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* School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom; Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, 80072, Arco Felice, Naples, Italy; and
Motac Neuroscience Ltd., Manchester MI3 9XX, U.K.
1Correspondence: J.B., 1.124 Stopford Building, School of Biological Sciences, University of Manchester, Oxford Rd, Manchester, M13 9PT, U.K. E-mail: j.brotchie{at}man.ac.uk and V.D.M., Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, Via Tolano 6, 80072 Arco Felice Naples, Italy. E-mail: vdimarzo{at}icmib.na.cnr.it
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Key Words: anandamide • 2-arachidonoyl glycerol • cannabinoids • dopamine • receptors
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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2
3)
, named ‘endocannabinoids’. These
molecules were suggested to have a neuromodulatory action (for a
review, see ref 4
), but to date there has been no clear
demonstration of a role for these endocannabinoids in controlling any
aspect of behavior.
The high levels of ‘central’ cannabinoid (CB1) receptors within the
basal ganglia (5)
suggest a potential role for
endocannabinoids in the control of voluntary movement and in basal
ganglia-related movement disorders such as Parkinson’s disease
(6
7
8)
. Within the basal ganglia, cannabinoid receptors
are particularly prominent on the terminals of GABAergic projections
from the striatum to the globus pallidus and substantia nigra pars
reticulata (the ‘indirect’ and ‘direct’ striatal output pathways,
respectively) (5)
. The interplay between activity in these
pathways is key to the selection and initiation of appropriate
voluntary movements and is tightly regulated by the dopaminergic
nigrostriatal system (9
, 10)
. Dopamine receptors exert
differential control of striatal outputs, D2-class dopamine receptors
inhibiting the activity of the indirect pathway while the direct
pathway is activated by D1-class dopamine receptors (11)
.
Stimulation of cannabinoid receptors in the globus pallidus, by
exogenous cannabinoid receptor agonists, reduces uptake of the
inhibitory neurotransmitter GABA (12
, 13)
and reduces
voluntary movements, producing Parkinson-like symptoms
(14)
. Stimulation of cannabinoid receptors also reduces
the anti-parkinsonian actions of D2, but not D1, dopamine receptor
agonists (15)
. It is possible, therefore, to hypothesize a
role for endocannabinoids in the modulation of signaling by the
indirect striatal output.
In this study, we have measured the levels and distribution of
anandamide and 2-AG in rat brain by using a highly sensitive and
specific isotope dilution gas chromatography-mass spectrometric (GC-MS)
method (16)
. Furthermore, we have compared endocannabinoid
levels in different brain regions of vehicle-treated or
reserpine-treated rats, a widely used animal model of Parkinson’s
disease, in the presence or absence of dopamine receptor agonists. We
provide evidence suggesting that changes in endocannabinoid signaling
in the globus pallidus of the reserpine-treated rat correlate with the
modulation of voluntary movement in this model.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Tissue dissection, extraction, and endocannabinoid level
measurement
Anandamide and 2-AG in lipid extracts from different brain
regions were quantitated following the isotope dilution GC-MS procedure
described previously (16)
. Briefly, brain areas from eight
rats belonging to each different group of treatments were dissected,
pooled, and frozen in liquid nitrogen in the Manchester laboratory. A
maximum of 3 min elapsed between tissue dissection and freezing. The
frozen tissue was sent on dry ice to the Naples laboratory, stored at
-80°C, and weighed prior to its extraction with 3 volumes of
chloroform/methanol/Tris-HCI 50 mM buffer (pH 7.4) (2: 1: 1 by vol).
The extraction mixture contained 2 nmol each of
d8-anandamide and d8-2-AG
synthesized from d8 arachidonic acid and
ethanolamine or glycerol, as described previously (1
, 22)
.
