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 Previous Article
The Journal of Neuroscience, November 1, 1998, 18(21):9139-9151
Dopamine Decreases the Excitability of Layer V Pyramidal Cells in
the Rat Prefrontal Cortex
Allan T.
Gulledge and
David B.
Jaffe
Division of Life Sciences, University of Texas at San Antonio, San
Antonio, Texas 78249
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ABSTRACT |
In both primates and rodents, the prefrontal cortex (PFC) is highly
innervated by dopaminergic fibers originating from the ventral
tegmental area, and activation of this mesocortical dopaminergic system
decreases spontaneous and evoked activity in the PFC in vivo. We have examined the effects of dopamine (DA), over a
range of concentrations, on the passive and active membrane properties of layer V pyramidal cells from the rat medial PFC (mPFC). Whole-cell and perforated-patch recordings were made from neurons in rat mPFC. As
a measure of cell excitability, trains of action potentials were evoked
with 1-sec-long depolarizing current steps. Bath application of
DA (0.05-30 µM) produced a reversible decrease in the
number of action potentials evoked by a given current step. In
addition, DA reversibly decreased the input resistance
(RN) of these cells. In a
subset of experiments, a transient increase in excitability was
observed after the washout of DA. Control experiments suggest that
these results are not attributable to changes in spontaneous synaptic activity, age-dependent processes, or strain-specific differences in dopaminergic innervation and physiology. Pharmacological analyses, using D1 agonists (SKF 38393 and SKF 81297), a D1 antagonist (SCH 23390), a D2 receptor agonist (quinpirole), and a D2 antagonist (sulpiride) suggest that decreases in spiking and
RN are mediated by D2 receptor activation.
Together, these results demonstrate that DA, over a range of
concentrations, has an inhibitory effect on layer V pyramidal neurons
in the rat mPFC, possibly through D2 receptor activation.
Key words:
dopamine; prefrontal cortex; electrophysiology; pyramidal
cell; whole-cell recording; perforated-patch recording
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INTRODUCTION |
The prefrontal cortex (PFC)
is an area of associational cortex important for a form of short-term
information storage often described as "working memory" (Funahashi
et al., 1991 ). In addition to receiving excitatory input from the
thalamus (Condé et al., 1990), the hippocampus (Carr and Sesack,
1996), and other cortical areas (Condé et al., 1995), the rat
medial PFC (mPFC), like the dorsolateral PFC of primates, is highly
innervated by dopaminergic projections from the ventral tegmental area
(VTA) (Bjorklund et al., 1978; Emson and Koob, 1978; Brown et al.,
1979; Descarries et al., 1987). In both primates and rats, this
mesocortical dopamine (DA) system is important for the learning of
delay-dependent memory tasks (Brozoski et al., 1979; Simon et al.,
1980; Bubser and Schmidt, 1990; Sawaguchi and Goldman-Rakic, 1991).
A number of investigations have examined the influence of DA on
neuronal activity in rat mPFC in vivo. Stimulation of
dopaminergic cells in the VTA depresses both thalamically evoked and
spontaneous mPFC activity (Ferron et al., 1984; Mantz et al., 1988;
Pirot et al., 1992), and this effect can be blocked by 6-OHDA lesions (Ferron et al., 1984). Similar depression of spontaneous cell firing in
the rat mPFC and other frontal cortical areas has been observed in
response to iontophoretic application of DA (Bernardi et al., 1982;
Pirot et al., 1992).
Although the in vivo data suggests that DA has a general
inhibitory effect on PFC activity, there has been much less consensus regarding the effect of DA on the excitability of individual neurons as
assessed in vitro. In one study, low concentrations of DA
(0.1-10 µM) decreased the number of spikes evoked by
depolarizing current steps (Geijo-Barrientos and Pastore, 1995),
whereas in three other reports, higher concentrations of DA (2-50 and
400 µM) produced an increase in excitability (Penit-Soria
et al., 1987; Yang and Seamans, 1996; Shi et al., 1997).
A number of recent studies in both primates and rodents suggest that
there is a critical concentration of DA required for normal PFC
function (Brozoski et al., 1979; Sawaguchi and Goldman-Rakic, 1994;
Murphy et al., 1996; Zahrt et al., 1997); if DA levels are too high or
too low, there will be significant cognitive deficits. It is therefore
a reasonable hypothesis that the cellular effects of DA in the mPFC are
concentration-dependent (Zahrt et al., 1997). For example, low
concentrations of DA might enhance neuronal excitability, whereas high
levels may result in depression. In this study, we have used whole-cell
and perforated-patch recording techniques to measure the effect of DA
on the active and passive membrane properties of layer V pyramidal
cells in the rat mPFC. We report that DA, over a range of
concentrations, depresses the excitability of layer V pyramidal neurons
in rat mPFC. Our experiments also suggest that this depression is
mediated via D2 receptor activation.
A preliminary report has been presented in abstract form (Gulledge and
Jaffe, 1997).
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MATERIALS AND METHODS |
Brain slices. Coronal slices (300 µm) containing
mPFC were harvested with a vibratome from 17- to 30-d-old Sprague
Dawley rats (Harlan, Indianapolis, IN) in cold (4°C) artificial
CSF (aCSF) containing (in mM): 124 choline chloride,
26 NaHCO3, 2.5 KCl, 1.25 Na2HPO4, 2 MgCl2, 2 CaCl2, and 10 dextrose. For some experiments, slices
were harvested from either larger 10-week-old Sprague Dawley rats or
20- to 30-d-old Long-Evans rats (Charles River, Wilmington, MA). Only
coronal sections anterior to and no more than 2 mm away from the genu
of the corpus callosum were used for this study. Slices were allowed to
incubate for at least 1 hr at room temperature (~23°C) in aCSF in
which NaCl replaced choline chloride. Slices were transferred as needed
into a submerged recording chamber perfused with oxygenated aCSF (~2
ml/min). All aCSF solutions were oxygenated continuously with 95%
O2-5% CO2. In some experiments, the
aCSF contained picrotoxin (10 µM) and kynurenate (1 mM) to block fast synaptic transmission. Experiments were
performed at room temperature (~23°C) unless otherwise noted.
