1Laboratoire de Neurobiologie et Neuropharmacologie du Developpement, Institut des Neurosciences, Centre National de la Recherche Scientifique-Université Paris VI, 75005 Paris; and 2Sanofi Recherche, 34184 Montpellier, France
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ABSTRACT |
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Auclair, Nathalie,
Satoru Otani,
Philippe Soubrie, and
Francis Crepel.
Cannabinoids Modulate Synaptic Strength and Plasticity at
Glutamatergic Synapses of Rat Prefrontal Cortex Pyramidal Neurons.
J. Neurophysiol. 83: 3287-3293, 2000.
Cannabinoids receptors have been reported to modulate synaptic
transmission in many structures of the CNS, but yet little is known
about their role in the prefrontal cortex where type I cannabinoid
receptor (CB-1) are expressed. In this study, we tested first the acute
effects of selective agonists and antagonist of CB-1 on glutamatergic
excitatory postsynaptic currents (EPSCs) in slices of rat prefrontal
cortex (PFC). EPSCs were evoked in patch-clamped layer V pyramidal
cells by stimulation of layer V afferents. Monosynaptic EPSCs were
strongly depressed by bath application (1 µM) of the cannabinoid
receptors agonists WIN55212-2 (50.4 ± 8.8%) and CP55940
(
42.4 ± 10.9%). The CB-1 antagonist SR141716A reversed these
effects. Unexpectedly, SR141716A alone produced a significant increase
of glutamatergic synaptic transmission (+46.9 ± 11.2%), which
could be partly reversed by WIN55212-2. In the presence of strontium in
the bath, the frequency but not the amplitude of asynchronous synaptic
events evoked in layer V pyramidal cells by stimulating layer V
afferents, was markedly decreased (
54.2 ± 8%), indicating a
presynaptic site of action of cannabinoids at these synapses. Tetanic
stimulation (100 pulses at 100 Hz, 4 trains) induced in control
condition, no changes (n = 7/18), long-term depression
(LTD; n = 6/18), or long-term potentiation (LTP;
n = 5/18) of monosynaptic EPSCs evoked by stimulation of layer V afferents. When tetanus was applied in the presence of WIN
55,212-2 or SR141716-A (1 µM) in the bath, the proportion of
"nonplastic" cells were not significantly changed
(n = 7/15 in both cases). For the plastic ones
(n = 8 in both cases), WIN 55,212-2 strongly favored
LTD (n = 7/8) at the apparent expense of LTP
(n = 1/8), whereas the opposite effect was observed
with SR141716-A (7/8 LTP; 1/8 LTD). These results demonstrate that cannabinoids influence glutamatergic synaptic transmission and plasticity in the PFC of rodent.
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INTRODUCTION |
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Marijuana, a compound well known for its
psychoactive properties, has also significant analgesic, anti-emetic
and appetite stimulant effects, which are of interest for cancer and
AIDS patients (Weinroth et al. 1995). The major
psychoactive component of marijuana,
9-tetrahydrocanabinol
(
9THC), also impairs some cognitive processes
including memory (Abood and Martin 1992
). Effects of
cannabinoids are thought to be mediated through the activation of
receptors negatively coupled to adenylate cyclase, the so-called type 1 (CB-1) and type 2 (CB-2) cannabinoid receptors. The latter is mainly
localized in the peripheral immune system and is largely absent from
brain (Galiegue et al. 1995
; Munro et al.
1993
; Pertwee 1997
), whereas the former is
widely expressed in the CNS (see references in Bidaut-Russell et
al. 1990
; Matsuda et al. 1993
) and in several
peripheral tissues (Galiegue et al. 1995
).
