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The Journal of Neuroscience, May 15, 1999, 19(10):3723-3730
Properties and Plasticity of Excitatory Synapses on Dopaminergic
and GABAergic Cells in the Ventral Tegmental Area
Antonello
Bonci1 and
Robert C.
Malenka1, 2
Departments of 1 Psychiatry and
2 Physiology, University of California, San Francisco,
California 94143
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ABSTRACT |
Excitatory inputs to the ventral tegmental area (VTA) influence the
activity of both dopaminergic (DA) and GABAergic (GABA) cells, yet
little is known about the basic properties of excitatory synapses on
these two cell types. Using a midbrain slice preparation and whole-cell
recording techniques, we found that excitatory synapses on DA and GABA
cells display several differences. Synapses on DA cells exhibit a
depression in response to repetitive activation, are minimally affected
by the GABAB receptor agonist baclofen, and express NMDA
receptor-dependent long-term potentiation (LTP). In contrast, synapses
on GABA cells exhibit a facilitation in response to repetitive
activation, are depressed significantly by baclofen, and do not
express LTP. The relative contribution of NMDA and non-NMDA receptors
to the synaptic currents recorded from the two cell types is the same
as is the depression of synaptic transmission elicited by the
application of adenosine, serotonin, or methionine enkephalin
(met-enkephalin). The significant differences in the manner in which
excitatory synaptic inputs to DA and GABA cells in the VTA can be
modulated have potentially important implications for understanding the
behavior of VTA neurons during normal behavior and during pathological
states such as addiction.
Key words:
midbrain; ventral tegmental area; dopamine; synaptic
plasticity; long-term potentiation; addiction
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INTRODUCTION |
The ventral tegmental area (VTA) is a
critical component of the neural system that is thought to underlie
natural reinforcement as well as the reinforcing properties of drugs of
abuse (Robbins and Everitt, 1996 ; Wise, 1996; Koob and LeMoal, 1997).
It contains two major cell types: primary dopaminergic neurons, the
axon terminals of which release dopamine (DA) in target areas such as
the nucleus accumbens and prefrontal cortex, and secondary neurons, the
majority of which are GABAergic (GABA) and thus function as local
interneurons to control the firing of the principal DA neurons (Johnson
and North, 1992; Kalivas, 1993; White, 1996; Overton and Clark, 1997). Recent work has confirmed that most VTA non-DA cells are indeed GABAergic and that, in addition to providing inhibitory inputs to VTA
DA cells, they send axon projections to cortex (Van Bockstaele and
Pickel, 1995; Steffensen et al., 1998).
The firing of VTA DA neurons is thought to reflect information about
the rewarding or motivationally relevant properties of external stimuli
(White, 1996; Overton and Clark, 1997; Schultz, 1998). An important
factor controlling VTA DA cell firing is the direct input from
prefrontal cortex (Kalivas, 1993; White, 1996; Overton and Clark,
1997), which forms excitatory synapses on both DA and GABA cells
(Christie et al., 1985; Sesack and Pickel, 1992). Both cell types
express NMDA and non-NMDA glutamate receptors (Kalivas et al., 1989;
Seutin et al., 1990; Wang and French, 1993, 1995) that contribute to
the generation of synaptic responses (Mereu et al., 1991; Johnson and
North, 1992; White, 1996; Overton and Clark, 1997; Steffensen et al.,
1998). However, the relative contributions of NMDA and non-NMDA
receptors to excitatory synaptic transmission on the two cell types
have not been examined nor have several other of the basic properties
of these synapses, such as their responses to repetitive stimulation or
their modulation by presynaptic receptor agonists. That important
functional differences may exist is suggested by recent work in the
hippocampus (Maccaferri et al., 1998; Scanziani et al., 1998) and
cortex (Markram et al., 1998; Reyes et al., 1998), which has
demonstrated that excitatory synapses formed by the same axon on
different postsynaptic targets can have profoundly different properties.
