Download Dopamine Receptor–Mediated Mechanisms Involved in the

Dopamine Receptor–Mediated Mechanisms Involved in the Expression
of Learned Activity of Primate Striatal Neurons
KATSUSHIGE WATANABE 1,2 AND MINORU KIMURA 1
1
Faculty of Health and Sport Sciences, Osaka University, Toyonaka, Osaka 560; and 2 Department of Neurosurgery,
School of Medicine, Gunma University, Maebashi, Gunma 371, Japan
INTRODUCTION
To acquire a new behavioral repertoire under new environmental conditions is one of the most important functions of
the brain. It is especially true for humans, who have a large
variety of behavioral repertoires. It has been suggested that
the cerebellum and its related subcortical structures are critically involved in motor learning, such as adaptive learning in
the vestibuloocular reflex (Ito 1984; Raymond and Lisberger
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1996), conditioned eye blink response (Krupa et al. 1993),
and coordination in limb movement control (Thach et al.
1992).
The basal ganglia have recently been suggested to play a
major role in the process of behavioral learning (Aosaki et
al. 1994a,b; Cools 1980; Hikosaka 1992; Kimura 1995;
Schultz et al. 1997). Marsden (1982) drew a conclusion
that the basal ganglia are responsible for automatic execution
of learned motor plans, based on the observations of motor
abnormalities in a large number of Parkinson’s disease patients. The involvement of the basal ganglia in learning
seems different from that of the cerebellum. Cools (1980)
suggested that the nigrostriatal dopamine (DA) system takes
part in sequencing and selecting behavioral strategies. In a
positron emission tomography (PET) study using human
subjects, Seitz and Roland (1992) demonstrated a selective
increase of regional blood flow in the putamen and globus
pallidus in the process of learning sequential finger movements. Matsumoto et al. (1994) showed that there is a selective impairment of learning arm movement sequences after
destruction of the nigrostriatal DA system by local infusion
of dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP).
Two important findings have recently been made on the
neuronal mechanisms through which the basal ganglia play
a role in behavioral learning. One came from observations
of the activity of midbrain DA neurons of monkeys during
learning behavioral tasks (Ljungberg et al. 1992; Mirenowicz and Schultz 1996; Schultz et al. 1993). These DA neurons are activated by appetitive but not aversive stimuli
(Mirenowicz and Schultz 1996), and thus respond to stimuli
predictive of reward. Interestingly, the response of the DA
neurons to reward predictive stimuli gradually disappeared
when monkeys became able to execute behavioral tasks automatically through overtraining (Ljungberg et al. 1992;
Schultz et al. 1993). The other finding is the modification
of striatal neuron activity through behavioral learning and
its control by the nigrostriatal DA system. Aosaki et al.
(1994b) recorded the activity of a class of striatal neurons
of monkeys, tonically active neurons (TANs), which are
believed to be cholinergic interneurons in the striatum (Aosaki et al. 1995; Kawaguchi 1992; Kimura et al. 1996; Wilson et al. 1990). The monkeys were trained to associate
sensory stimuli with reward. These authors demonstrated
that there is a remarkable increase in the number of TANs
(from 10–20% to 50–70% of TANs examined) that responded to reward-associated stimuli through the process of
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Watanabe, Katsushige and Minoru Kimura. Dopamine receptor–mediated mechanisms involved in the expression of learned
activity of primate striatal neurons. J. Neurophysiol. 79: 2568–
2580, 1998. To understand the mechanisms by which basal ganglia
neurons express acquired activities during and after behavioral
learning, selective dopamine (DA) receptor antagonists were applied while recording the activity of striatal neurons in monkeys
performing behavioral tasks. In experiment 1, a monkey was trained
to associate a click sound with a drop of reward water. DA receptor
antagonists were administered by micropressure using a stainless
steel injection cannula (300 mm ID) through which a Teflon-coated
tungsten wire for recording neuronal activity had been threaded.