Besides inhibiting N- and Q-type voltage-gated calcium (Ca) channels
and enhancing inwardly rectifying A-type potassium (K) channels in
expression systems and in cultured hippocampal neurons (see references
in Childers and Deadwyler 1996; Deadwyler et al. 1993
; Mackie et al. 1995
), CB1 receptors acutely
depress glutamatergic synaptic transmission through a presynaptic
mechanism in the hippocampus and in the cerebellum (Levenes et
al. 1998
; Shen et al. 1996
). Activation of CB1
receptors also impairs induction of long-term potentiation (LTP) in the
hippocampus (Nowicky et al. 1987
; Stella et al.
1997
; Terranova et al. 1995
) and long-term
depression (LTD) in the cerebellum (Levenes et al.
1998
).
Despite the fact that CB-1 receptors are less expressed in the
prefrontal cortex (PFC) of rodents than in cerebellum, hippocampus, or
basal ganglia (Herkenham et al. 1991; Tsou et al.
1998
), the density of cannabinoid receptors in this structure
is relatively high compared with other G-protein-coupled receptors
(Herkenham et al. 1990
). Accordingly,
9THC in the PFC of rodents has been reported
to induce disruption of spatial working memory (Jentsch et al.
1997
, 1998
). Since PFC is also involved in
cognitive and memory functions (Aggleton et al.
1995
; Eichenbaum et al. 1983
; Ragozzino
et al. 1998
; Seamans et al. 1995
), we decided to
study the effects of the selective cannabinoid receptor agonists WIN
55212-2 and CP 55940 (Devane et al. 1988
),
and of the selective antagonist SR141716A
[N-(piperidin-1-yl)-5-(-4-chlorophenyl)-1-(2.4dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide hydrochloride] (Rinaldi-Carmona et al. 1994
) on
synaptic transmission and synaptic plasticity in this structure.
Indeed, long-term changes in synaptic efficacy are generally considered
as the cellular basis of learning and memory. The study was focused on
layer V pyramidal cells since they can express both LTP and LTD of
glutamatergic synaptic transmission (Hirsch and Crepel
1990
).
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METHODS |
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Brain slice preparation
Coronal brain slices from 17- to 22-day-old male Sprague-Dawley
rats containing the prelimbic area of PFC (300 µm; 2.2-3.7 mm from
bregma) were sectioned with a vibratome in chilled (0°C) oxygenated (95% O2-5%
CO2) artificial cerebrospinal fluid (ACSF) of the
following composition (mM): 124 NaCl, 3 KCl, 24 NaHCO3, 1.15 KH2PO4, 1.15 MgSO4, 2 CaCl2, and 11 glucose, final pH 7.35, 325 mosmol/l at 28°C. The slices were allowed
to recover for at least 2 h at room temperature (
20°C) in a
chamber filled with continuously oxygenated ACSF. A slice was then
transferred to a submerged-type recording chamber and continuously
perfused with oxygenated ACSF (28°C) containing 1 µM of bicuculline
methochloride (GABAA antagonist; Sigma) at the
rate of 2 ml/min.
Recording and stimulation
Layer V pyramidal neurons in prelimbic area of PFC were
identified initially by videomicroscopy with Nomarski optics under infrared illumination through the ×40 water immersion objective (Stuart et al. 1993) as well as by biocytin staining
performed after experiments. Excitatory postsynaptic currents (EPSCs)
were recorded in whole cell voltage-clamp mode with a patch-clamp
amplifier (Axopatch 200A, Axon Instruments) and filtered at 2 kHz.