In addition to influencing the normal functioning of VTA cells, the
prefrontal excitatory afferent input to the VTA is important for the
development of behavioral sensitization to psychostimulants (for
review, see Wolf, 1998), a model for the intensification of drug
craving that contributes to drug addiction (Robinson and Berridge,
1993). Because behavioral sensitization and long-term potentiation
(LTP) share several features, it has been suggested that synaptic
plasticity at excitatory synapses on VTA DA neurons may be critically
important for triggering this behavioral change (Karler et al., 1991;
Schenk and Snow, 1994; Clark and Overton, 1998; Wolf, 1998). Thus, in
addition to examining the basic properties of excitatory synapses on
VTA DA and non-DA cells, we determined whether these synapses could
generate LTP. Given the distinct functional roles of DA and GABA cells
in the VTA, differences in the properties of their excitatory synapses
should have important implications for the understanding of the role of
the VTA in normal and pathological behavior such as drug dependence and addiction.
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MATERIALS AND METHODS |
Slice preparation. The preparation of VTA slices was
as described previously (Cameron and Williams, 1994). Briefly, Sprague Dawley rats (14-42 d) were anesthetized with halothane and
killed. A block of tissue containing the midbrain was sliced in
the horizontal plane (190-250 µm) with a vibratome (Leica, Nussloch,
Germany). Slices (two to three per animal) were placed in a holding
chamber and allowed to recover for at least 1 hr before being placed in the recording chamber and superfused with a bicarbonate buffered solution (32-34°C) saturated with
95%O2/5%CO2 and containing (in mM): 126 NaCl, 1.6 KCl, 1.2 NaH2PO4, 1.2 MgCl2,
2.5 CaCl2, 18 NaHCO3, and 11 glucose.
Whole-cell recording. Cells were visualized with an upright
microscope with infrared illumination, and whole-cell voltage-clamp recordings were made by using an Axopatch 2D amplifier (Axon
Instruments, Foster City, CA). Electrodes (3-8 M ) contained (in
mM): 117 cesium gluconate, 2.8 NaCl, 20 HEPES, 0.4 EGTA, 5 TEA-Cl, 2.5 MgATP, and 0.25 MgGTP, pH 7.3-7.4 (285-295 mOsm). For
perforated patch recordings (Rae et al., 1991) the electrodes (2-5
M) were filled with a solution containing (in mM): 117 cesium gluconate, 2.8 NaCl, 20 HEPES, 0.4 EGTA, and 5 TEA-Cl (pH 7.2 with CsOH, 285-295 mOsm). Amphotericin B (1.2 mg/ml; Sigma, St. Louis,
MO) dissolved in DMSO (0.6% final concentration) was added to this
solution, triturated, and used to backfill pipettes. Experiments were
begun only after series resistance had stabilized (typically 15-40
M). Series resistance and input resistance were monitored
continuously on-line with a 4 mV depolarizing step (25 msec), which was
given with every afferent stimulus. Data were filtered at 2 KHz,
digitized at 10 KHz, and collected on-line with acquisition software
developed in this laboratory by D. Selig.
DA and non-DA cells were identified by the presence or absence,
respectively, of a large Ih current (Johnson and
North, 1992) that was assayed immediately after break-in, using a
series of incremental 10 mV hyperpolarizing steps from a holding
potential of  70 mV. A bipolar stainless steel stimulating electrode
was placed 100-300 µm rostral to the recording electrode and was
used to stimulate excitatory afferents at 0.1 Hz. Neurons were
voltage-clamped at a membrane potential of 70 mV, except where noted.
All EPSCs were recorded in the presence of picrotoxin (100 µM). The amplitudes of EPSCs were calculated by taking
the mean of a 2-3 msec window around the peak and comparing this with
the mean of a 10 msec window immediately before the stimulation artifact.
Drugs were added to the superfusing medium at known concentrations
immediately before application to the slice. D-APV
[D()-2-amino-5-phosphonopentanoic acid], CNQX
(6-cyano-7-nitroquinoxaline-2,3-dione), and MCPG
[(RS)- -methyl-3-carboxy-4-hydroxyphenylglycine] were
obtained from Tocris (Ballwin, MO). Picrotoxin and methionine enkephalin (met-enkephalin) were obtained from Sigma. Serotonin, baclofen, and adenosine were obtained from Research Biochemicals (Natick, MA). Results in the text and figures are presented as the
mean ± SEM. We considered p < 0.05 statistically significant.
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RESULTS |
The results of this study are based on recordings made from 54 DA
cells and 41 GABA cells that were identified by the presence or
absence, respectively, of a prominent hyperpolarization-induced inward
current (Ih) (Johnson and North,
1992).