Electrophysiology. Whole-cell and perforated-patch
recordings were made from visually identified layer V pyramidal cells
from the mPFC using infrared video differential interference contrast (DIC) microscopy (Stuart et al., 1993) with a 40× water-immersion objective. To ensure that these cells did not have cut apical dendrites, we positioned our slices such that the apical dendrites were
either in the same plane as the soma or descended into the slice.
Several cells were filled with biocytin for postexperiment verification
of dendritic presence (see Fig. 1B) (Chitwood et al.,
1997). Patch pipettes (2-5 M ) were filled with (in mM): 120 K-gluconate, 10 HEPES, 0.1 EGTA, 20 KCl, 2MgCl2,
3 Na2ATP, and 0.3 NaGTP, pH 7.3. Perforated-patch
recordings were made by adding nystatin to the pipette solution (final
concentration was 500 µg/ml, 0.30% DMSO).
Current-clamp recordings were made using an AxoClamp 2B amplifier (Axon
Instruments, Foster City, CA) and were digitized at 1 or 3 kHz using an
ITC-16 interface (Instrutech, Great Neck, NY) connected to a Power
Macintosh 8100 computer running AxoData (Axon Instruments) acquisition
software. Whole-cell pipette series-resistance (RS) was less than 20 M and was bridge
compensated. Analyses of electrical responses were performed using
custom software written with Igor Pro (Wavemetrics, Lake Oswego, OR).
Only one neuron experiencing a single drug treatment was used from each
brain slice. In all cases, only cells with a resting potential of at least  60 mV and stable baseline responses were given drug
treatments.
Experimental paradigm. To measure cell excitability, action
potentials were evoked by 1-sec-long depolarizing current
injections (100-400 pA) at 0.1 Hz. Input resistance
(RN) was determined from linear
regression in the linear range (generally ± 10 mV from resting
potential) of the voltage-current relationship established by plotting
the steady-state voltage change in response to a series of depolarizing
and hyperpolarizing current injections (see Fig. 2C,D). After baseline measurements of
action potential number and RN, DA
(0.01-30 µM) was bath applied for ~5 min. Two
gravity-fed perfusion lines were used to change solutions. New
solutions reached the recording chamber in <1 min, as determined by
exchanging water with a dyed solution, and reached full concentration
in ~2 min. Although complete washout from the chamber took between 10 and 12 min, the majority of dye was removed after 5 min. Both control and drug aCSF were continuously oxygenated throughout experiments. Ascorbate (1 µM) and nomifensine (1 µM)
were added to all DA solutions to reduce oxidation and to prevent DA
uptake into dopaminergic fibers, respectively.
Experimentally produced changes in membrane potential
(Vm) were compensated with a bias current to
maintain Vm at baseline levels. The bias current
was removed where noted. Stock solutions of all drugs were made fresh
daily and mixed into oxygenated aCSF as needed. Dopaminergic agonists
and antagonists were obtained from Research Biochemicals (Natick, MA).
Other substances were purchased from Sigma (St. Louis, MO).
Analysis and statistics. For each cell, the number of spikes
evoked by depolarizing current steps was quantified by averaging the
number of spikes produced in five consecutive traces immediately before, at the end of, and 5 min after drug application. Furthermore, for cells that showed a change in evoked spikes during a given drug
treatment, only those that exhibited a reversible effect (a washout of
at least 50% of the effect) were used for analysis to ensure that the
effect was not caused by a general rundown. Numerical values are
expressed as mean ± SEM. In most experiments, the effects of DA
or DA agonists were compared with controls using a Student's
t test for unpaired samples. "Within-cell"
comparisons used a Student's t test for paired samples
where noted. Comparisons of dopaminergic effects across concentrations
were made using a one-way ANOVA.
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RESULTS |
We examined the effects of bath-applied DA or DA agonists on
visually identified layer V pyramidal cells from the anterior cingulate
and prelimbic areas of the rat dorsal mPFC (Fig.
1A). These neurons were
identified using DIC video microscopy by their large pyramidal-shaped
somas ( 20 µm diameter) and by the presence of long apical
dendrites extending toward the pial surface (Fig. 1B). Of 53 cells for which the dorsoventral
position was recorded, 68% were identified as prelimbic because of
their position below the dorsal peak of the forceps minor of the corpus
callosum. The remainder of these cells was from the anterior cingulate.
Baseline physiology and responses to DA were similar in cells from both regions.
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Figure 1.
Location and morphology of recorded cells.
A, Illustration of a coronal slice that includes the
mPFC. The box shows the area in which cells for this
study were patched. Shaded areas denote corpus callosum.
B, Photomicrograph of a biocytin-labeled layer V
pyramidal cell from the rat mPFC. Scale bar, 100 µm.