Electrodes (2-4 M
) were filled with a solution containing (mM) 8 NaCl, 100 potassium gluconate, 40 KCl, 10 HEPES, 2 ATP-Mg, 0.5 EGTA,
and 26 biocytin (Sigma); pH 7.24, 295 mosmol/l. The mode of spike discharge was routinely examined in current-clamp mode by application of a 0.5-nA depolarizing current step (200 ms). Neurons were classified as regular spiking, burst spiking, and irregular spiking [70, 17, and
13% of the recorded cells, respectively, following in principle the
classification made by Law-Tho et al. (1995)
],
and no correlation has been found between a discharge mode, the sense of plasticity induction, or the CB-1 agonists/antagonist effects. Cells
were then held at
70 mV after a partial compensation (80%) of access
resistance. A monopolar stimulating electrode was placed in layer V,
10-30 µm laterally to the apical dendrite of the recorded cell. The
EPSCs were elicited at 0.1 Hz on 10-mV hyperpolarizing voltage steps
that allowed monitoring of the passive electrical properties of the
recorded cell throughout the experiment. For plasticity experiments,
after a baseline period of at least 8 min, tetanic stimuli consisting
of 4 trains of 100-Hz burst (100 pulses) were delivered at 0.1 Hz under
current-clamp mode. The voltage-clamp mode and the baseline stimulation
were restored 10 s after the end of the last tetanic stimulation.
Pharmacological treatment
Drugs used were as follows: SR141716A (a generous gift from Sanofi Recherche, Montpellier, France), WIN 55212-2 (Tocris Cookson), and CP 55940 (Tocris Cookson). Stock solutions of SR141716A, WIN 55212-2, or CP 55940 (10 mM in dimethylsulphoxide, DMSO) were dissolved in ACSF at right concentrations (see RESULTS); a sonicator facilitated dissolving of these DMSO solutions. In pilot experiments (n = 10), we ascertained that the final concentration of DMSO in the bath (0.1-0.2%, depending on experiments) had no detectable effects on bioelectrical or synaptic activities of pyramidal neurons.
Data collection and analysis
Digitized data were acquired and analyzed on-line and off-line
with Acquis1 software (Gérard Sadoc, Center National de la Recherche Scientifique, Gif-sur-Yvette, France). The initial slope of
the EPSCs (a 1-ms period from its onset; pA/ms), which contains only
the monosynaptic component of the responses (Hirsch and Crepel 1990), was used to determine changes in synaptic efficacy of
monosynaptic afferents impinging on layer V pyramidal cells. For this
purpose, all responses were normalized to the mean initial slope
recorded during a 10-min control period. Cells were considered as
exhibiting increase/decrease for acute effects of compounds or LTP/LTD
for plasticity experiments, when changes in synaptic efficacy in any direction was found significant with ANOVA test (P < 0.05). Values are expressed as means ± SE.
For analysis of the evoked quantal events in the presence of strontium
(Sr2+), synaptic currents were further filtered
at 2 kHz and analyzed off-line with Detectivent, Labview-based software
developed by N. Ankri (Unité INSERM U261 and Institut Pasteur,
Paris). Synaptic events were detected on the basis of the slope of
their rising phase, and of windows for allowed minimum/maximum times to
peak and decay time constants (Ankri et al. 1994). These
parameters were adjusted so that most visible synaptic events were
detected. For each cell, analysis was performed on a few hundred of
such selected evoked synaptic events. Although the method of detection did not take into account absolute detection thresholds for evoked quantal EPSC amplitudes, it is clear from raw and cumulative amplitude distributions that events smaller than 10 pA were probably generally not detected, most of them therefore being likely to be buried in the
background noise.
Biocytin staining
Recordings with biocytin-containing electrodes were made from one cell per slice to verify that it was a pyramidal cell in layer V that was recorded. Slices were then fixed overnight in 4% paraformaldehyde in phosphate-buffered saline (PBS) at 4°C and rinsed three times (10 min each) in PBS. The biocytin was revealed by preincubating the slices with Vectastain ABC standard peroxydase (Valbiotech) and 0.1% Triton X-100 (Sigma) for permeabilization in PBS for 4 h. Slices were then rinsed three times (10 min each) before being incubated with peroxydase kit substrate (Valbiotech) for 10 min. The reaction was stopped by rinsing again three times (10 min each) with PBS, and the slices were mounted in PBS 50%/glycerol 50%. Pyramidal neurons were visualized with a ZEISS axiovert microscope, and images were taken using a camera (Hamamatsu) mounted on the microscope.
