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NEUROPHARMACOLOGY
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
Received May 9, 2003; accepted June 2, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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). Anandamide is synthesized by sequential activities of an
N-acyltransferase and phospholipase D, whereas 2-AG is synthesized by
phospholipase C-mediated cleavage of phosphatidylinositol bis-phosphate,
generation of diacylglycerol, and the subsequent activity of a diacylglycerol
lipase. The effects of anandamide and 2-AG are terminated via degradation by
fatty acid amide hydrolase and monoglyceride lipase, respectively
(Cravatt et al., 2001;
Dinh et al., 2002). Several in
vitro studies suggest that endocannabinoids serve as activity-dependent
retrograde inhibitors of neurotransmitter release within the striatum and
prefrontal cortex (Auclair et al.,
2000; Gerdeman et al.,
2002; Robbe et al.,
2002). According to this hypothesis, endocannabinoids are produced
by postsynaptic cells (striatal medium spiny neurons and cortical pyramidal
neurons) in response to glutamate receptor activation. Endocannabinoids then
activate presynaptic CB1 receptors, which function to inhibit further
glutamate release (Gerdeman and Lovinger,
2001; Huang et al.,
2001).
Dopaminergic transmission within the limbic forebrain contributes to
optimal cognitive function, psychomotor control, and the expression of
motivated behavior (Braver and Barch,
2002; Salamone et al.,
2003). An essential function of dopaminergic transmission is to
enhance the signal-to-noise ratio of information processing via modulation of
cortical and striatal glutamatergic transmission and the responsivity of
postsynaptic neurons to glutamatergic inputs
(Horvitz, 2002;
O'Donnell, 2003). Although the
precise molecular mechanisms by which this function is expressed remain
controversial, studies suggest that activation of D1 family (D1 and D5)
receptors decreases the responsivity of striatal GABAergic and cortical
pyramidal neurons to non-N-methyl D-aspartate (NMDA)
receptor activation, while enhancing signaling through NMDA receptors
(Cepeda et al., 1993;
Seamans et al., 2001;
Wang and O'Donnell, 2001).
Such a mechanism has been suggested to facilitate strong, sustained, and
highly efficacious synaptic activity that results from NMDA receptor
activation, while decreasing the effects of weak and transient
non-NMDA-mediated depolarization (Seamans
et al., 2001). Activation of D2 family (D2, D3, and D4) receptors
located postsynaptically is associated with either a decrease or no effect on
NMDA and non-NMDA receptor responsivity
(Cepeda et al., 1993;
Cepeda and Levine, 1998).
However, evidence suggests that DA inhibits glutamate release via activation
of presynaptic D2 heteroceptors on cortico-striatal glutamatergic afferents
(Hsu et al., 1995);
consequently, D2 receptor knockout mice exhibit increased striatal
glutamatergic transmission (Cepeda et al.,
2001).
Therefore, because dopaminergic activity seems to negatively modulate the
overall response of striatal and prefrontal cortical neurons to glutamatergic
input (Kiyatkin and Rebec,
1999; Seamans et al.,
2001; Horvitz,
2002; O'Donnell,
2003), and glutamatergic input is likely an important activator of
endocannabinoid synthesis in the limbic forebrain, we have tested the
hypothesis that increased dopaminergic tone results in decreased
endocannabinoid content in mouse limbic forebrain. There is support for this
hypothesis from other laboratories. In one study, lesioning of dopaminergic
neurons with 6-hydroxy dopamine was found to produce a 3-fold increase in
anandamide, but not 2-AG, content within the striatum
(Gubellini et al., 2002). This
increase was reversed when dopamine was restored by chronic L-DOPA
treatment (Maccarrone et al.,
2003). It has also been reported that monoamine depletion by
reserpine results in a 2.5-fold increase in both anandamide and 2-AG content
within the striatum (Di Marzo et al.,
2000b). In addition, Giuffrida et al.