Excitatory synapses on DA and GABA cells respond differently to
repetitive stimulation
In other brain regions it has been found that the excitatory
synapses made by the same axon onto different target cells can differ
significantly in their responses to repetitive stimulation (Maccaferri
et al., 1998; Markram et al., 1998; Reyes et al., 1998; Scanziani et
al., 1998). Therefore, in our first set of experiments we compared this
property of the excitatory synapses on DA and GABA cells. Figure
1, A and B, shows
that the change in synaptic strength elicited by paired stimuli given
at an interval of 50 msec was significantly different for synapses on
DA versus GABA cells. Synapses on DA cells exhibited a paired-pulse
depression (s2/s1 ratio = 0.68 ± 0.03; n = 9), whereas synapses on GABA cells exhibited paired-pulse facilitation
(s2/s1 ratio = 1.28 ± 0.03; n = 12). This
difference was not a consequence of differences in the amplitude of the
EPSCs recorded from the two populations of cells (Fig. 1C)
and was observed at all three of the interstimulus intervals tested
(Fig. 1D).
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Figure 1.
Dopaminergic (DA) neurons display
paired-pulse depression, whereas GABAergic (GABA)
neurons show paired-pulse facilitation. A, Sample EPSCs
in response to paired stimuli (50 msec interstimulus interval) for a DA
(A1) and GABA
(A2) neuron (traces are the
average of 20 consecutive sweeps). B, Average of the
paired-pulse ratio for DA (n = 9) and GABA
(n = 12) neurons. C, Graph of the
paired-pulse ratio as a function of the first EPSC amplitude. The
amount of paired-pulse facilitation or depression is independent of the
amplitude of the EPSC. Each symbol represents a distinct
cell. D, The paired-pulse ratio for DA and GABA neurons
as a function of interstimulus interval.
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We also examined whether the excitatory synapses on the two cell types
differ in their response to brief bursts of presynaptic stimuli. The
normal firing pattern of many neurons in the CNS consists of
brief bursts of action potentials (Ranck, 1973; O'Keefe, 1976; Wilson
and McNaughton, 1993), which can cause synaptic responses that either
facilitate or depress. Differences in this dynamic response of synapses
to presynaptic bursts likely have important functional consequences for
how a network processes incoming information (Buonomano and Merzenich,
1995; Markram et al., 1998). Consistent with the results from the
paired-pulse experiments, excitatory synapses on DA cells displayed
a depression in reponse to 10 stimuli given at 25 Hz (Fig.
2A,B, left panels). In
contrast, excitatory synapses on GABA cells displayed a facilitation in
response to the same stimulation (Fig. 2A,B, right
panels). Similar results were obtained when synapses were
stimulated at 40 or 100 Hz (n = 3 or 4 cells in each
group; data not shown).
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Figure 2.
Repetitive stimulation produces a depression in DA
neurons and a facilitation in GABA neurons. A, Sample
EPSCs in response to 10 stimuli at 25 Hz for a DA
(A1) and GABA (A2) neuron
(traces are the average of 10 consecutive episodes). B,
Graphs show the changes in EPSC amplitude during the 10 pulse train for
DA (B1, n = 5) and GABA neurons
(B2, n = 5).
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Relative contribution of AMPA adn NMDa receptors to EPSCs in DA and
GABA cells
It is now well established that many excitatory synapses in the
mammalian brain express both AMPA receptors (AMPARs) and NMDA receptors
(NMDARs) but that the relative contribution of these receptor subtypes
at individual synapses can vary widely (Malenka and Nicoll, 1997; Rao
and Craig, 1997; Gomperts et al., 1998; Nusser et al., 1998; Liao e
al., 1999; Petralia et al., 1999). Given the critical importance of
NMDARs both in controlling the firing pattern of neurons in response to
afferent inputs and in triggering synaptic plasticity, an important
question is whether excitatory synapses on DA and GABA cells in the VTA
express the same proportion of synaptic AMPARs and NMDARs. To compare
the relative contribution of AMPARs and NMDARs with the EPSCs recorded from DA and GABA cells, we held cells at +40 mV and then applied the
NMDAR antagonist D-APV (50 µM). The average
AMPAR-mediated EPSC (AMPAR EPSC) was obtained by averaging 20-40
responses taken after the effect of D-APV had stabilized.