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Once selected, patch electrodes were sealed onto the somas of these
cells for whole-cell or perforated-patch recording. In response to
suprathreshold current steps (1 sec duration), these cells exhibited
modest spike frequency accommodation, often after an initial spike
"doublet" (see Figs. 2A, 6A,
7A). Doublets were observed in 75% of recorded cells. This
firing pattern was similar to the "intrinsic bursting" cells
reported by Yang et al. (1996). Furthermore, when single spikes were
evoked, these same cells regularly demonstrated depolarizing
afterpotentials (data not shown) (Yang et al., 1996; Haj-Dahmane and
Andrade, 1997). Burst firing, corresponding to "repetitive
oscillatory bursting" cells (Yang et al., 1996), was only observed in
six cells.
Effect of DA on neuron excitability
The effect of bath-applied DA on the excitability of layer V
pyramidal cells was studied by measuring changes in spike number in
response to a 1-sec-long depolarizing current injection. The amplitude
of the injected current (100-400 pA) was adjusted to evoke
approximately six action potentials (the mean number of baseline action
potentials was 6.1 ± 0.1 spikes; n = 119). After 2-5 min of baseline measurements, DA (0.01-30 µM) was
bath applied for ~5 min, followed by a 5-10 min washout period. In
39 of 41 cells (95%), we observed a reversible decrease in the number
of evoked spikes (Fig.
2A). The mean decrease
in action potential number for all cells was 57 ± 4%
(n = 41). In one experiment, there was a nonreversible
increase in evoked spikes during DA treatment (an increase from seven
to eight spikes in 10 nM DA), whereas in another cell DA
had no effect. An effect of DA on the number of evoked spikes could be
seen within 2 min after the onset of DA application (Fig.
2B). Biphasic responses to DA (i.e., transient increases in spike number preceding depression) were not observed during drug application.
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Figure 2.
DA decreases the excitability of layer V pyramidal
cells. A, Representative action potentials evoked by a
1-sec-long depolarizing current injection before (top),
during (middle), and after (bottom) the
bath application of 1 µM DA. B, Time
course illustrating the reduction in spike number during the
application of DA. A decrease in the number of spikes is seen within 2 min of DA application. Note the transient rebound increase in the
number of spikes after DA washout. C, Membrane response
to a variety of positive and negative current steps before
(top), during (middle), and after
(bottom) the application of 1 µM DA.
D, A plot of the voltage-current relationship before
(open circles), during (filled
circles), and after (open squares) DA
application. All data shown are from the same layer V pyramidal
cell.
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In control experiments, 5 min treatment (after 2-5 min of baseline
measurements) with 1 µM ascorbate and 1 µM
nomifensine alone decreased the number of evoked spikes by 11 ± 6% (n = 7). This change from baseline was neither
reversible nor significant (df = 6; t = 1.7;
p > 0.05; Student's t test for paired
samples). The reduction in spike number produced by DA was
significantly different from changes observed in controls (df = 46; t = 4.3; p < 0.05). When grouped
according to the concentration of DA applied, significant decreases in
spike number were observed at DA concentrations >10 nM
(Fig. 3A). There was, however,
no dose dependence at concentrations between 50 nM and 30 µM (df = 35; F = 0.92;
p > 0.05; ANOVA).
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Figure 3.
DA decreases the excitability of layer V pyramidal
cells over a range of concentrations. A, Summary of the
percent decrease in spike number for different DA concentrations.
B, Summary of changes in RN
for a range of DA concentrations. For this and other figures,
asterisks denote significant changes in the number of
spikes and RN (p < 0.05).
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DA produced a reversible depression of excitability over a wide range
of current intensities (Fig.
4A). In six of seven
cells, the number of spikes produced by varying levels of depolarizing current injection was reversibly depressed by the addition of DA (30 µM) to the aCSF. Doublets were observed at the beginning of spike trains in all of these cells, although the current intensities needed to generate them varied from cell to cell. In the presence of
DA, the amount of current required to trigger doublets was significantly increased by 9.1 ± 1.5% (df = 6;
t = 5.3; p < 0.05; Student's
t test for paired samples). The increase in threshold for
doublet generation was reversible after the washout of DA, and in six
of seven cells, less current was required for doublet expression after
DA treatment than was required in baseline conditions.
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Figure 4.
Dopaminergic depression of the number of evoked
spikes is not dependent on the level of excitatory input but is
correlated with changes in RN.
A, An example of the current-spike relationship for a
cell treated with 30 µM DA. This cell, and five of six
others, demonstrated an overall depression of excitability, followed by
a rebound excitation. B, Plot of the relationship
between changes in spike number and RN for
all cells from which both measurements were taken.
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During more prolonged exposures to DA (15-20 min), the effect of 10 µM DA on excitability was unstable; after an initial
decrease in the number of spikes, the membrane excitability transiently returned to near baseline levels without overshooting (data not shown).
Repeatedly, DA produced a transient depression in spike number. This
oscillatory response had a period of ~5 min and lasted for the
duration of DA application (n = 4).
We also monitored the RN of 30 of the 48 cells
referred to above before, during, and after DA treatment, as described
(Fig. 2C,D). The initial
RN for these neurons was 111 ± 5 M.
Bath application of DA produced a reversible decrease of
RN in 24 of the 30 cells (80%). The mean
decrease in RN was 11 ± 2%
(n = 30). This was significantly different from changes
observed in control cells (n = 7), which showed
only a 2 ± 3% decrease in RN (df = 35; t = 2.7; p < 0.05). Significant
decreases in RN were observed at DA
concentrations between 50 nM and 1 µM.
Interestingly, unlike changes in action potential number, an inverted
"U-shaped" dose dependence was observed for
RN. At 30 µM, DA had no
significant effect on RN. Changes in
RN for cells treated with 30 µM DA
were significantly different from those treated with concentrations between 50 nM and 1 µM (df = 26;
F = 6.3; p < 0.05; ANOVA).