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RESULTS |
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The results of the present study were obtained from 119 pyramidal
cells. An example of one of those cells is illustrated in Fig.
1A. Input resistance, holding
current (i.e., <200 pA at 70 mV), and synaptic responses were
checked during baseline acquisition.
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EPSCs evoked in layer V pyramidal cells by stimulation of layer V
At 70 mV, all pyramidal cells responded to layer V stimulation
with a short latency (range: 2-4 ms) inwardly directed postsynaptic current (PSC). Superfusion with low doses of bicuculline methochloride (1 µM) significantly decreased (P < 0.05;
n = 3; Wilcoxon test) the PSC amplitude measured at
70 mV (Fig. 1B). In the presence of bicuculline, holding
the cell at progressively more depolarized potentials revealed an
apparent reversal potential for the EPSC of
3.2 ± 6 mV
(n = 5; Fig. 1, D and E). On
the other hand, in the absence of bicuculline, bath application of 5 µM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 30 µM
2-amino-5-phosphonovaleric acid (APV) revealed an inhibitory
postsynaptic current (IPSC) component with an apparent reversal
potential of
35.5 ± 4 mV because of the presence of 40 mM KCl
in the micropipettes (data not shown). These results confirm the
participation of EPSCs and IPSCs in the recorded PSCs. On the whole,
PSCs evoked by layer V stimulation in layer V pyramidal cells were
therefore very similar to those evoked by stimulation of more
superficial layers in previous studies (Hirsch and Crepel 1990
; Otani et al. 1998
). In subsequent
experiments, cells were bathed with 1 µM bicuculline methochloride to
isolate the EPSC component. The initial rising slope of the EPSC was
measured to follow the monosynaptic component of the EPSC (Fig.
1C) and avoid any contamination by the polysynaptic component.
Acute effects of cannabinoid agonists and antagonists on monosynaptic EPSCs
In three of the four cells tested, bath application of the CB-1
agonist WIN 55212-2 (1 µM) for 10 min induced a significant decrease
of the initial slope of monosynaptic EPSCs to 50.4 ± 8.8%,
which lasted thereafter for the whole duration of experiments, i.e.,
usually up to 30 min (Fig.
2A). In the remaining cell, no effect was observed. In four of six other cells, a similar effect was
obtained with bath application of the CB-1 agonist CP 55940 (1 µM),
which also induced an apparently irreversible and significant decrease
of the initial slope of the EPSCs (42.4 ± 10.9%). Again, in the
two remainders, no effect was observed. The depressant effect of
cannabinoids on EPSCs was never accompanied by any detectable changes
in passive bioelectrical properties of the cells or in their holding
current.
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We next determined whether bath application of the CB-1 antagonist 1 µM SR141716A alone has any effects on the amplitude and kinetics of
the EPSC. In marked contrast with previous studies (Collins et
al. 1995; Levenes et al. 1998
; Shen et
al. 1996
; Terranova et al. 1995
), bath
application of SR141716A (10 min) induced, in four of the nine tested
cells, a significant increase of the initial slope of the EPSC, which
amounted to +46.9 ± 11.2% and also lasted thereafter for the
whole duration of experiments (Fig. 2B). In the five
remaining cells, however, no significant effect of SR141716A on the
EPSCs was observed. In no cell, detectable changes in passive
bioelectrical properties or their holding current were noted during
application of SR141716A.
In separate experiments (n = 6), bath application of 1 µM SR141716A fully or partly reversed the depressant effect of 1 µM WIN 55212-2 on monosynaptic EPSCs, when WIN 55212-2 was washed out at the same time as SR141716A was applied (Fig. 2C). In contrast, in four other cells, when perfusion of WIN 55212-2 was maintained during SR141716A application, no reversal of the depressant effect of WIN 55212-2 on EPSCs was observed (data not shown).