This average AMPAR EPSC was subtracted from the average control EPSC
(in the absence of D-APV) to obtain the average NMDAR EPSC.
Then the AMPAR/NMDAR ratio was calculated by dividing the peak
amplitude of the average AMPAR EPSC by the peak amplitude of the
average NMDAR EPSC (Hsia et al., 1998). Consistent with previous work
(Mereu et al., 1991; Johnson and North, 1992; White, 1996; Overton and
Clark, 1997; Steffensen et al., 1998), EPSCs recorded from both DA and
GABA cells had components mediated by both AMPARs and NMDARs, and the evoked synaptic current was blocked completely by the application of
D-APV (50 µM) with the AMPAR antagonist CNQX
(10 µM) (Fig. 3A).
However, there was no significant difference in the AMPAR/NMDAR ratio
for these two cell types (DA cells, 0.74 ± 0.1, n = 7; GABA cells, 0.68 ± 0.1, n = 8;
p > 0.05) (Fig. 3B).
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Figure 3.
EPSCs recorded from DA and GABA neurons express a
similar AMPA/NMDA ratio. A, Sample EPSCs recorded from a
DA neuron under control conditions, in the presence of
D-APV (50 µM), and in the presence of
D-APV (50 µM) plus CNQX (10 µM). (Each trace is an average of 20 consecutive sweeps.)
B, Summary graph of the AMPA/NMDA ratio for DA
(n = 7) and GABA (n = 8)
neurons.
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Comparison of presynaptic modulation of excitatory synaptic
transmission at DA and GABA cells
The presynaptic depression of transmitter release at excitatory
synapses by a wide variety of neurotransmitters is a ubiquitous mechanism of modulating synaptic strength that has been characterized extensively in a number of structures, most notably the hippocampus (Thompson et al., 1993; Miller, 1998). However, the actions of only a
very limited number of neurotransmitter receptor agonists on excitatory
synaptic transmission in the VTA have been examined. Therefore, we
performed a survey of the actions in the VTA of a number of agonists
that have been found in other brain regions to depress excitatory
synaptic transmission. Furthermore, because excitatory synapses formed
by the same afferent on different target cells can be modulated
differentially by the same receptor agonist (Scanziani et al., 1998),
we compared the actions of these agonists on EPSCs recorded from both
DA and GABA cells.
Adenosine, primarily acting on presynaptic A1 receptors, depresses
excitatory synaptic transmission at many synaptic relays (Greene and
Haas, 1991; Thompson et al., 1993; Miller, 1998). In the VTA, adenosine
(100 µM) reversibly depressed EPSCs recorded from both DA
and GABA cells to the same extent (Fig.
4A,D) (DA cells, 39.6 ± 6% decrease, n = 3; GABA cells, 33.7 ± 6%
decrease, n = 3; p > 0.05). Similarly,
serotonin (20 µM), a neurotransmitter that likely
contributes to the behavioral actions of psychostimulants (Cunningham
et al., 1996), also caused an equivalent decrease of excitatory
synaptic transmission in DA and GABA cells (Fig. 4B,D) (DA cells, 18.7 ± 4%, n = 3; GABA cells, 14.3 ± 4%, n = 3;
p > 0.05). We also examined the actions of
met-enkephalin, because µ-opioid receptor agonists have been found to
depress inhibitory and excitatory synaptic transmission in other brain regions (Thompson et al., 1993; Grudt and Williams, 1995; Miller, 1998). Again, met-enkephalin (30 µM) depressed
transmission at excitatory synapses on DA and GABA cells to the same
extent (Fig. 4C,D) (DA cells, 28.6 ± 5%,
n = 4; GABA cells, 32.6 ± 5%, n = 3; p > 0.05).
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Figure 4.
The magnitude of depression of EPSCs caused by
adenosine, serotonin, and met-enkephalin is similar in DA and GABA
neurons. A, Graph shows examples of the effects of
adenosine (100 µM) in a DA ( ) and GABA ( ) neuron.
B, Examples of the effects of serotonin (20 µM) in a DA () and GABA () neuron.
C, Examples of the effects of met-enkephalin (30 µM) in a DA () and GABA () neuron.