The two phases were separated and the aqueous phase extracted three
more times with an equal volume of chloroform. The pooled organic
phases were dried down in a rotating evaporator, transferred to
siliconized vials, and purified by normal phase-high pressure liquid
chromatography (NP-HPLC) carried out as described previously
(22)
. Monoarachidonoylglycerols and anandamide standards
were eluted after 18–23 min and 27–28 min, respectively. The
mono-arachidonoylglycerol HPLC fraction contained both 1-
(3)
and 2-stereoisomers. HPLC fractions were dried down
under a flow of nitrogen and derivatized with 15 µl
N-methyl-N-tris-methyl-sylyl-trifluoroacetamide containing 1%
trimethylchlorosylane for 2 h at room temperature, thus yielding
the tris-methyl-sylyl derivatives of anandamide and 2-AG. The two
derivatized fractions were analyzed separately by GC-MS carried out as
described previously (16
, 22)
. The tris-methyl-sylyl
ethers of both deuterated and nondeuterated anandamide, 2-AG and 1-
(3)
arachidonoylglycerol standards were eluted after
~18, 19, and 19.5 min, respectively. MS detection was run in the
selected ion monitoring mode to improve sensitivity. Selected ions for
anandamide were at m/z = 427 and 419, corresponding to
the molecular ions of d8-anandamide and
nondeuterated anandamide, and m/z = 412 and 404,
corresponding to the loss of a methyl group in both compounds. Selected
ions for 2-AG were at m/z = 530 and 522, corresponding
to the molecular ions of d8-2-AG, and
nondeuterated 2 AG and m/z = 515 and 507, corresponding
to the loss of a methyl group in both compounds. The endogenous
cannabinoids were identified on the basis of the presence, at the same
retention time as the deuterated internal standards, of the
corresponding MS signals with the appropriate relative abundance. The
amounts of anandamide and 2-AG were calculated from the peak area
ratios between the signals at m/z = 404 and 412, and
m/z = 507 and 515, respectively. A linear correlation
between these area ratios and the amounts of anandamide (25–10000
pmol) or 2-AG (50–10000 pmol) standards was observed in separate
studies. In the case of 2-AG, the amounts of the 1- (3)
isomers, which are almost exclusively formed during tissue workup and
lipid purification (23)
and were 25–30% of the total
monoarachidonoylglycerols, were added to the amounts of the 2-isomer.
Each brain region in each group of animals was analyzed in
quadruplicate. Measurements in each monoplicate were carried out in
duplicate. Results are expressed in pmol/g wet tissue weight and are
means ± SEM of the four separate
determinations. Means from different groups were compared by using
1-way ANOVA, followed by Tukey-Kramer analysis. It can be estimated
that 96 different samples (six brain regions in four different groups
of treatments, each in quadruplicate, each from eight rats) had to be
extracted, purified, and analyzed in the present study.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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to measure the levels and distribution of the
endocannabinoids anandamide and 2-AG in the brain of vehicle-treated
Sprague Dawley rats (Fig. 1
). Anandamide levels were similar in striatum, cerebral cortex,
cerebellum, and hippocampus and the values reported here are similar to
those previously described for these regions (16
, 17)
.
Although cannabinoid receptors are expressed at high levels within the
globus pallidus and substantia nigra, the levels of endocannabinoids
within these important motor regions have not previously been reported.
The levels of 2AG in these two regions were similar to other brain
regions and generally lower than those previously observed in Wistar
rat brain (16)
. However, the levels of anandamide in the
globus pallidus and substantia nigra were ~threefold higher than
those previously reported in any brain region (Fig. 1B
). In
the globus pallidus this difference was statistically significant
(P<0.05). These data further support the speculation
(12
13
14)
that endocannabinoids may play a key role in the
functioning of the striatal outputs in the control of movement.
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To investigate this potential role of endocannabinoids in motor
control, we have used the reserpine-treated rat as a model system in
which the initiation and execution of movements can easily be assessed
and manipulated. In this model, catecholamine stores are depleted and a
motor syndrome characterized by decreased initiation and speed of
voluntary movements, rigidity, and a hunched posture is observed
(18)
. These symptoms bear many similarities to those seen
in Parkinson’s disease (19)
and are ameliorated by
dopaminergic anti-parkinsonian drugs (18
19
20
21)
. Thus, the
reserpine-treated rodent provides a useful model of Parkinson’s
disease; indeed, it was in this model that the key role of decreased
dopamine transmission in parkinsonism was identified and the
therapeutic potential of dopamine replacement therapy in Parkinson’s
disease first highlighted (19)
. Other currently used
animal models of this disorder, e.g., the 6-hydroxy-dopamine (6-OHDA)
-lesioned rat or the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) -lesioned monkey were not utilized in this study for two
different reasons: 1) although more selective than reserpine
for the depletion of dopamine stores, 6-OHDA-induced lesions do not
lead to overt symptoms of Parkinson’s disease, an important point for
our study aimed at finding a possible correlation between these
symptoms and endocannabinoid levels; 2) it was estimated
that at least 72 MPTP-lesioned monkeys would have been necessary to
carry out a study with equivalent statistical rigor as the present one.