(1999) demonstrated that local
infusion of the D2 receptor agonist quinpirole increased anandamide outflow
within the dorsal striatum, whereas no 2-AG was detected in dialysate samples
(Giuffrida et al., 1999).
Because activation of D2 autoreceptors inhibits release of dopamine
(Mottola et al., 2002), these
data are consistent with the hypothesis that decreased dopaminergic
transmission increases endocannabinoid content within forebrain regions that
receive dopaminergic innervation.
We have investigated the effects of acute regulation of dopamine tone on limbic forebrain anandamide and 2-AG content. We report that basal dopaminergic transmission exerts a net inhibition of both anandamide and 2-AG content via activation of D1 and D2 receptors, respectively. In addition, augmentation of dopaminergic transmission decreases both anandamide and 2-AG content. These data shed new light on the dopaminergic modulation of endocannabinoid signaling and suggest the possibility of functionally separate anandamide and 2-AG endocannabinoid systems within the limbic forebrain.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Tissue Preparation for Endocannabinoid Quantification. Animals were acclimated to the testing room for 24 h before experimentation. Animals were treated with vehicle or drugs and sacrificed by decapitation at given times after drug administration. Control animals would often sleep during the experiments but were awakened by removal of the cage cover 10 to 15 min before sacrifice to ensure drug-induced changes in endocannabinoid (EC) contents were compared with contents within awake animals. Upon sacrifice, brains were removed and limbic forebrain region (all tissue anterior to bregma +1.0, excluding the olfactory bulbs) dissected and frozen on dry ice 2 min after decapitation. Tissue was stored at -80°C until extraction. Tissue samples were weighed and placed into borosilicate glass culture tubes containing 2 ml of acetonitrile with 84 pmol of [2H8]anandamide and 186 pmol of [2H8]2-AG for extraction. Tissue was homogenized with a glass rod and sonicated for 2 h. Samples were incubated overnight at -10°C to precipitate proteins. Samples were centrifuged at 1,500g, and supernatants were removed to a new glass tube and evaporated to dryness under N2 gas. The samples were resuspended in 500 µl of methanol to recapture any lipids adhering to the glass tube, and dried again. Finally, lipid extracts were suspended in 20 µl of methanol, 5 µl of which was used for analysis by liquid chromatography/mass spectrometry.
Liquid Chromatography/Mass Spectrometry. The amounts of anandamide
and 2-AG were determined by liquid chromatography-atmospheric pressure
chemical ionization-mass spectrometry (1100 LC-MSD, SL model; Agilent
Technologies Inc., Wilmington, DE). Samples (5 µl) were separated on a
reverse-phase C18 column (Kromasil, 250 x 2 mm, 5-µm
diameter) using mobile phase A (deionized water, 1 mM ammonium acetate, and
0.005% acetic acid) and mobile phase B (methanol, 1 mM ammonium acetate, and
0.005% acetic acid). Samples were eluted at a flow rate of 300 µl/min by a
linear gradient. The percentage of solvent B increased linearly from 85%
solvent B to 100% solvent B in 25 min then held at 100% solvent B for 10 min.
Over the next 10 min, solvent B decreased linearly from 100 to 85% and was
held at 85% for an additional 10 min. Detection was made in a positive ion
mode. Selective ion monitoring was used to detect
[2H8]anandamide (m/z 356; retention
time = 13.7 min), anandamide (m/z 348; retention time = 13.9
min), [2H8]2-AG and 1(3)-AG (m/z 387;
retention times = 14.3 and 15.1 min, respectively), and 2-AG and 1(3)-AG
(m/z 379; retention times = 14.5 and 15.3 min,
respectively). 2-AG is usually observed as a doublet because it isomerizes to
1(3)-AG during extraction (Stella et al.,
1997), the area of both peaks were combined to yield total 2-AG.
Endocannabinoid contents were normalized to wet tissue weight.