Since SR141716A by itself potentiated the EPSCs, we ascertained whether such an effect could be also antagonized by WIN 55212-2. Indeed, in four of six other cells where the EPSCs were potentiated by bath application of 1 µM SR141716A, a subsequent application of 1 µM WIN 55212-2 during wash out of the SR141716A partly or fully reversed the potentiation of the EPSCs (Fig. 2D). Here again, in four other cells where perfusion of SR141716A was maintained during WIN 55212-2 application, no such reversal of the potentiating effect of SR141716A on EPSCs was observed (data not shown). Altogether, these results demonstrate that interactions between WIN 55212-2 and SR141716A occur specifically at the level of CB-1 receptors. The reversals of the effects do not simply represent algebraic summation of there opposite effects on EPSCs.
Site of action of agonist cannabinoids
To determine whether the depressant effect of cannabinoids
on EPSCs has a pre- and/or postsynaptic origin, we have substituted the
Ca2+ in the bathing medium by
Sr2+. This treatment is known to induce a
reduction of the stimulation-evoked synchronous release of transmitter,
and selectively enhance asynchronous release of quanta, thus allowing
detailed analysis of evoked quantal events (Miledi 1966;
Oliet et al. 1996
). In the six cells tested, this substitution led to a marked decrease in the amplitude of the
EPSCs (Fig. 3A) and to the
appearance of numerous asynchronous quantal events, which lasted for a
few hundred milliseconds after the stimulus. Figure 3B
illustrates such asynchronous events recorded from one of the six cells
tested in control condition and in the presence of WIN55212-2 (1 µM)
in the bath. As can be seen in this typical example, WIN55212-2
markedly reduced both the amplitude of the residual EPSC, and the
frequency of occurrence of subsequent asynchronous evoked quantal
events. Similar results were observed in four of these six cells,
WIN55212-2 having no detectable effects on the two others. In these
four cells kinetics of evoked quantal events were not affected by
WIN55212-2 (Fig. 3C). We next compared for these cells, the
raw and the cumulative amplitude distribution of the evoked
asynchronous EPSCs that occurred during a 400-ms time window after
stimulation in the presence or in the absence of WIN55212-2 in the
bathing medium. Neither the raw amplitude, nor the cumulative amplitude
distribution (n = 4; Kolmogorov-Smirnov test,
P < 0.05) are affected by the application of
WIN55212-2 (Fig. 3, D and E). In contrast, such
WIN55,212-2 in strontium medium significantly decreased in four of the
six cells (n = 4; Student's paired t-test;
P < 0.05) the mean detection rate of the events from
20.8 ± 4.1 (SE) Hz in control conditions to 9.55 ± 0.8 Hz
(i.e.,
54.2 ± 8%; Fig. 3F). These results strongly
suggest that the site of action of WIN55212-2 on layer V afferents
mediated EPSCs is entirely presynaptic.
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Changes in synaptic efficacy induced by tetanization of layer V
In control medium (i.e., 1 µM bicuculline methochloride in the
bathing medium), tetanic stimulation applied after a control period of
at least 10 min (see METHODS) induced no long-lasting changes in the initial slope of the monosynaptic EPSCs in 7 of 18 tested cells. In the 11 others, either a clear LTP (mean increase of
the initial slope is 34.3 ± 8.3%; n = 5; Fig.
3A) or a clear LTD (mean decrease of the initial slope is
+33.0 ± 7%; n = 6; Fig.
4B) of the monosynaptic EPSCs
was induced. These LTP and LTD lasted as long as the cells were
recorded, usually up to 40 min. Thus in control medium, about one-third
of the cells were not plastic, and, for the other two-thirds, LTP and
LTD were roughly equally induced (Fig.
5).
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When WIN 55212-2 (1 µM) was added to the perfusion medium 10 min prior to the recording session (i.e., 20 min before tetanus), synaptic plasticity was markedly shifted in favor of LTD. Indeed, in 15 cells tested in this condition, only 1 cell exhibited LTP of the EPSC, with an increase of the initial slope of +27.4%, whereas 7 others exhibited LTD of the monosynaptic EPSC, with mean decrease of the initial slope 36.5 ± 3.3% (Fig. 4C). The other seven cells were not plastic.