After treatment of rats with reserpine, locomotion was dramatically
reduced (locomotor activity in vehicle-treated rats was 1251±228
mobile counts/h compared to 9±2 in reserpine-treated rats,
P<0.001, t test, n=12) as has been
previously described. In association with this decreased locomotion, a
sevenfold elevation in the levels of 2AG in the globus pallidus was
observed (Fig. 1)
. Although average 2AG levels increased slightly in
all the other brain regions analyzed, this effect was never as marked
as in the globus pallidus (e.g., a 2.5-fold stimulation was found in
striatum) and was never statistically significant. There was no
statistically significant reserpine-induced change in the levels of
anandamide in any brain region. These data highlight the fact that
catecholamines play an important role in the inhibitory regulation of
2AG synthesis in the globus pallidus. The most likely mechanism
underlying such an effect would be an action of dopamine on the
striatal neurons projecting to the globus pallidus. In situations of
decreased dopamine transmission, the activity of the indirect striatal
output pathway is increased (9)
. Increased depolarization
of striatopallidal terminals after reserpine treatment may enhance 2AG
synthesis, as depolarization has been shown to elevate 2AG levels in
other cells (22
, 23)
. The mechanism underlying this
depolarization-induced increase in 2AG levels involves activation of
calcium-dependent enzymes such as phospholipase C (23
, 24)
, phosphatidic acid phosphohydrolase, and phospholipase
A2 (25)
. The functional relevance of
this enhanced endocannabinoid synthesis in the globus pallidus may be
great, since (as described above) activation of cannabinoid receptors
in the globus pallidus by exogenous agonists has been shown to elicit
parkinsonian symptoms (14)
. Thus, enhanced 2AG signaling
in the globus pallidus might be part of the neural mechanisms
underlying hypokinesia in the reserpine-treated rat.
These data also underscore the complexity by which endocannabinoid
levels might be regulated in vivo. Thus, catecholamines
appear to regulate 2AG levels differentially in different populations
of striatal output neurons (levels in the substantia nigra, the target
of the direct striatal output pathway, were not significantly elevated)
whereas different endocannabinoids are regulated differentially within
a given region (pallidal anandamide levels were not elevated after
reserpine treatment). The lack of effect on anandamide levels may be
due to the fact that there is high endocannabinoid tone at rest in the
globus pallidus and the basal amounts of anandamide actually represent
the maximal level of synthesis possible in this structure. As
anandamide levels are elevated by neuronal depolarization
(26)
, this would suggest that basal firing rate in the
indirect striatal output pathway is sufficient to maximally stimulate
anandamide synthesis. During the early preparation of this paper,
Giuffrida et al. (27)
reported that anandamide, but not
2AG, is released into microdialysates from the dorsal striatum of
freely moving rats. In a previous study (23)
the same
authors found that 2-AG, but not anandamide, could be produced by
electrically stimulated hippocampal slices. These reports point to the
possible differential regulation of different endocannabinoids in
different brain regions.
Administration of the D2 dopamine receptor agonist quinpirole (0.1
mg/kg) to reserpine-treated rats reduced 2AG and anandamide levels in
the globus pallidus (Fig. 2
). Anandamide levels were reduced by 75% whereas 2AG levels were
reduced by 53%. These falls in anandamide and 2AG levels were
accompanied by increased locomotion in reserpine-treated rats
(Fig. 3
).Quinpirole did not significantly alter 2AG or
anandamide levels in any other region of the brain (data not shown).
The reduction in pallidal 2AG and anandamide levels accompanying
alleviation of parkinsonian symptoms by the D2 dopamine receptor
agonist is further suggestive of a causative role for enhanced
endocannabinoid signaling in the indirect pathway in parkinsonism.
Indeed, stimulation of D2 receptors alleviates parkinsonism by reducing
the activity of the indirect striatal output pathway (28)
.
The reduction in 2AG and anandamide levels may be due to this reduction
in activity and, in the case of 2AG, reflect reversal of the
depolarization-induced activation of calcium-dependent enzymes
described above; anandamide levels have also been shown to be
maintained by depolarization (26)
. It is worthwhile
mentioning that infusion with quinpirole was recently shown to enhance
anandamide release from the dorsal striatum of normal rats
(27)
. The authors presented no evidence to show that
endogenous dopamine tonically increases anandamide release from the
striatum, and we found here no decrease in anandamide levels in the
striatum of catecholamine-depleted rats (Fig. 1B
). However,
this report, taken together with our present data, may suggest that in
different regions of the basal ganglia, and under different conditions,
stimulation of D2 dopamine receptors may have opposing consequences on
endocannabinoid biosynthesis.
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Administration of the D1 dopamine receptor agonist Cl-APB (0.1 mg/kg)
was also accompanied by a reduction in endocannabinoid levels in the
globus pallidus (Fig. 2)
and an increase in locomotion (Fig. 3)
.