Statistical Analysis. Differences in the mean endocannabinoid content between treatment groups were determined by one-way analysis of variance followed by post hoc Dunnett's or Bonferonni's test as indicated. Data are presented as percentage of control endocannabinoid content (n = 5 animals/group throughout). A p < 0.05 was considered significant throughout.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Wang et al.,
2003). In vehicle-treated mice, anandamide and 2-AG were both
easily detected within the limbic forebrain; a representative chromatograph
depicting the presence of deuterated standards and endogenous anandamide and
2-AG from this region is shown (Fig.
1). The mean values (± S.E.M., n = 23) obtained
were 18.3 ± 1.3 ng/g tissue weight for anandamide and 3.6 ± 0.2
µg/g tissue weight for 2-AG. These values agree with those reported by
other laboratories (Di Marzo et al.,
2000b; Wang et al.,
2003). The limbic forebrain endocannabinoid content of control
animals varied among individual experiments due to small changes in the
sensitivity of analytical hardware; therefore, each experiment included a
control (vehicle-treated) group, and statistical analyses were confined to
comparisons among samples subjected to the same experimental and analytical
procedures.
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Effects of Indirect Dopaminergic Agonists on Endocannabinoid
Content. We determined the effects of indirect dopaminergic agonists on
anandamide and 2-AG within the limbic forebrain. The effects of
methylphenidate and cocaine on anandamide and 2-AG content were determined 40
min after drug administration, a time point at which maximal elevations in
dopamine levels have been reported
(Gerasimov et al., 2000;
Carboni et al., 2001). The
effects of GBR 12909 were determined 60 min after administration due to its
relatively slow onset of action (Carboni et
al., 2001). Methylphenidate (Ritalin; 1, 10, and 20 mg/kg), a
potent dopamine- and norepinephrine-releasing compound
(Kuczenski and Segal, 1997;
Gerasimov et al., 2000),
produced significant and dose-related decreases in both anandamide and 2-AG
content, reaching maximal inhibition at 10 mg/kg
(Fig. 2). GBR 12909, a compound
known to selectively inhibit uptake of dopamine and increase extracellular
dopamine within the striatum (Carboni et
al., 2001), produced a dose-dependent decrease in anandamide,
reaching statistical significance at a dose of 20 mg/kg
(Fig. 3a). GBR 12909 also
tended to decrease 2-AG, but the reduction was not significant
(Fig. 3b). Interestingly,
cocaine, a nonselective monoamine uptake inhibitor, reduced anandamide content
slightly at 1 mg/kg but did not reach statistical significance at any dose
tested (Fig. 4a). Conversely,
cocaine significantly increased 2-AG content at a dose of 20 mg/kg
(Fig. 4b).
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Effects of Dopamine Receptor Subtype-Specific Antagonists on Endocannabinoid Content. To determine whether endogenous dopamine modulates anandamide or 2-AG content within the limbic forebrain via activation of D1 or D2 receptors, we administered the D1 receptor antagonist SCH 23390 (0.2 and 2 mg/kg) or the D2 receptor agonist eticlopride (0.2 and 2 mg/kg). Amounts of anandamide and 2-AG were determined 40 min after drug administration. SCH 23390 dose dependently increased anandamide content but did not affect 2-AG content (Fig. 5). Eticlopride significantly increased 2-AG content but did not affect anandamide content at any dose (Fig. 6).
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Effects of Dopamine Receptor Subtype-Specific Agonists on
Endocannabinoid Content. To further evaluate the contribution of D1 and D2
receptor activation to the suppression of endocannabinoid content by dopamine,
we administered the D1 agonist SKF 33939 (1, 10, and 30 mg/kg) or the D2
agonist quinpirole (0.1, 1, and 10 mg/kg). The effects of SKF 33939 on the
amount of anandamide and 2-AG were determined 40 min after drug
administration. SKF 33939 dose dependently decreased anandamide
(Fig. 7a) but exhibited a
biphasic effect on 2-AG (Fig.