D, Summary of the effects on EPSCs of adenosine,
serotonin, and met-enkephalin in DA and GABA neurons
(n = 3 for each column).
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In contrast to the actions of the agonists tested thus far (adenosine,
serotonin, and met-enkephalin), the GABAB receptor agonist
baclofen had dramatically different effects at synapses on DA versus
GABA cells. Whereas 1 µM baclofen had no significant effect on EPSCs recorded from DA cells (6.0 ± 2% inhibition;
n = 4) (Fig.
5A,C), this same concentration of
baclofen dramatically depressed EPSCs recorded from GABA cells
(49.9 ± 8%; n = 4) (Fig. 5B,D). This
large difference in the actions of baclofen was apparent at all three
concentrations that were tested (Fig. 5C,D).
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Figure 5.
Baclofen depresses synaptic transmission in GABA
neurons but has minimal effect on DA neurons. A,
B, Examples of the effects of baclofen (1 µM) on EPSCs recorded from a DA (A)
and GABA (B) neuron. Baclofen caused a marked
depression of EPSC amplitude in a GABA neuron while having minimal
effect on the DA neuron. C, D,
Dose-response curves displaying the EPSC inhibition as a function of
baclofen concentration for DA (C) and GABA
(D) neurons. Each point is an
average of at least four cells.
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Synaptic plasticity in DA and GABA cells
The most extensively studied form of synaptic plasticity in the
mammalian brain has been the LTP observed at excitatory synapses on CA1
pyramidal cells (Bliss and Collingridge, 1993; Malenka, 1994; Nicoll
and Malenka, 1995). Surprisingly, despite the in vivo data
suggesting that an LTP-like process in the VTA contributes to the
development of behavioral sensitization (Karler et al., 1991; Schenk
and Snow, 1994; Clark and Overton, 1998; Wolf, 1998), whether or not
LTP can be elicited at excitatory synapses in the VTA has not been
examined. Initially, we made standard whole-cell recordings from DA
cells and attempted to induce LTP by using a pairing protocol that
reliably elicits LTP in hippocampal CA1 pyramidal cells (cells were
held at +10 mV while stimulating the afferents 200 times at 1 Hz).
Although a stable long-lasting increase in synaptic strength
occasionally could be observed after this protocol, the induction of
LTP was not reliable (only 2 of 11 cells displayed a potentiation
lasting >10 min). Because the ability to generate LTP can
"wash-out" during the course of a whole-cell recording (Malinow and
Tsien, 1990), we next made perforated patch recordings and applied the
same pairing protocol. As shown in Figure
6A, this resulted in a
small but stable increase in synaptic strength (20 ± 3% measured
as the average increase in the period 30-35 min after the induction
protocol; n = 6) that lasted for the duration of the
recording. The triggering of LTP in VTA DA cells by using perforated
patch recording was fairly reliable; an increase in synaptic strength
of >10% measured 30-35 min after the induction protocol was observed
in all six cells.
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Figure 6.
LTP can be elicited at excitatory synapses on DA
neurons, but not on GABA neurons. A, B,
Time course of the effects of a pairing protocol (+10 mV, 200 stimuli
at 1 Hz) on EPSC amplitude for DA (A,
n = 9) and GABA (B,
n = 6) neurons. All recordings were made with the
perforated patch-clamp recording technique.
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In contrast to the results from DA cells, when perforated patch
recordings were made from GABA cells and the same pairing protocol was
applied, LTP was not elicited (Fig. 6B) (3.2 ± 3% increase; n = 4). This finding is consistent with
work in the hippocampus where excitatory synapses on the majority of
GABAergic interneurons do not express LTP (Maccaferri and McBain,
1996).