Because decreases in RN will tend to reduce the
number of spikes evoked by depolarizing current injections, we tested
whether there was a correlation between changes in
RN and the number of evoked action potentials
(Fig. 4B). As expected, there was a significant correlation between changes in evoked spikes and changes in
RN (r2 = 0.27;
n = 88; p < 0.05). This suggests that
DA-induced changes in RN may contribute, at
least in part, to the inhibition of pyramidal neuron firing.
Control experiments
The results described above conflict with a number of previous
reports (Table 1) on the effects of DA on
layer V pyramidal neurons in rat mPFC (Penit-Soria et al., 1987; Yang
and Seamans, 1996; Shi et al., 1997). In an attempt to account for why
our results differed so significantly from Yang and Seamans (1996) and
to possibly resolve any differences in experimental procedures, the
following control experiments were performed.
Absence of synaptic transmission
Inhibitory neurons in mPFC that synapse onto layer V pyramidal
cells (Houser et al., 1983; Kawaguchi, 1993; Kawaguchi and Kubota,
1993) express DA receptors (Vincent et al., 1993) and may exhibit
DA-induced changes in cell excitability (Penit-Soria et al., 1987; Yang
et al., 1997; Zheng et al., 1997). Because spontaneous synaptic input
can modulate the passive properties of neurons (Sah et al., 1989;
Softky and Koch, 1993), we tested the hypothesis that DA reduces the
excitability of layer V pyramidal cells by increasing spontaneous
synaptic transmission. We added the nonselective ionotropic glutamate
receptor antagonist kynurenate (1 mM) and the
GABAA receptor blocker picrotoxin (10 µM) to
the aCSF before the application of 500 nM DA to block fast
excitatory and inhibitory synaptic input (Fig.
5). Under these conditions (n = 6), DA still produced a significant decrease in
the number of evoked spikes of 60 ± 12% (df = 11;
t = 3.6; p < 0.05) (Fig. 5A,B). Consistent with our previous
experiments, RN was also significantly reduced
by 18 ± 3% (df = 11; t = 4.0;
p < 0.05) (Fig. 5C). These results indicate
that the effects of DA are not caused by changes in spontaneous
synaptic transmission.
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Figure 5.
Changes in spontaneous synaptic transmission are
not responsible for DA-induced decreases in neuron excitability.
A, In the presence of kynurenate (1 mM) and
picrotoxin (10 µM), 500 nM DA reversibly
reduced the number of evoked spikes. B, Summary of the
effects of DA on six cells treated with kynurenate and picrotoxin.
C, Summary of normalized RN
for the same cells as in B.
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Perforated patch experiments
In previous investigations, sharp microelectrode recordings were
used to assess the effects of DA on the excitability of layer V neurons
in vitro (Penit-Soria et al., 1987; Law-Tho et al., 1994;
Geijo-Barrientos and Pastore, 1995; Yang and Seamans, 1996; Shi et al.,
1997). We next tested the possibility that, through the use of the
whole-cell recording technique, we were unknowingly changing the
internal environment of these cells sufficiently to mask other effects
of DA (i.e., an increase in excitability). To control for this
possibility, perforated-patch recording methods were used in 11 experiments (Fig. 6). Again, as observed
with whole-cell recordings, the number of spikes evoked in the presence of 500 nM DA was significantly less than the number of
spikes evoked in baseline conditions. The mean change observed was
28 ± 6% (df = 10; t = 4.5;
p < 0.05; Student's t test for paired samples). This change, however, was not significantly different from
whole-cell DA experiments.
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Figure 6.
DA-induced decreases in neuron excitability are
not caused by whole-cell washout. A, Perforated-patch
recording of evoked spikes. In this example, 500 nM DA
reversibly depressed the number of spikes. B, Summary of
the number of spikes before, during, and after the application of 500 nM DA for 11 cells recorded with the perforated-patch
technique.
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Experiments at ~31°C
Most previous studies on the effects of DA on layer V pyramidal
neuron excitability were performed at temperatures above 30°C. This
variable might affect the response of layer V neurons to DA. Additional
experiments were conducted at ~31°C (as opposed to room
temperature, ~23°C). For these experiments, we chose a concentration of DA (30 µM) within the range used in
previous investigations (Table 1). Application of 30 µM
DA produced a significant and reversible depolarization of 1.8 ± 0.4 mV from baseline levels (df = 8; t = 4.8;
p < 0.05; Student's t test for paired
samples), which is consistent with previous reports (Penit-Soria et
al., 1987; Law-Tho et al., 1994; Geijo-Barrientos and Pastore, 1995;
Shi et al., 1997). Despite this modest depolarization, DA still
decreased the number of evoked spikes from baseline levels by 44 ± 12% (df = 8; t = 3.8; p < 0.05; Student's t test for paired samples) (Fig.
7A,B).
When the membrane potential of the neuron was returned to
baseline levels, DA reduced the number of evoked spikes by 88 ± 6% (df = 8; t = 14; p < 0.05;
Student's t test for paired samples) (Fig.
7A,C). This was significantly
greater than the effects of 30 µM DA at room temperature
(df = 13; t = 3.7; p < 0.05).
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Figure 7.
The effect of DA on neuron excitability at
~31°C. A, Application of 30 µM DA
depolarized the resting potential from 75 mV to 73 mV. The number
of action potentials generated by 300 pA decreased from six to four
spikes (left traces). When bias current (~25 pA) was
used to hold the membrane potential at 75 mV, 300 pA was unable to
evoke spikes (top right). After 5 min washout, membrane
potential returned to 75 mV and 300 pA injection evoked eight spikes
(bottom right). B, Summary of the effects
of DA when the membrane potential was allowed to depolarize (no bias
current was applied). C, Summary of the effects of DA
when bias current was used to hold the Vm to
baseline values.