Conversely, when SR141716A (1 µM) was added to the bath 10 min before recording the cells, synaptic plasticity induced by tetanic stimulation was now markedly shifted in favor of LTP. Thus in 15 cells tested in such a condition, again seven cells exhibited no change in initial EPSC slope. For the eight others, only one exhibited LTD of the EPSC, with a decrease of the initial slope of 43.2%, whereas the remaining seven exhibited LTP of the EPSC, with mean increase of the initial slope 34.7 ± 9% (Fig. 4D).
Interestingly, in both experiments with SR141716A and with WIN 55212-2, the proportion of nonplastic cells was nearly the same and not
statistically different from the proportion of nonplastic cells in
control medium (Fig. 5). On the other hand the proportion of LTD and
LTP under SR141716A compared with those obtained under WIN55212-2 were
statistically different (2 test,
P < 0.05). The results suggest that nonplastic cells
are not rendered plastic by WIN 55212-2 or by SR141716A, and that those
two compounds induce a shift in synaptic plasticity in the same
population of plastic neurons or synapses.
Finally, WIN 55212-2 and SR141716A mutually inhibited their effects on synaptic plasticity. Thus in 14 tested cells, when both compounds were added to the perfusing medium 15 min prior to the tetanus, LTP and LTD were induced in five and four cells, respectively, i.e., in proportions, not different to those obtained in control medium (Fig. 5).
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DISCUSSION |
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The present study demonstrates that, in rat PFC, cannabinoid receptor agonists inhibit glutamatergic synaptic transmission between layer V afferents and layer V pyramidal cells via a presynaptic action, and favor LTD at the expense of LTP at the same synapses. More importantly, the present study also establishes for the first time that the specific cannabinoid receptor antagonist SR141716A acutely increases glutamatergic transmission and favors LTP at the expense of LTD.
The acute effects of cannabinoid agonists on excitatory synaptic
responses are consistent with recently published studies in hippocampal
glutamatergic transmission in cultures (Shen et al.
1996) and in the cerebellum (Levenes et al.
1998
), although in our case, some cells did not respond to
these compounds. This could be explained by a poor diffusion of
cannabinoids through slices, due to their lipophilic nature, which
probably decreases their actual concentrations at the level of CB-1
receptors. Higher concentrations could not be tested because the drugs
were dissolved in DMSO, which induced by itself a decrease of the
synaptic responses at concentration higher than 0.2%. The fact that
WIN 55212-2 and CP 55940, two specific CB-1 receptor agonists
(Devane et al. 1988
) have the same acute depressant
effect on EPSCs, and that WIN 55212-2 and the specific cannabinoid
receptor antagonist SR141716A mutually inhibit their respective effects
on EPSCs and synaptic plasticity (see RESULTS) confirm that
all these effects are genuinely mediated through the activation of CB-1
receptors. The decrease by WIN55212-2 of the frequency of evoked
quantal synaptic events, without affecting their amplitude, strongly
suggests that cannabinoids exert their effects on monosynaptic EPSCs
through a presynaptic mechanism, which is also in agreement with
results in other structures (Levenes et al. 1998
;
Shen et al. 1996
).
The impairment of LTP in layer V pyramidal cells by WIN 55212-2 is in
keeping with the inhibition by cannabinoid agonists of LTP in the
hippocampus (Nowicky et al. 1987; Stella et al. 1997
; Terranova et al. 1995
) and of LTD in the
cerebellum (Levenes et al. 1998
). In the present study,
this impairment does not result from a general impairment of synaptic
plasticity but rather represents a shift of long-term changes in
synaptic efficacy toward LTD (see RESULTS). In this
respect, the acute and long-term effects of cannabinoid agonists on
glutamatergic synaptic transmission in layer V pyramidal cells of the
rat PFC are reminiscent of those observed in the same cells by dopamine
(DA) (Law-Tho et al. 1995
; Otani et al. 1998
).