7b); a significant increase in 2-AG was observed at 10 mg/kg but
not 30 mg/kg. When administered systemically, quinpirole exhibits a biphasic
dose- and time-dependent effect on locomotion, with early locomotor
suppression seen at all doses, and locomotor stimulation seen at longer time
points at high doses only (Horvitz et al.,
2001). To more accurately correlate the behavioral state with
endocannabinoid content, the effects of quinpirole on anandamide and 2-AG
content were determined 2 h after drug administration, a time point at which a
0.1-mg/kg dose produces locomotor inhibition, whereas 1- and 10-mg/kg doses
produce locomotor stimulation (S. Patel and C. J. Hillard, unpublished
observations; Horvitz et al.,
2001). Quinpirole administration resulted in a biphasic effect on
anandamide, with 0.1 and 1 mg/kg significantly increasing, and 10 mg/kg
demonstrating no difference from control, but a significant decrease from the
0.1-mg/kg dose (Fig. 8a).
Quinpirole also tended increase 2-AG at 0.1 and 1 mg/kg; however, these
effects did not reach statistical significance
(Fig. 8b).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Robbe et al.,
2002). Similar effects have been demonstrated within the
prefrontal cortex (Auclair et al.,
2000). In addition, striatal and cortical neurons in culture
produce anandamide in response to non-NMDA glutamate receptor activation and
depolarization, whereas 2-AG is produced by cortical neurons in response to
NMDA receptor activation (Di Marzo et al.,
1994; Stella et al.,
1997; Stella and Piomelli,
2001). Because dopaminergic activity modulates the response of
postsynaptic neurons to glutamatergic input (see Introduction), we have tested
the hypothesis that manipulation of dopaminergic tone results in alterations
in endocannabinoid content of the limbic forebrain in mice. Our findings
support this hypothesis and indicate that two endocannabinoids, anandamide and
2-AG, are reciprocally and differentially regulated by dopamine receptor
activity in vivo.
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Our results indicate that anandamide content in the limbic forebrain is
under tonic inhibitory control by dopamine acting through D1 receptors. Data
to support this conclusion are that the D1 receptor agonist SKF 33939
decreased, whereas the D1-selective antagonist significantly increased,
anandamide content. In addition, pharmacological elevation of synaptic
dopamine decreased limbic forebrain anandamide content. Overall, our findings
agree with data indicating that activation of postsynaptic D1 receptors
decreases non-NMDA-mediated excitatory influences on postsynaptic neurons
(Cepeda and Levine, 1998;
Kiyatkin and Rebec, 1999;
O'Donnell, 2003) and that D1
antagonists increase the mean firing rate of striatal neurons in vivo
(Kiyatkin and Rebec, 1999). In
addition, dopaminergic depletion-induced elevation in cortico-striatal
transmission, which is associated with increased anandamide but not 2-AG
content, is dependent upon non-NMDA glutamate receptor activation
(Gubellini et al., 2002).
These observations strongly suggest that elevated anandamide content is
correlated with increased neuronal activity in vivo. This contention is
further supported by in vitro data that anandamide synthesis is increased by
membrane-depolarizing agents and non-NMDA glutamate receptor agonists
(Di Marzo et al., 1994).