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We found that the mean RN of all cells recorded
at ~31°C was 81 ± 10 M (n = 20), which was
significantly lower than the RN of cells
recorded at room temperature (df = 94; t = 4.2;
p < 0.05). RN was measured
before, during, and after the application of 30 µM DA
(n = 8) and showed a significant decrease of 16 ± 3% (df = 7; t = 3.5; p < 0.05).
In these and all other experiments, measurements of
RN were made while the membrane potential was
maintained at baseline levels.
In five of nine of these experiments, as well as in a subset of the
previous experiments, a transient increase in the number of spikes,
above baseline levels, was observed after the washout of DA (Fig. 7;
see also Figs. 2A, 4A,
6A). The magnitude of this rebound effect was
3.2 ± 0.6 spikes (n = 5), with a corresponding increase in RN of 9 ± 3% from
baseline. The time course of this effect was highly variable and not
quantified in the present study. Of the cells recorded at room
temperature (described above), a rebound excitation in spike number was
observed in 16 of the 39 experiments (41%) with a mean rebound of
1.1 ± 0.2 spikes (n = 16).
We also examined the effect of DA on spike threshold and spike latency
for cells treated at ~31°C. Although there was a general trend for
the spike threshold to shift to more depolarized levels in DA, the
effect was small (<1 mV), was not significant, and did not reverse
after the removal of DA. As expected, we observed a reversible increase
in spike latency (the time from the beginning of the current pulse to
the peak of the first action potential). The increase in spike latency
was 79 ± 13%. In five of nine cells, we also observed shorter
spike latency after the washout of DA compared with baseline values,
consistent with the rebound effect on spike number, as described
above.
Controls for animal age and strain
Rats may show both developmental and strain-related differences in
dopaminergic innervation and physiology (Buzsaki et al., 1990; Godefroy
et al., 1991). We examined the effect of DA on young adult
(10-week-old) Sprague Dawley rats. Figure
8A summarizes the
effect of 30 µM DA on pyramidal cells from the mPFC of
10-week-old Sprague Dawley rats. In these cells (n = 4)
recorded at ~31°C, 30 µM DA produced a significant
75 ± 12% decrease in the number of spikes (df = 9;
t = 5.1; p < 0.05). Additionally, DA
elicited a significant change in RN of 16 ± 3% (df = 9; t = 3.2; p < 0.05). Similar results were obtained in cells from Long-Evans rats
(20- to 30-d-old) treated with 10 µM DA (Fig.
8B). Of the four cells recorded from Long-Evans
mPFC, one was recorded at ~31°C, and the other three were recorded
at room temperature. In these experiments, DA induced a 71 ± 11% change in the number of spikes (df = 9; t = 5.1; p < 0.05) and a 13 ± 3% change in
RN (df = 9; t = 2.5; p < 0.05). Together, these results suggest that DA has
a generalized depressive effect on PFC pyramidal cell excitability,
which is neither age- nor animalstrain-specific.
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Figure 8.
Effects of DA are not age- or
animal-strain-specific. A, Summary of data collected
from PFC slices obtained from 10-week-old Sprague Dawley rats. The
application of 30 µM DA reversibly decreased both spike
number and RN (n = 4).
B, Summary of data obtained from four cells recorded
from slices of PFC from Long-Evans rats. In these experiments, 10 µM DA induced decreases in spike number and
RN similar to those seen in Sprague Dawley
rats.
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Pharmacology of dopaminergic depression of excitability
To determine which DA receptor subtype might mediate the observed
changes in spike number and RN, the
effects of DA were challenged by antagonists to either the D1 or D2
family of DA receptors (Fig. 9A). In the presence of the D1
receptor antagonist SCH 23390 (1 µM), 500 nM
DA (n = 7) significantly decreased the number of spikes compared with control cells (mean change, 47 ± 12%; df = 12; t = 2.6; p < 0.05). The change in
spikes observed in SCH 23390 was not significantly different from
changes observed when 500 nM DA was applied alone (df = 11; t = 0.5; p > 0.05). Conversely, when 1 µM DA was applied 5 min after the bath application
of the D2 receptor antagonist sulpiride (1 or 10 µM), the
change in the number of spikes was only 17 ± 11%
(n = 7). This change was not significantly different
from control cells treated with nomifensine and ascorbate alone
(df = 12; t = 0.5; p > 0.05) but
was significantly different from cells treated with 1 µM
DA (df = 22; t = 3.9; p < 0.05).
Additional within-cell experiments (n = 3) were
performed with sulpiride under heated (~31°C) conditions. Much like
the experiments described above, DA (10 µM) was added to
a bathing solution already containing sulpiride (10 µM).
After 5 min of recording, sulpiride was removed from the bath, leaving
DA alone (Fig. 10). Figure
10A shows the time course of action potential number
for one of these cells. As expected, DA had no effect on spike number
while sulpiride was present. However, once sulpiride was removed from
the bathing solution, the number of evoked spikes decreased 81 ± 5% (df = 8; t = 6.6; p < 0.05)
(Fig. 10B). The application of 10 µM DA
in the presence of sulpiride produced only a 8 ± 8% change in
RN. Once it was removed, however, there was a
significant decrease in RN of 19 ± 4%
(df = 8; t = 3.4; p < 0.05) (Fig.
10C). These data suggest that DA modulates pyramidal cell
excitability via activation of D2 type receptors.
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Figure 9.
