA was also detected in some other peripheral tissues, its level remained very low. In spleen and tonsils, the CB2 mRNA content was equivalent to that of CB1 mRNA in the central nervous system. Among the main human blood cell subpopulations, the distribution pattern of the CB2 mRNA displayed important variations. The rank order of CB2 mRNA levels in these cells was B-cells > natural killer cells > monocytes > polymorphonuclear neutrophil cells > T8 cells > T4 cells. The same rank order was also established in human cell lines belonging to the myeloid, monocytic and lymphoid lineages. The prevailing expression of the CB2 gene in immune tissues was confirmed by Northern-blot analysis. In addition, the expression of the CB2 protein was demonstrated by an immunohistological analysis performed on tonsil sections using specific anti-(human CB2) IgG; this experiment showed that CB2 expression was restricted to B-lymphocyte-enriched areas of the mantle of secondary lymphoid follicles. These results suggest that (a) CB1 and CB2 can be considered as tissue-selective antigens of the central nervous system and immune system, respectively, and (b) cannabinoids may exert specific receptor-mediated actions on the immune system through the CB2 receptor.