We have also determined the effects of D2 receptor ligands on anandamide
content. Whereas the D1 receptor is predominantly postsynaptic, at least three
functionally distinct D2 receptor "pools" are operative in the
striatum. First, D2 receptors on glutamatergic terminals inhibit glutamate
release (Hsu et al., 1995;
Cepeda et al., 2001); second,
D2 receptors on dopaminergic neurons act as release- and synthesis-inhibiting
autoreceptors (Skirboll et al.,
1979); and third, D2 receptors are expressed postsynaptically on
those GABAergic neurons that mediate outflow via the indirect, striatopallidal
pathway (Harrison et al.,
1992). Notably, the two pools of presynaptic D2 receptors exert
opposite effects on the activity of the GABAergic neurons; agonist binding to
D2 receptors on dopaminergic terminals will reduce dopamine release that will
indirectly increase cortico-striatal drive and GABAergic cellular activity
(Calabresi et al., 1993;
Gubellini et al., 2002),
whereas agonist binding to D2 receptors on glutamate terminals will reduce
glutamate release, and hence reduce GABAergic cellular activity. Consistent
with these mechanisms, the D2 agonist quinpirole has a biphasic effect on
limbic forebrain anandamide content, i.e., a low dose of quinpirole produced a
robust increase in anandamide content, whereas higher doses produced
progressively smaller increases. This pattern is consistent with our
hypothesis because at low doses we expect quinpirole to preferentially reduce
dopaminergic transmission and therefore indirectly increase striatal or
cortical neuronal activity, and anandamide content
(Fig. 9c). As the quinpirole
dose increases, D2-mediated inhibition of glutamate release predominates,
which reduces the excessive glutamatergic input and reduces the elevated
anandamide content (Fig. 9d).
This hypothesis is supported by data suggesting that the two presynaptic pools
of D2 receptors exhibit differential sensitivity to dopamine, with the
receptor on dopaminergic terminals being most sensitive to agonists
(Skirboll et al., 1979).
Interestingly, the D2 receptor antagonist eticlopride did not alter anandamide
content, suggesting either that the presynaptic D2 receptors are quiescent
during normal dopaminergic transmission or that the combined effect of this
inhibitor on the functionally diverse D2 receptor pools results in no overall
change in anandamide content. Alternatively, because blockade of D2 receptors
increases dopamine release, it is possible that activation of D1 receptors by
dopamine could actively suppress anandamide synthesis as outlined above.
We have also found that the limbic forebrain content of a second endocannabinoid, 2-AG, is modulated by changes in dopaminergic transmission. The pattern of regulation shares with anandamide a dependence on dopaminergic tone, but suggests differences in the dopamine receptors involved. 2-AG content was significantly reduced when synaptic dopamine was increased by methylphenidate and was slightly reduced by GBR 12909. Interestingly, cocaine, a nonselective monoamine uptake inhibitor, produced a significant elevation in 2-AG content at a dose of 20 mg/kg. Although untested, these data suggest that increases in either norepinephrine and/or serotonin could increase 2-AG content.
Unlike anandamide, 2-AG content was not affected by the D1 receptor
antagonist, but inhibition of D2 receptors with eticlopride resulted in a
doubling of 2-AG content in the limbic forebrain. These data are consistent
with an overall tonic suppression of 2-AG synthesis by activation of D2
receptors. Unlike the D1 antagonist SCH 23390, eticlopride does not affect
mean firing rate of striatal neurons
(Kiyatkin and Rebec, 1999) but
does increase expression of the immediate early gene c-fos within the striatal
complex (S. Patel and C. J. Hillard, unpublished data;
Keefe and Adams, 1998). Fos
expression is dependent upon changes in neuronal calcium concentrations and is
likely increased by D2 antagonists secondary to suppression of
dopamine-mediated inhibition of glutamate release, increased NMDA receptor
activation, and calcium influx (Morgan and
Curran, 1988; Keefe and Adams,
1998). It is our current hypothesis that a detectable increase in
2-AG content requires sustained depolarization and prolonged elevations in
intracellular calcium induced by NMDA, metabotropic, or neuropeptide receptor
activation. Our finding that the D1 agonist increased 2-AG content supports
this contention, because D1 receptor activation results in increased
NMDA-mediated postsynaptic responses
(Cepeda et al., 1993;
Wang and O'Donnell, 2001).
Similarly, 2-AG, but not anandamide, is produced by cortical neurons in
response to NMDA receptor activation in vitro
(Stella and Piomelli, 2001),
and NMDA-dependent long-term potentiation induction by high-frequency
stimulation of Schaffer collaterals results in selective synthesis of 2-AG in
hippocampal slice preparations (Abraham and
Huggett, 1997; Stella et al.,
1997).