DA may depress layer V pyramidal neuron
excitability via a D2 receptor subtype. A, The number of
spikes before, during, and after the bath application of DA in
the presence of a D1 or D2 antagonist (top row) or the
application of a D1 or D2 agonist (bottom row). The D2
antagonist sulpiride (1 or 10 µM) blocked the effects of
500 nM DA, whereas the D1 antagonist SCH 23390 (1 µM) had no significant effect. In addition, only the D2
agonist quinpirole (1 µM) mimicked the effect of DA.
B, Changes in RN for the
different agonist and antagonist treatments, as well as for 500 nM DA alone.
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Figure 10.
Sulpiride reversibly blocks the effect of DA.
A, Example of time course from an experiment in which
sulpiride (10 µM) was bath applied before the addition of
10 µM DA. In the presence of sulpiride, DA did not
depress spike number. However, once sulpiride was washed out, a
reversible decrease in the number of spikes was observed.
B, Summary of changes in the number of evoked spikes for
within-cell sulpiride experiments (n = 3).
C, Summary of changes in
RN.
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To further characterize the receptor subtype involved, specific
agonists to D1 or D2 receptors were applied (Fig. 9A). Bath application of the D1 receptor agonist SKF 38393 (5 µM)
resulted in an 18 ± 6% decrease in the number of spikes
(n = 7), although this was not significantly different
from controls (df = 12; t = 0.8; p > 0.05). Similarly, the bath application of another more selective D1
agonist, SKF 81297, did not produce a significant change in spike
number (mean change, 10 ± 3%; n = 4). Although these D1 agonists appear ineffective in inhibiting pyramidal cell firing, exposure to the D2 receptor agonist quinpirole (1 µM) resulted in a significant 47 ± 14% decrease in
the number of evoked spikes (n = 5; df = 10;
t = 2.6; p < 0.05).
In contrast to their effects on spike number, neither the D1 antagonist
SCH 23390 nor the D2 antagonist sulpiride blocked the effects of DA on
RN (Fig. 9B). However, only the D2
agonist quinpirole was consistently effective in producing a
significant decrease in RN compared with
controls (mean change, 15 ± 1%; df = 9; t = 3.3; p < 0.05). Neither SKF 38393 (mean change,
14 ± 6%; n = 7) nor SKF 81297 (mean change,
5 ± 2%; n = 4) produced significant changes in
RN. Together, these experiments indicate that D2
receptor activation may preferentially depress
RN, although a contribution of D1 receptors is
also suggested.
| |
DISCUSSION |
Cellular effects of DA
In this study, we found that DA depressed the excitability of
layer V pyramidal neurons, as indicated by decreases in both the number
of evoked spikes and RN. The effect of DA on
action potential number was comparable over a wide range of DA
concentrations (50 nM to 30 µM); there was no
inverted U-shaped relationship between DA and pyramidal neuron firing.
Interestingly, however, we did observe such a relationship between the
concentration of DA and decreases in RN. There
was a window of DA concentrations (50 nM to 1 µM) that effectively depressed RN.
Although our results are generally consistent with results from
in vivo experiments in rodents (Ferron et al., 1984; Mantz et al., 1988; Yang and Mogenson, 1990; Pirot et al., 1992) and the
in vitro study of Geijo-Barrientos and Pastore (1995), three other studies on layer V pyramidal neurons have reported DA-induced increases in excitability (Table 1). Yang and Seamans (1996) found that
D1 receptor activation was responsible for increasing pyramidal
neuron excitability via the facilitation and depression of
Na+ and K+ currents,
respectively. Shi et al. (1997) observed a significant DA-induced
depolarization with a concomitant increase in firing. In a study of the
actions of DA on synaptic transmission, no significant effect of DA on
excitability was reported (Law-Tho et al., 1994). The only consistent
observation among these studies is that DA depolarizes layer V
pyramidal neurons.
What might account for the wide variability in the results of the
different in vitro experiments described above? An
examination of the studies presented in Table 1 suggests no
significant differences in the age of the animals, no apparent
correlation with the concentration of DA, and no obvious differences in
the in vitro techniques used, except, perhaps, our use of
whole-cell patch recording.
Control experiments with perforated-patch electrodes rule out the
possibility that intracellular dialysis by whole-cell pipettes affected
our results. In these experiments, DA still induced a reduction in
evoked action potentials, albeit smaller than in whole-cell
experiments. During many of the perforated-patch experiments, there was
a progressive decrease in RS during the course
of the experiment, presumably caused by an increasing concentration of nystatin at the pipette tip. A slow decrease in
RS would, by itself, tend to increase the
membrane response to current injections. Alternatively, because DA
receptor coupling to second-messenger systems is dependent on
intracellular GTP (Jackson and Westlind-Danielsson, 1994), the
increased effect of DA during whole-cell experiments may be caused by
elevated levels of GTP in the pipette solution.
Might DA modulate neuron excitability through an effect on synaptic
transmission? DA has been reported to excite nonpyramidal and
presumably GABAergic cells in the rat mPFC (Penit-Soria et al., 1987;
Yang et al., 1997; Zheng et al., 1997). An increase in GABA
transmission would be expected to produce decreases in both
RN and spiking activity in pyramidal neurons.
All of the groups listed in Table 1, except Geijo-Barrientos and
Pastore (1995), included the GABAA receptor blocker
bicuculline in their experiments. Results from our experiments in which
both ionotropic glutamate and GABAA receptors were blocked
suggest that our results are not attributable to changes in fast
synaptic transmission. The influence of GABAB receptors or
the actions of other neuromodulators on pyramidal cell excitability,
however, cannot be ruled out.