Whether this reduction in endocannabinoid levels in the globus pallidus
could be responsible for the anti-parkinsonian actions of Cl-APB is
unclear since the anti-parkinsonian actions of D1 receptor stimulation
are mediated through activation of the direct, rather than indirect,
striatal output pathway (28)
. However, basal ganglia
outputs to the thalamus are a vital link in basal
ganglia-thalamo-cortical-basal ganglia loops, the cortical components
of which impinge directly onto striatal output neurons
(10)
. Therefore, activation of the direct pathway might
indirectly lead to decreased excitation of the indirect striatopallidal
pathway that (as described above) would be expected to reduce levels of
endocannabinoids in the globus pallidus. In this case, the reversal in
abnormalities in endocannabinoid transmission in the globus pallidus
induced by Cl-APB might be a consequence of an anti-parkinsonian action
resulting from normalization of abnormalities in the direct pathway. In
any event, these data, taken together, point to a clear reverse
correlation in reserpine-treated rats between locomotion and
endocannabinoid levels in the globus pallidus.
To address further the issue of whether the anti-parkinsonian
actions of dopamine receptor stimulation are mediated through a
reduction in endocannabinoid signaling, we assessed the behavioral
effects of treatment of reserpinized rats with quinpirole and the
selective antagonist of CB1 receptors, SR141716A (29)
.
SR141716A markedly potentiated the ability of the D2 dopamine receptor
agonist to elicit locomotion in the reserpine-treated rat (Fig. 3)
.
This finding strongly suggests that endocannabinoids counteract the
ability of D2 receptor stimulation to elicit locomotion and might be
responsible, in part at least, for the abnormalities in the indirect
pathway that underlie the generation of parkinsonian symptoms.
SR141716A had no significant effect on locomotion induced by the D1
agonist Cl-APB (Fig. 3)
. This suggests that the reduction in 2AG levels
brought about by Cl-APB (and the subsequent stimulation of the direct
striatal output pathway) is indeed a consequence rather than a cause of
its anti-parkinsonian action, as suggested above. The lack of effect of
SR141716A on D1 agonist-induced locomotion and the finding that
SR141716A has no effect on locomotion in non-parkinsonian animals (data
not shown) also suggest that it is unlikely that the effects of
SR141716A in enhancing D2 agonist-mediated locomotion are due to a
nonspecific increase in locomotion or to the proposed inverse agonist
properties of this compound (30)
. Furthermore, our
findings with SR141716A and quinpirole in the reserpine-treated rat are
in agreement with an analogous enhancement by the CB1 antagonist of
quinpirole-induced locomotion in normal rats reported early during the
preparation of this manuscript (27)
.
Our data show that reducing not only the levels, but also the action,
of endocannabinoids in the globus pallidus may lead to enhanced
locomotion in the reserpine-treated rat. These findings, therefore,
suggest that the selection, initiation, and execution of movement by
stimulation of the GABAergic indirect striatal output pathway, in the
parkinsonian brain at least, may be under a negative control by
endocannabinoids. Enhanced pallidal GABAergic transmission is a key
component of the neural mechanisms underlying the symptoms of
parkinsonism (9)
. Stimulation of cannabinoid receptors on
terminals of the indirect pathway reduces GABA reuptake (12
, 13)
, thereby enhancing GABA transmission in the globus pallidus.
Enhanced endocannabinoid signaling in the globus pallidus would thus
elicit parkinsonian symptoms.
In conclusion, high levels of endocannabinoids are found in regions of
the basal ganglia receiving input from the striatum. Endocannabinoids
and dopamine may have a close functional relationship whereby, under
physiological conditions, dopamine acts to suppress 2AG signaling in
the globus pallidus while endocannabinoids act as a ‘brake’ on
dopamine-receptor-stimulated locomotion in this as well as other areas
of the basal ganglia (see also ref 27
). Overactivation of
the endocannabinoid system in the globus pallidus may play a part in
the generation of parkinsonian symptoms. We suggest that
endocannabinoids provide a neurochemical substrate for the interactions
between transmitter systems that are, according to current thinking,
fundamental to the appropriate selection and initiation of voluntary
movements. Our findings may help to identify novel avenues of
therapeutic intervention in Parkinson’s disease
(31)
.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication August 20, 1999.
Revision received November 5, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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-aminobutyric acid uptake in the globus pallidus. Eur. J. Pharmacol. 308,161-164[Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and after induction of
hypokinesia by reserpine treatment (
). Data are presented as
mean ± SEM of 4 separate experiments each with
samples from 8 individual animals. ***P<0.001 compared
to vehicle by 1-way ANOVA with post hoc Tukey-Kramer
test. Abbreviations, SNr, substantia nigra pars reticulata; GP, globus
pallidus.
), the D2 dopamine receptor agonist quinpirole (0.1 mg/kg)
alone (