We suggest that the modulatory effects of dopamine on endocannabinoid content are mediated via alterations in glutamatergic transmission, which in turn, drives endocannabinoid synthesis. However, effects of dopamine receptor activation on endocannabinoid degradation or metabolism cannot be excluded from the present data. In addition, the effects of dopaminergic compounds on regions outside the limbic forebrain, for example, the substantia nigra, could contribute to the alterations in endocannabinoid content observed in this study.
The functional and clinical implications of dopamine modulation of
endocannabinoid signaling within striatum and prefrontal cortex are
far-reaching. Exogenous activation of striatal CB1 receptors profoundly
inhibits movement (Gough and Olley,
1978), and elevations in endocannabinoids have been demonstrated
in several animal models of Parkinson's disease
(Di Marzo et al., 2000b;
Gubellini et al., 2002). Thus,
converging data indicate that elevations in endocannabinoid content and CB1
receptor activity are associated with hypo-kinetic states (for review, see
Romero et al., 2002). Our data
indicate that decreased D1 and D2 receptor activation would result in
increased endocannabinoid content, which could contribute to the motor
dysfunction associated with Parkinson's disease and/or D1 and D2 receptor
antagonists. Interestingly, it has recently been reported that
coadministration of the D2 agonist quinpirole and the CB1 receptor antagonist
SR141716 produced greater locomotor stimulation than quinpirole alone
(Giuffrida et al., 1999;
Di Marzo et al., 2000b).
Furthermore, we have found that psychomotor stimulant administration, which
dramatically increases locomotor activity, results in a decrease in
endocannabinoid content, and others have reported that exogenous
administration of CB1 agonists attenuates amphetamine-induced hyperactivity
(Pryor et al., 1978). These
data suggest that reduced endocannabinoid signaling could play a permissive
role in the expression of locomotor activity.
Alterations in dopaminergic transmission also contribute to the
pathoetiology of schizophrenia. Specifically, decreased mesocortical
dopaminergic transmission and decreased activation of D1 receptors is
associated with diminished working memory function, a hallmark negative
symptom of the disease (Okubo et al.,
1997; Abi-Dargham et al.,
2002). Because our data indicate that decreased dopaminergic
transmission through D1 receptors is associated with increased anandamide
content, and exogenous administration of CB1 receptor agonists decreases
cognitive function in animals and humans (for review, see
Lichtman et al., 2002), it is
tempting to speculate that elevated anandamide content contributes to negative
schizophrenic symptoms. In fact, increased anandamide content has been
demonstrated in the cerebral spinal fluid of schizophrenic patients
(Leweke et al., 1999). This
hypothesis would predict that pharmacological manipulations that reduce
anandamide content or CB1 receptor activation represent a novel approach to
the treatment of negative schizophrenic symptoms
(Mortimer, 1997).
In summary, these data indicate that anandamide and 2-AG are differentially modulated by dopamine, via activation of D1 and D2 receptors, respectively. These data suggest that anandamide and 2-AG are not redundant molecules and that separate, overlapping anandamide and 2-AG signaling systems could operate within the limbic forebrain. These data provide a basis for understanding the relationship between dopaminergic transmission and endocannabinoid signaling and thus could represent a useful framework upon which to develop endocannabinoid-based treatments for dopamine-related neuropsychiatric disorders, including Parkinson's disease and schizophrenia.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CB1, neuronal cannabinoid receptor; AG, arachidonylglycerol; NMDA, N-methyl D-aspartate; EC, endocannabinoid; GBR 12909, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; SCH 23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF 33939, 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; SR 141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride.
Address correspondence to: Dr. Cecilia J. Hillard, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: chillard{at}mcw.edu
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,
p < 0.01, statistically different from quinpirole 0.1 mg/kg;
Bonferonni's multiple comparisons analysis. Vehicle content; AEA 12.8 ±
0.7 ng/g; 2-AG 3.0 ± 0.4 µg/g.