At least four of the other five studies listed in Table 1 were
performed at temperatures above 30°C (Shi et al., 1997 did not
specify temperature), and it is not implausible that DA-induced excitability is temperature dependent. If this were the case, excitatory effects of DA might not be observed in experiments conducted
at room temperature. However, in the present study, we have found that
at ~31°C, DA exerted a more potent inhibition of cell firing.
DA receptors can exhibit rapid desensitization after agonist binding
(Lohse, 1993; Freedman and Lefkowitz, 1996), and desensitization of
specific receptor types may occur during prolonged bath application of
DA (but see Law-Tho et al., 1994; Geijo-Barrientos and Pastore, 1995)
rather than during relatively brief exposure to DA (Yang and Seamans,
1996). If receptor desensitization were responsible for the decreases
in excitability reported here, we would have expected to see an initial
increase in excitability during DA application. As exemplified in
Figure 2B, no transient increases in excitability
were observed during the initial periods of DA exposure. Additionally,
inactivation during prolonged DA exposure might reveal an increase in
excitability. This was not supported by the experiments in which
the duration of DA exposure was increased from 5 to 20 min. Finally,
there may be more complex time-dependent effects of DA. For example,
tonic activation of DA receptors may inhibit the activity of PFC
neurons, whereas more acute or phasic exposure to DA may enhance
excitability. Further experiments will be needed to test this
hypothesis.
It may be possible that developmental differences account for the
action of DA on these neurons (Buzsaki et al., 1990; Godefroy et al.,
1991). Although all of the age-ranges listed in Table 1 are similar, we
attempted to make sure that our results were not dependent on the
developmental stage of these animals by repeating experiments using
older (10-week-old) rats. We observed no differences in the effects of
DA between younger and 10-week-old animals, suggesting that the effects
of DA on these cells are stable throughout young adulthood.
Whereas most of the studies outlined in Table 1 used Sprague Dawley
rats, both Geijo-Barrientos and Pastore (1995) and Penit-Soria et al.
(1987) used slices obtained from Wistar rats, raising the possibility
that there may be strain-specific differences in DA physiology in the
mPFC. Our results from young Long-Evans rats and the results of
Geijo-Barrientos and Pastore (1995) suggest instead that the action of
micromolar concentrations of DA on layer V pyramidal cells of the mPFC
is consistent across a variety of animal strains.
Pharmacology of dopamine response
In contrast to the numerous behavioral reports
demonstrating D1 effects on PFC function in nonhuman primates and
rodents (Sawaguchi and Goldman-Rakic, 1991; Seamans et al., 1995;
Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996; Zahrt et al.,
1997; Seamans et al., 1998; but see Verma and Moghaddam, 1996), there
are a number of in vivo studies suggesting that D2 receptor
activation results in an inhibition of neuronal firing in rat mPFC
(Sesack and Bunney, 1989; Parfitt et al., 1990; Yang and Mogenson,
1990). Consistent with these in vivo studies, the
dopaminergic depression of cell firing we report here appears to be
associated with D2 receptor activation (Fig. 9).
The effect of DA on RN appeared to be
better associated with D2 receptor activation because the D2 agonist
preferentially produced decreases in RN,
whereas the D1 agonists did not. However, the experiments with D1 and
D2 antagonists suggest that the effects of DA on
RN may result from cross-reactivity between the
two receptor subtypes or the activation of other receptor types.
DA modulates the excitability of cells in other brain systems,
including CA1 pyramidal cells in the rat hippocampus. As in the mPFC,
reports of the effects of DA on CA1 cells have been difficult to
reconcile. Several studies have indicated that DA has an inhibitory
effect on their excitability (Stanzione et al., 1984; Pockett, 1985;
Cantrell et al., 1997), whereas others have suggested an excitatory
role (Malenka and Nicoll, 1986; Pedarzani and Storm, 1995). Although
inhibitory influences of DA have been shown to be mediated via DA
receptor activation (Stanzione et al., 1984; Cantrell et al., 1997),
the excitatory effects of DA were not blocked by DA receptor
antagonists (Malenka and Nicoll, 1986; Pedarzani and Storm, 1995). An
interesting finding by Malenka and Nicoll (1986) was that DA (10-100
µM) increases cell excitability via the activation of
 -adrenergic receptors. Although Pedarzani and Storm (1995) dispute
this finding, it may be that DA can activate adrenergic receptors in
mPFC. Under certain conditions, these or other receptors may be
amenable to DA activation, and such cross-reactivity may explain the
highly variable results observed in both the hippocampus and mPFC.
Models of dopaminergic modulation
A functional result of dopaminergic inhibition of excitability is
to increase the signal-to-noise level of pyramidal cell output. Only
those cells receiving strong synaptic input, presumably those with
significant information content, will fire (Spitzer and Neumann, 1996).
In addition to damping the effect of excitatory synaptic input, DA may
also play a roll in synaptic plasticity; DA facilitates the induction
of long-term depression of synapses onto layer V mPFC neurons (Law-Tho
et al., 1995; Otani et al., 1998).
Yang and Seamans (1996) have proposed an interesting model for
dopaminergic modulation of signal integration in layer V pyramidal cells in the mPFC. They suggest that D1 receptor activation may transiently change the integrative weight of apical (presumably cortico-cortical) verses basal (presumably subcortical) synaptic input
to layer V pyramidal cells and therefore modify PFC output. An
integrative modulation such as this, together with signal filtering proposed here via a D2-associated depression of excitability, may
establish a necessary state of the PFC network for proper working
memory function. A more detailed understanding of the effects of DA on
these and other cell types of the mPFC will provide a basis for a more
complete understanding of information processing in this area of the
brain.
| |
FOOTNOTES |
Received June 15, 1998; revised Aug. 19, 1998; accepted Aug. 21, 1998.