Interestingly, CB-1 receptors and D2 dopaminergic receptors are both
known to be negatively coupled to adenylate cyclase in rat brain
(Bidaut-Russell et al. 1990
; Jaber et al. 1996
). Now, are the present results consistent with the theory of synaptic plasticity developed by Bienenstock, Cooper, and Munro and
referred to as the BMC theory (Bienenstock et al. 1982
)?
If one considers that cells exhibiting no long-lasting change in synaptic efficacy are, for some reason, nonplastic in our experimental conditions (see RESULTS), the present results as well as
those of our previous studies with DA (Law-Tho et al.
1995
; Otani et al. 1998
) are consistent with the
view that both cannabinoid agonists and DA shift the floating threshold
defined by the BMC theory toward more depolarized values, and thus
favor LTD at the expense of LTP.
Two alternative hypotheses can explain the potentiating effects of
SR141716A on synaptic transmission and the shift of synaptic plasticity
in favor of LTP at the expense of LTD. The first one is that this
effect results from inverse agonist properties of SR141716A
(Bouaboula et al. 1997; Landsman et al.
1997
; Pan et al. 1998
). The second one
is that glutamatergic EPSCs evoked in layer V pyramidal cells are
tonically inhibited by endogenous cannabinoids. Clearly, the first
hypothesis cannot be ruled out on the basis of the present results.
However, we favor the second one for several reasons. Indeed, if
inverse agonist properties have been reported in heterologous
expression system and in pelvic ganglion neurons (Pan et al.
1998
), they have not been reported in native neurons in the
cerebellum (Levenes et al. 1998
) and in the hippocampus
(Shen et al. 1996
) where apparently the same CB1
receptors as in the PFC are represented (Rinaldi-Carmona et al.
1996
). On the other hand, if effects of SR141716A on
synaptic transmission and synaptic plasticity were due to inverse
agonist properties of the compound, one would expect to have observed these effects as consistently as those of WIN55212-2, given their similar lipophilic nature and similar affinities for CB1 receptors, which was not the case. On the contrary, the fact that the effects of
SR141716A were less consistently observed than those of WIN55212-2 fits
well with the presence of endogenous cannabinoids, if one simply
assumes that their concentration in slices may vary depending on the
physiological state of the animal. Finally, Piomelli's group found an
activity-dependant release of the endocannabinoid anandamide that binds
to cannabinoid receptors in the striatum (Giuffrida et al.
1999
), which also argues in favor of an endogenous cannabinoid
release. Further studies will be performed to clarify the issue, as for
instance looking at the effects of anandamide uptake blockers on
synaptic transmission and synaptic plasticity in layer V pyramidal cells.
In conclusion, the present study brings compelling evidence for a major
role of cannabinoids in controlling glutamatergic synaptic transmission
and plasticity in rat PFC. These findings are of prime importance,
given the role of PFC in higher cognitive processes and memory
function, as well as its close association with reward system. Finally,
the shift in favor of LTP induced by SR141716A might account for the
promnesic effects of SR141716A (Terranova et al. 1996),
which makes this compound a candidate of potential interest in the
treatment of memory disorders and other cognitive deficits.
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ACKNOWLEDGMENTS |
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We thank H. Daniel for comments on the manuscript.
This work was supported by Sanofi Recherche (France), Biotech (CT96-0049), and MILDT (Grant MILDT99D10).
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FOOTNOTES |
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Address for reprint requests: N. Auclair, Laboratoire de Neurobiologie et Neuropharmacologie du Developpement, Institut des Neurosciences-boite n°8-Université Pierre et Marie Curie-Paris VI, 7, quai Saint Bernard, 75252 Paris cedex 05, France.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 December 1999; accepted in final form 10 February 2000.
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REFERENCES |
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