Although the majority of excitatory synapses in the mammalian brain
expresses NMDAR-dependent LTP, there are other forms of LTP for
which the triggering does not require NMDARs (Johnston et al., 1992;
Nicoll and Malenka, 1995). Given that the development of behavioral
sensitization appears to require the activation of NMDARs in the VTA
(for review, see Wolf, 1998), it was important to determine whether LTP
in DA cells in VTA slices is prevented by D-APV. Because
metabotropic glutamate receptors (mGluRs) also have been implicated in
playing a role in hippocampal LTP (Bashir et al., 1993), we also
examined the effect of the mGluR antagonist MCPG. Figure
7A shows that the induction of LTP
is prevented by the simultaneous application of D-APV (50 µM) and MCPG (500 µM) (1.0 ± 11.3%
increase; n = 6). This blockade of LTP was entirely attributable to the presence of D-APV because normal LTP
could be elicited when the pairing protocol was performed in the
presence of MCPG alone (Fig. 7B) (43 ± 6.0% increase;
n = 6). Thus these pharmacological experiments
demonstrate that, like behavioral sensitization, the triggering of LTP
at excitatory synapses on VTA DA cells requires the activation of
NMDARs.
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Figure 7.
The triggering of LTP in DA cells requires
activation of NMDA receptors, but not metabotropic glutamate receptors
(mGluRs). A, In the presence of the NMDA receptor
antagonist D-APV (50 µM) and the mGluR
antagonist MCPG (500 µM), a pairing protocol fails to
elicit LTP (n = 6). B, Application
of MCPG (500 µM) alone does not prevent LTP in DA neurons
(n = 6).
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DISCUSSION |
In vivo electrophysiological experiments have
demonstrated that prefrontal cortical afferents to the VTA play an
important role in controlling the firing pattern of both DA (Kalivas,
1993; White, 1996; Overton and Clark, 1997) and GABA cells (Steffensen et al., 1998). Using an in vitro VTA slice
preparation, we have examined and compared some of the basic properties
of excitatory synapses on these two cell populations. Several
significant differences were found, including (1) the manner in which
the synapses respond to repetitive presynaptic stimulation, (2) the
magnitude of the depression of synaptic transmission caused by the
GABAB receptor agonist baclofen, and (3) the ability to
express LTP.
Before we discuss these findings, it is important to mention two
limitations to the approach we have taken. First, we cannot identify
definitively the source of the excitatory afferents that we stimulated
in the slice preparation. We have assumed that the majority of these
comes from prefrontal cortex, because this region appears to provide
the major excitatory input to the VTA (Kalivas, 1993; White, 1996;
Overton and Clark, 1997). Afferent projections also arise from the
subthalamic nucleus and pedunculopontine region, but these have been
reported to project preferentially to the substantia nigra (Scarnati et
al., 1986; Christie et al., 1987; Kita and Kitai, 1987). Importantly,
if stimulation of these noncortical afferents contributed to the EPSCs
that we recorded, the properties of these synapses still must differ
significantly, depending on whether they are formed on DA or GABA
cells. A second limitation is that we have divided our cells into two
groups predominantly according to whether they expressed a prominent
Ih current. This electrophysiological criterion
appears warranted (Grace and Onn, 1989; Lacey et al., 1989; Johnson and
North, 1992) but may have oversimplified the heterogeneity of cell
types in the VTA, which may contain cells that are neither dopaminergic
nor GABAergic (Cameron et al., 1997). Therefore, we cannot be certain
that all cells lacking Ih were indeed GABAergic;
conversely, we did not demonstrate directly that all cells expressing
Ih were dopaminergic. Nonetheless, the fact that
classifying the cells in this manner enabled us to demonstrate profound
physiological and pharmacological differences in synaptic properties
provides strong experimental evidence that validates this approach.
Recent work in slices of the hippocampus (Ali et al., 1998; Maccaferri
et al., 1998; Scanziani et al., 1998) and cortex (Markram et al., 1998;
Reyes et al., 1998) demonstrates that synapses made by the same axon or
set of axons onto different postsynaptic targets can express profoundly
different physiological properties. Similarly, we found that excitatory
synapses on DA cells were depressed by paired stimuli or brief bursts
of stimuli given at physiologically relevant frequencies, whereas
synapses on GABA cells were facilitated in response to the same
patterns of stimulation. This form of short-term modulation of synaptic
strength is likely attributable to changes in presynaptic function
(Zucker, 1989; Dobrunz and Stevens, 1997), and thus the differences we
observed strongly suggest that fundamental properties of
neurotransmitter release mechanisms differ between the excitatory
synapses on DA and GABA cells in the VTA. The functional significance
of this difference is unclear. If the same cell or group of cells in
prefrontal cortex projects to both DA and GABA cells and these GABA
cells provide feed-forward inhibition to the DA cells, the synaptic
properties we have described would help significantly to limit the
duration of firing of the DA cells in response to cortical activity.