Responses to sound by tonically active neurons (TANs), a class
of neurons in the primate striatum, were recorded through a tungsten wire electrode during the application of either D1- or D2-class
DA receptor antagonists (total volume õ1 ml, at a rate of 1 ml/5–
10 min). Application of the D2-class antagonist, ( 0 )-sulpiride
(20 mg/ ml, 58 mM, pH 6.8), abolished the responses of four of
five TANs examined. In another five TANs, neither the D2-class
antagonist nor the D1-class antagonists, SCH23390 (10 mg/ ml, 31
mM, pH 5.7) or cis-flupenthixol (30 mg/ ml, 59 mM, pH 6.6)
significantly suppressed responses. In experiment 2, four- or fivebarreled glass microelectrodes were inserted into the striatum. The
central barrel was used for extracellular recording of activity of
TANs. Each DA receptor antagonist was iontophoretically applied
through one of the surrounding barrels. SCH23390 (10 mM, pH
4.5) and ( 0 )-sulpiride (10 mM, pH 4.5) were used. The effects
of iontophoresis of both D1- and D2-class antagonists were examined in 40 TANs. Of 40 TANs from which recordings were made,
responses were suppressed exclusively by the D2-class antagonist
in 19 TANs, exclusively by the D1-class antagonist in 3 TANs,
and by both D1- and D2-class antagonists in 7 TANs. When 0.9%
NaCl, saline, was applied by pressure ( õ1 ml) or by iontophoresis
( õ30 nA) as a control, neither the background discharge rates nor
the responses of TANs were significantly influenced. Background
discharge rate of TANs was also not affected by D1- or D2-class
antagonists applied by either micropressure injection or iontophoresis. It was concluded that the nigrostriatal DA system enables
TANs to express learned activity primarily through D2-class and
partly through D1-class receptor–mediated mechanisms in the striatum.
DA RECEPTOR MECHANISMS IN THE STRIATUM FOR LEARNING
In experiment 2, another monkey (monkey B) performed a visually guided push button task. A light-emitting diode (LED) and a
push button were positioned on a panel placed 50 cm in front of
the monkey. Illumination of the LED triggered a button pushing
movement by the monkey. If the button was depressed within 850
ms after the illumination of LED, a drop of reward water was
delivered. After the monkey had learned this task ( Ç2 wk), we
started to record the activity of TANs in the striatum contralateral
to the task-performing hand (Fig. 1B). The activity of TANs was
recorded first in the right hemisphere while the monkey was performing the task with its left hand, then in the left hemisphere after
switching to the right hand.
Electrophysiological procedures
The activity of single neurons was recorded extracellularly with
either glass-insulated elgiloy microelectrodes (Suzuki and Azuma
1976) or Teflon-coated tungsten wire electrodes in an injectionrecording device (experiment 1) or carbon fiber electrodes in multibarreled glass microelectrodes (experiment 2). Electrical signals
from the electrodes were amplified and filtered in a conventional
manner. Action potentials of single neurons were detected using a
time-amplitude window discriminator and were registered in computer memory (NEC PC98BA). Bipolar Teflon-coated stainless
steel wire electrodes were chronically and/or acutely implanted in
METHODS
We performed two types of experiments using two macaque
monkeys (Macaca fuscata) weighing 6.0 kg (monkey A) and 9.0
kg (monkey B). The experiments were carried out in compliance
with the guidelines for the care and use of experimental animals
by the Physiological Society of Japan. The monkeys were trained
to sit in a primate chair in an isolated, electrically shielded room.
Each monkey was trained to associate the click sound of a solenoid
valve with a liquid reward delivered to a spoon in front of its
mouth. The monkey’s head was mechanically fixed to the chair
through two bolts to record striatal neuron activity and to apply
drugs to the recorded neurons during task performance. The drop
of reward water on the spoon was not visible to the animals. The
behavior of the animals was routinely monitored by a video camera.
Behavioral procedures
In experiment 1, activities of single TANs were recorded in the
caudate nucleus and putamen of monkey A, before and after the
acquisition of behavioral association of a solenoid click with reward water (auditory click-reward association task). A drop of
water was delivered at irregular 5- to 10-s intervals on a spoon in
front of the monkey’s mouth 280 ms after the click sound of
solenoid valve (Fig. 1A).
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FIG . 1. Experimental paradigms used in the present study. A: in experiment 1, monkey A was trained to associate the click sound of a solenoid
valve with a drop of water as a reward. B: in experiment 2, monkey B
performed a visually guided push button task. When a light-emitting diode
(LED) on the board, placed in front of the animal, was illuminated, the
monkey pushed the button to obtain a reward delivered with a solenoid
click.