This work was supported by the National Institute of General Medical
Sciences Grant GM0P194-1751.
Correspondence should be addressed to David B. Jaffe, Division of Life
Sciences, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, TX 78249.
| |
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Copyright © 1998 Society for Neuroscience 0270-6474/98/18219139-13$05.00/0
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X. Sun, Y. Zhao, and M. E. Wolf
Dopamine Receptor Stimulation Modulates AMPA Receptor Synaptic Insertion in Prefrontal Cortex Neurons
J. Neurosci.,
August 10, 2005;
25(32):
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[Abstract]
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J. Wu and J. J. Hablitz
Cooperative Activation of D1 and D2 Dopamine Receptors Enhances a Hyperpolarization-Activated Inward Current in Layer I Interneurons
J. Neurosci.,
July 6, 2005;
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[Abstract]
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S. Bandyopadhyay, C. Gonzalez-Islas, and J. J. Hablitz
Dopamine Enhances Spatiotemporal Spread of Activity in Rat Prefrontal Cortex
J Neurophysiol,
February 1, 2005;
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864 - 872.
[Abstract]
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H. Trantham-Davidson, L. C. Neely, A. Lavin, and J. K. Seamans
Mechanisms Underlying Differential D1 versus D2 Dopamine Receptor Regulation of Inhibition in Prefrontal Cortex
J. Neurosci.,
November 24, 2004;
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[Abstract]
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D. Eytan, A. Minerbi, N. Ziv, and S. Marom
Dopamine-Induced Dispersion of Correlations Between Action Potentials in Networks of Cortical Neurons
J Neurophysiol,
September 1, 2004;
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[Abstract]
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K. Y. Tseng and P. O'Donnell
Dopamine-Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms
J. Neurosci.,
June 2, 2004;
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Y. Wang and P. S. Goldman-Rakic
D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons
PNAS,
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[Abstract]
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A. T. Gulledge and G. J. Stuart
Action Potential Initiation and Propagation in Layer 5 Pyramidal Neurons of the Rat Prefrontal Cortex: Absence of Dopamine Modulation
J. Neurosci.,
December 10, 2003;
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S. Otani, H. Daniel, M.-P. Roisin, and F. Crepel
Dopaminergic Modulation of Long-term Synaptic Plasticity in Rat Prefrontal Neurons
Cereb Cortex,
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[Abstract]
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S. B. Floresco and A. A. Grace
Gating of Hippocampal-Evoked Activity in Prefrontal Cortical Neurons by Inputs from the Mediodorsal Thalamus and Ventral Tegmental Area
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May 1, 2003;
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Y. Dong and F. J. White
Dopamine D1-Class Receptors Selectively Modulate a Slowly Inactivating Potassium Current in Rat Medial Prefrontal Cortex Pyramidal Neurons
J. Neurosci.,
April 1, 2003;
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C. Gonzalez-Islas and J. J. Hablitz
Dopamine Inhibition of Evoked IPSCs in Rat Prefrontal Cortex
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A. T. Gulledge and D. B. Jaffe
Multiple Effects of Dopamine on Layer V Pyramidal Cell Excitability in Rat Prefrontal Cortex
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August 1, 2001;
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M. Rubinstein, C. Cepeda, R. S. Hurst, J. Flores-Hernandez, M. A. Ariano, T. L. Falzone, L. B. Kozell, C. K. Meshul, J. R. Bunzow, M. J. Low, et al.
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J. K. Seamans, N. Gorelova, D. Durstewitz, and C. R. Yang
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J. Wang and P. O'Donnell
D1 Dopamine Receptors Potentiate NMDA-mediated Excitability Increase in Layer V Prefrontal Cortical Pyramidal Neurons
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B. A. Sorg, N. Li, and W.-R. Wu
Dopamine D1 Receptor Activation in the Medial Prefrontal Cortex Prevents the Expression of Cocaine Sensitization
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N. Maurice, T. Tkatch, M. Meisler, L. K. Sprunger, and D. J. Surmeier
D1/D5 Dopamine Receptor Activation Differentially Modulates Rapidly Inactivating and Persistent Sodium Currents in Prefrontal Cortex Pyramidal Neurons
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April 1, 2001;
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E. K. Lambe, L. S. Krimer, and P. S. Goldman-Rakic
Differential Postnatal Development of Catecholamine and Serotonin Inputs to Identified Neurons in Prefrontal Cortex of Rhesus Monkey
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December 1, 2000;
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F. M. Benes, J. B. Taylor, and M. C. Cunningham
Convergence and Plasticity of Monoaminergic Systems in the Medial Prefrontal Cortex during the Postnatal Period: Implications for the Development of Psychopathology
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[Abstract]
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N. A. Gorelova and C. R. Yang
Dopamine D1/D5 Receptor Activation Modulates a Persistent Sodium Current in Rat Prefrontal Cortical Neurons In Vitro
J Neurophysiol,
July 1, 2000;
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[Abstract]
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D. Durstewitz, J. K. Seamans, and T. J. Sejnowski
Dopamine-Mediated Stabilization of Delay-Period Activity in a Network Model of Prefrontal Cortex
J Neurophysiol,
March 1, 2000;
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[Abstract]
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D. Durstewitz, M. Kelc, and O. Gunturkun
A Neurocomputational Theory of the Dopaminergic Modulation of Working Memory Functions
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Top
Abstract
Introduction