We also examined the effects on excitatory synaptic transmission of a
number of different neurotransmitter receptor ligands. Adenosine,
serotonin, and met-enkephalin all reversibly depressed synaptic
transmission to the same extent in both DA and GABA cells. To our
knowledge, this is the first report of such actions of these
neurotransmitters in the VTA. Further work will be necessary to
determine the subtypes of receptors mediating these effects, their
mechanism of action, and the functional consequences of this sort of
synaptic modulation. In contrast to the effect of these other ligands,
the GABAB receptor agonist baclofen strongly depressed
synaptic transmission in GABA cells but had minimal effects on
excitatory synapses on DA cells. Thus GABAB receptor agonists may provide an important tool by which excitatory inputs onto
GABA cells may be manipulated independently of the inputs onto DA cells.
In terms of the role of the VTA in normal behavior and in mediating
some of the behavioral changes in response to drugs of abuse, perhaps
our most important finding is that excitatory synapses on DA cells can
express NMDAR-dependent LTP. This provides important evidence in
support of the hypothesis that the development of behavioral
sensitization to psychostimulants involves an LTP-like process in the
VTA (Karler et al., 1991; Schenk and Snow, 1994; Clark and Overton,
1998; Wolf, 1998). Assuming that in vivo psychostimulant administration does, in fact, elicit LTP at excitatory synapses on VTA
DA cells and that this is a critical trigger for behavioral sensitization, study of the mechanisms of LTP in the VTA slice preparation will provide a tractable approach for elucidating some of
the molecular changes underlying this form of behavioral plasticity.
The results presented here represent just a small portion of the data
that will be necessary to develop a comprehensive model of how afferent
inputs and intrinsic circuit and cellular properties interact to
control the behavior of VTA neurons. Nonetheless, they provide new and
useful information about some of the most basic properties of
excitatory synaptic transmission in the VTA. They also provide
information that will facilitate the development of pharmacological
agents that can be used to probe the role of the VTA in various forms
of reinforcement-dependent behavior and perhaps to prevent or alleviate
the neural changes that contribute to the development of pathological
states such as drug addiction.
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FOOTNOTES |
Received Jan. 13, 1999; revised Feb. 26, 1999; accepted March 4, 1999.
R.C.M. is supported by grants from National Institutes of Health and an
Investigator Award from the McKnight Endowment Fund for Neuroscience.
We thank members of the Malenka and Nicoll labs for many useful
comments and discussions during the course of these experiments.
Correspondence should be addressed to Dr. Robert Malenka, Department of
Psychiatry, LPPI, Box 0984, University of California, San Francisco, CA 94143.
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C. D. Fiorillo and J. T. Williams
Selective Inhibition by Adenosine of mGluR IPSPs in Dopamine Neurons After Cocaine Treatment
J Neurophysiol,
March 1, 2000;
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1307 - 1314.
[Abstract]
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[PDF]
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E. Koga and T. Momiyama
Presynaptic dopamine D2-like receptors inhibit excitatory transmission onto rat ventral tegmental dopaminergic neurones
J. Physiol.,
February 15, 2000;
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163 - 173.
[Abstract]
[Full Text]
[PDF]
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V. Seutin, F. Mkahli, L. Massotte, and A. Dresse
Calcium Release From Internal Stores Is Required for the Generation of Spontaneous Hyperpolarizations in Dopaminergic Neurons of Neonatal Rats
J Neurophysiol,
January 1, 2000;
83(1):
192 - 197.
[Abstract]
[Full Text]
[PDF]
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S. Jones and J. A. Kauer
Amphetamine Depresses Excitatory Synaptic Transmission via Serotonin Receptors in the Ventral Tegmental Area
J. Neurosci.,
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[Abstract]
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C. Flores, A.-N. Samaha, and J. Stewart
Requirement of Endogenous Basic Fibroblast Growth Factor for Sensitization to Amphetamine
J. Neurosci.,
January 15, 2000;
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RC55 - RC55.
[Abstract]
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F. Georges and G. Aston-Jones
Potent Regulation of Midbrain Dopamine Neurons by the Bed Nucleus of the Stria Terminalis
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August 15, 2001;
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION