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learning for Ç3 wk. Quite importantly, it was found that the
acquired responses of TANs almost disappeared when the
nigrostriatal DA system was inactivated either permanently
by MPTP or reversibly by the DA receptor antagonist, haloperidol (Aosaki et al. 1994a). Thus it was suggested that
the nigrostriatal DA system is indispensable for the expression of learned activities of the striatal neurons, TANs.
Molecular cloning studies have shown that there are at
least five DA receptor genes in the striatum (D1a, D2, D3,
D4, and D1b) (Sibley 1995). These receptors can be
grouped into D1 (D1a, D1b) and D2 (D2, D3, and D4)
classes. How these DA receptors are distributed among the
classes of neurons in the striatum has been the subject of
debate. In situ hybridization studies suggested that D1a and
D2 mRNA are segregated primarily in the two major projection neuron classes, one projecting to substantia nigra and
the other projecting to the globus pallidus (Gerfen 1992;
Le Moine and Bloch 1995). Electrophysiological studies
revealed that striatal neurons respond not only to D1-class
but also to D2-class DA receptor agonists (Cepeda et al.
1993; Uchimura et al. 1986). On the other hand, most cholinergic interneurons in the striatum have D2-class receptors
and some of them have D1-class receptors (Le Moine et al.
1991; Levey et al. 1993; Weiner et al. 1991; Yan et al.
1997).
To understand the mechanisms through which the basal
ganglia neurons acquire new activities during behavioral
learning and retrieve learned activity, in particular behavioral
contexts after learning, it is essential to know from where
the striatal neurons receive inputs and which classes of DA
receptor mechanisms are involved in modifying the activities
of the striatal neurons through the process of learning and
memory. In the present study, our goal was to identify DA
receptor subtypes through which the expression of acquired
activities of a class of striatal neurons, TANs, are controlled.
The results of the present study have been published in abstract form (Watanabe et al. 1996).
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the prime mover muscles for the task performance to record an
electromyogram (EMG). These were digastrics, triceps and biceps
brachii. Single-neuron activity and EMG activity were displayed
on the computer display in the form of peristimulus time histograms
during the experiment. The computer controlled the behavioral
tasks.
Surgical procedures
In experiment 1, surgery of monkey A was performed under
initial anesthesia with Ketamine (15 mg/kg im) and then pentobarbital sodium (initial 30 mg/kg im, supplement 5 mgrkg 01rh 01 ).
Local anesthetic, 1 and 8% lidocaine hydrochloride, was also used
to reduce pain. A stainless steel recording chamber was stereotaxically positioned over the skull of the right hemisphere and tilted
laterally by 457 to avoid damage to the motor cortex and internal
capsule. Four T-shape bolts were implanted in the skull with dental
acrylic cement to fix the chamber on the skull, and to fix the head
to the chair head holder during the experiment.
In experiment 2, after monkey B had achieved a consistent performance of ú90% correct in the visually guided push button task,
surgery was performed under the same anesthesia used in experiment 1. The skull was exposed, and four T-shape bolts and two
stainless steel holders, used for fixation of the head to the primate
chair during unit recording, were mounted with dental acrylic cement on the skull. The recording chamber was not used. At each
recording, a small hole (3–4 mm diam) was made by drilling the
skull over the striatum. Then a small incision ( Ç1 mm diam)
was made in both the dura and pia matters for the insertion of a
multibarreled glass microelectrode. Local anesthetic, 8% lidocaine
hydrochloride, was used to reduce pain during the drilling and
dural incision.
Data analysis
Data analysis was performed off-line using a NEC PC98BA
computer. Responses of TANs were defined as increasing or decreasing discharge rate after LED or solenoid click relative to that
before each stimulus if they achieved at a significance level of
P õ 0.05 using a two-tailed Wilcoxon test (Kimura 1986). The
onset time of a response was defined as the first of three consecutive
15-ms bins of peristimulus time histogram in which the increase
or decrease of activity first became significant.
Histological reconstruction
Several small electrolytic lesions were made in each hemisphere
to mark the recording sites by passing a positive DC current through
TABLE 1. Effects of dopamine receptor antagonists on
background discharge rate of TANs
Experiment 1
Experiment 2
4.2 { 0.9 (10)
4.3 { 1.0 (5)
4.2 { 0.9 (5)
4.3 { 0.7 (42)
4.2 { 0.7 (11)
4.3 { 0.8 (31)
Application of DA receptor antagonists
Before
After D1-class
After D2-class
In experiment 1, DA receptor antagonists were administered
locally in the striatum by pressure microinjection. We used a stain-
Values are means { SD of discharges per s; number of neurons is in
parentheses. TANs, tonically active neurons.
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FIG . 2. Photograph of a coronal histological section at the plane of
the recording sites in the right hemisphere of monkey A. Arrow indicates
electrolytic lesion mark made by the recording electrode in the putamen.
Stars indicate microelectrode tracks directed to the putamen. Recording
sites in the striatum covered about the dorsal 2/3s of the nuclei at the level
caudal to the anterior commissure. Top and left correspond to dorsal and
lateral, respectively. Cd N., caudate nucleus; Put., putamen; IC, internal
capsule; GPe, external segment of globus pallidus; GPi, internal segment
of globus pallidus. Calibration bar: 5 mm.
less steel injection cannula (300 mm ID) through which a Tefloncoated tungsten wire (50-mm base diameter, 75-mm coated diameter) for recording neuronal activity had been threaded with its cut
tip protruding 0.7–0.8 mm from the tip of the cannula. The proximal end of the cannula was connected to a microsyringe (1 ml,
Hamilton) with Teflon tubing. A guide tube was fixed to a microdrive, and the injection-recording device was positioned inside the
guide tube. After the tip of the guide tube was inserted 10 mm
below the dura matter into the brain, the injection-recording device
was advanced to the striatum while neuronal activity was recorded.
Once responses of TANs to sensory cues were recorded through
the tungsten wire electrode, either D1- or D2-class DA receptor
antagonist was injected (total volume õ1 ml, at a rate of 1 ml/
5–10 min). SCH23390 (10 mg/ ml in saline, 31 mM, pH 5.7; RBI)
or cis-flupenthixol (30 mg/ ml in saline, 59 mM, pH 6.6; RBI)
were used as the D1-class antagonists. ( 0 )-Sulpiride (20 mg/ ml
in saline, 58 mM, pH 6.8; RBI) was used as the D2-class antagonist. As a control experiment, we applied saline ( õ1 ml) to confirm
that the activity of TANs was not significantly influenced.
In experiment 2, four- or five-barreled glass microelectrodes
were inserted into the striatum. The central barrel contained a
carbon fiber (7 mm diam) and was filled with 1 M NaCl (1–3 MV
impedance measured at 1 kHz). This was used for extracellular
recording of the activity of TANs. Each DA receptor antagonist
was iontophoretically applied through one of the barrels. We used
SCH23390 (10 mM in saline, pH 4.5; RBI) as the D1-class antagonist and ( 0 )-sulpiride (10 mM in saline, pH 4.5; RBI) as the
D2-class antagonist. During recording, a small retaining current
( õ10 nA) was applied to prevent the leakage of the DA receptor
antagonists from the injection pipettes. When TANs responsive to
conditioned cues were encountered, their activity was recorded for
ú30 successive trials in Ç5 min. Then one class of DA receptor
antagonist was iontophoretically applied with current of õ50
nA (anodal current) through a Micro Iontophoretic Injector
(SEZ-3104, Nihon Kohden) to examine the effects of application
of the DA receptor antagonists on the activity of TANs. The effects
of both D1- and D2-class antagonists were examined in most of
the recorded neurons. Recovery from the effects of DA receptor
antagonists of TAN responses to either the LED that triggered
button pushing or the click associated with reward was confirmed.
DA RECEPTOR MECHANISMS IN THE STRIATUM FOR LEARNING
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FIG . 3. Specimen records of the effects of micropressure application of dopamine (DA) receptor antagonists on the
activities of 2 tonically active neurons (TANs): one was suppressed by D2-class antagonist [( 0 )-sulpiride, 0.7 ml, A–D],
the other was not suppressed by D1-class antagonist (cis-flupentixol, 0.7 ml, E–H). Activity of a TAN is shown before (A),
and 9 min (B), 31 min (C), and 81 min (D) after injection of D2-class antagonist. Activity of another TAN is shown before
(E), and 16 min ( F), 46 min (G) and 107 min (H) after injection of D1-class antagonist. Each row in the raster display
indicates a spike train in a single trial, with dots representing single spike discharges. Histograms are constructed by summation
of spike discharge in each raster. Neuronal activity is aligned at the time of the click preceding the reward.
the elgiloy microelectrode (20 mA for 30 s). After all the experiments
were completed, the animals were then deeply anesthetized with an
overdose of pentobarbital sodium (70 mg/kg im) and were perfused
transcardially with heparin-containing saline and then 10% formaldehyde. Each brain was cut into several blocks, and frozen sections of
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50-mm thickness were made in the coronal plane and stained with
cresyl violet. Comparison of electrode tracks and electrolytic lesions
with descriptions of depth profiles of electrical activity in the penetrations during the recording sessions allowed us to reconstruct the recording tracks and recording sites in the striatum (Fig. 2).
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RESULTS
2. Effects of pressure application of dopamine receptor
antagonists on the response of TANs
TABLE
Effects of DA receptor antagonists on background
discharge rate of TANs
It has been suggested that DA in the striatum would set
the baseline firing rate very low, based on the observation
Antagonist
Effective
Examined
D1-class
D2-class
Total
0
4
4
5
5
10
Figures indicate number of neurons. TANs, tonically active neurons.
of a dramatic decrease of spontaneous discharge rates of
striatal neurons of monkeys that were performing behavioral
tasks (Rolls et al. 1984). This let us examine the effects of
DA receptor antagonists on the background discharge rates
of TANs in both experiment 1 and experiment 2. Average
background discharge rates of TANs before and after application of DA receptor antagonists are summarized in Table
1. In both experiment 1, in which DA receptor antagonists
were applied by micropressure, and experiment 2, in which
DA receptor antagonists were iontophoretically applied, the
discharge rates of TANs after administration of both
D1-class and D2-class antagonists were not significantly different from those before administration (P ú 0.05, paired
t-test). Therefore neither D1- nor D2-class antagonists affect
the mechanisms that set the background discharge rates
of TANs.
Effects of topical application of DA receptor antagonists
on learned responses of TANs
TANs have been proposed to be cholinergic interneurons
in the striatum with large, elongated dendrites extending up
to 600 mm on an average (Aosaki et al. 1995; Kawaguchi
1992; Kimura et al. 1996; Wilson et al. 1990; Yelnik et
al. 1993). Thus in experiment 1, we locally applied either
FIG . 4. Specimen records of the population response of TANs to reward-associated click that was suppressed by
D2-class antagonist [( 0 )-sulpiride; A], but was not sensitive to application of D1-class antagonist (SCH23390 and cisflupentixol) by pressure (B). Neuronal activity is aligned at the time of the click with reward.
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In experiment 1, monkey A was tested with the auditory
click-reward association task, and in experiment 2, monkey
B was tested by both the auditory click-reward association
task and visually guided push button task.
The activities of 75 TANs in monkey A and 220 TANs in
monkey B were recorded extracellularly before (in experiment 1) and after behavioral conditioning (in experiment 1
and experiment 2). TANs were identified based on the shape
of extracellularly recorded action potentials and the pattern
of background discharges (Aosaki et al. 1994b; Apicella et
al. 1991; Kimura 1986; Raz et al. 1996).
The vast majority of TANs (36 of 42 recorded) did not
respond to the click before conditioning. After behavioral conditioning, 18 of 33 TANs showed responses to the clicks associated with reward. The response consisted of a pause in tonic
firing of Ç250-ms duration (18 of 18 TANs) and was flanked
by brief initial (11 of 18) and late facilitation of firing (12 of
18). The responsiveness of 20 TANs to the click without reward (nonconditioned stimulus) was examined. Only 4 of the
20 TANs responded to the nonconditioned stimulus, and no
significant pause in discharge was observed. About a one-half
of TANs (122 of 220 TANs examined) became responsive to
the LED illumination used as a trigger stimulus for button
pushing. The responses consisted of a pause (122/122) with
initial (44/122) and late facilitation (76/122) of tonic firing.
However, almost no TANs (4/220) responded to the click
associated with reward, as if through learning the push button
task, the responses to reward had shifted in time to the preceding predictive sensory event, the LED illumination.
DA RECEPTOR MECHANISMS IN THE STRIATUM FOR LEARNING
selective D1- or D2-class antagonist by micropressure, while
recording the activity of TANs, to examine the effects of
DA receptor antagonists on the acquired responses of TANs
to the conditioned stimuli.
Figure 3 shows sample records of the effects of micropressure application of DA receptor antagonists on the activities
of two TANs. A TAN illustrated in Fig. 3, A–D, showed a
pause of its tonic firing followed by late excitation at a
latency of 135 ms after the click sound of the solenoid valve
associated with reward water (Fig. 3A). An application of
0.7 ml of ( 0 )-sulpiride suppressed the pause response 9 min
after application (Fig. 3B). The suppression of the pause
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response continued at least 81 min after the application of
the drug. The late excitation, on the other hand, persisted
after application of ( 0 )-sulpiride (Fig. 3, B–D). We could
test the effects of only a single DA receptor antagonist on
the responses of an individual TAN, because the effects of
pressure application continued for a few hours. Another
TAN illustrated in Fig. 3, E–H, showed no significant sensitivity to D1-class antagonist (cis-flupentixol). A pause in
firing flanked by initial and late excitations triggered by the
click associated with the reward continued to appear at least
107 min after application of the drug.
We carried out a total of 10 experiments of pressure appli-
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FIG . 5. Effects of iontophoretic application of D1-class and D2-class receptor antagonists on the responses of a TAN to
the LED used as a trigger stimulus for the button push task. A–C: application of ( 0 )-sulpiride with /30 nA current abolished
responses to the LED. D–F: in the same neuron, no effect on activity of the application of SCH23390 using /30 nA current
was observed. Histograms are centered at the time of presentation of the LED. The raster display was reordered sequentially
from top to bottom based on the time between LED onset and the button push (reaction time).
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suppressed by the D2-class antagonist. The initial and late
excitation, on the other hand, persisted after administration
of D2-class antagonist (Fig. 4A). On the contrary, none of
five TANs tested for D1-class antagonists was sensitive to
the drug, and thus, the population response histograms obtained before and after administration of D1-class antagonist
were quite similar with a pause flanked by initial and late
excitation (Fig. 4B). Latencies of initial excitation before
and after application of the antagonists were 75 and 78 ms,
respectively, those of the pause were 154 and 156 ms, and
those of late excitation were 280 and 293 ms, respectively.
Effects of iontophoretic application of DA receptor
antagonists on learned responses of TANs
We applied DA receptor antagonists to the TANs iontophoretically in experiment 2. Sample records of the effects
of iontophoretic application of both D1- and D2-class antagonists on a TAN are illustrated in Fig. 5. After the monkey
had learned the visually guided push button task, almost no
TAN responded to the reward-associated click, but instead
responded to LED illumination (Fig. 5A). Thus it is suggested that TANs respond to the LED as a reward-predictive
stimulus. An application of ( 0 )-sulpiride with a current of
/30 nA suppressed the pause response of the TAN (P ú
0.05, Wilcoxon test, Fig. 5B). The response of the TAN
recovered in 16 min after the administration (Fig. 5C).
When the response had fully recovered from administration
of ( 0 )-sulpiride, the D1-class antagonist, SCH23390, was
applied with a current of /30 nA. SCH23390 did not
have significant effects on the response of the TAN (Fig.
5, D–F).
FIG . 6. Population response of TANs to
LED illumination as a trigger for the button
pushing movement task to summarize the
effects of iontophoretic application of DA
receptor antagonists. A: population activities of 31 of 49 TANs examined that were
sensitive to D2-class antagonists. B: population activities of 11 of 41 TANs examined
that were sensitive to D1-class antagonists.
Population histograms are centered at the
time of LED onset. Number of neurons included for each histogram is shown in parentheses.
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cation of DA receptor antagonists, in which D1-class antagonists were applied in 5 experiments (3 injections of
SCH23390 and 2 injections of cis-flupentixol) and D2-class
antagonists were applied in another 5 experiments (Table
2). In none of the five applications of D1-class antagonists
was a significant effect of the antagonist on the responses of
TANs to reward-associated clicks observed. On the contrary,
responses of TANs were suppressed in four of five applications of D2-class antagonists.
We recorded activity of 3 TANs beneath the injection
sites of DA receptor antagonists in 2 of 10 experiments. The
response of a TAN 600 mm beneath the site of injection of
the D2-class antagonist, ( 0 )-sulpiride (0.9 ml), was suppressed similarly to the response of the TAN recorded at the
injection site, whereas response of another TAN located
1,200 mm beneath the injection site was apparently unaffected.
Because temporal profiles of TAN responses, a pause of
tonic discharge flanked by initial and/or late facilitation,
recorded in different locations in the striatum were quite
similar to each other, we obtained a population response by
calculating the ensemble average of responses of multiple
TANs to reward-associated click before and after application
of DA receptor antagonists.
Population responses of 10 TANs to the reward-associated
click are illustrated in Fig. 4. Responses of five TANs that
were tested for the effects of D2-class antagonists (Fig. 4A)
and those of another five TANs tested for the effects of
D1-class antagonists (Fig. 4B) are separately illustrated. The
administration of D2-class antagonist almost completely
abolished the population pause response of the TANs examined. Responses of four of the five TANs were significantly
DA RECEPTOR MECHANISMS IN THE STRIATUM FOR LEARNING
3. Effects of iontophoresis of dopamine receptor
antagonists on the responses of TANs
TABLE
Effective
Antagonists
Exclusive
D1- and D2-class
Examined
D1-class
D2-class
3
19
7
7
40
40
In 40 TANs, effects of both D1- and D2-class antagonists were examined.
TANs, tonically active neurons.
Effects of D1-class antagonists were examined in 41
TANs that showed responses to LED illumination. Histograms in Fig. 6B illustrate population responses of 11 of the
41 TANs examined. Iontophoretic application of D1-class
antagonist to these 11 TANs abolished the pause response
to LED illumination (Fig. 6B, middle). The remaining 30
TANs were not sensitive to the iontophoretic application of
D1-class antagonist.
We examined the effects of both D1- and D2-class antagonists on 40 TANs. Out of these, responses of 10 TANs to
LED illumination were suppressed by the administration of
D1-class antagonists, whereas those of 26 TANs were suppressed by D2-class antagonists. The pause responses in 19
of 26 TANs were suppressed exclusively by the application
of D2-class antagonists, and those of 3 TANs were suppressed exclusively by the application of D1-class antagonists (Table 3). Seven TANs were sensitive to both D1- and
D2-class antagonists.
Of 40 TANs in which the effects of both D1- and D2class antagonists were examined, 21 TANs were examined
1st by D2-class antagonist, then by D1-class antagonist.
For these 21 TANs, responses of 3 TANs were suppressed
exclusively by D1-class antagonist, whereas those of 10
TANs were suppressed exclusively by D2-class antago-
FIG . 7. Effects of application of physiological saline on the response of TANs as
a control. The iontophoretic administration
of D2-class antagonist using /30 nA current suppressed the conditioned response of
a TAN (A–C). Subsequent application of
saline with /30 nA did not affect the response of the TAN (D). E: response recorded 12 min after the saline application.
Neuronal activities are centered at the time
of LED illumination.
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Figure 6 shows the population responses of TANs that
were sensitive to the iontophoretically applied DA receptor
antagonists. D2-class antagonists were iontophoretically applied to 49 TANs that showed characteristic responses to
LED illumination used as a trigger for the button pushing
movement task. In 31 of the 49 TANs, pause responses to
LED illumination were suppressed by administration of D2class antagonists, although an initial excitation remained.
The population responses, which are ensemble averages of
the activities of 31 TANs, are illustrated in Fig. 6A. Responses of the other 18 TANs were not significantly influenced by iontophoresis of D2-class antagonist.
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FIG . 8. Locations of micropressure injection in the striatum in experiment 1. Tracks of the injection cannula with
recording wire electrode were drawn on 4 levels of coronal
sections of the right hemisphere in monkey A, based on the
histological reconstruction of the tracks. Symbols indicate
locations where TANs were recorded and single DA receptor antagonists were administered. ●, SCH23390 (not sensitive); s, cis-flupentixol (not sensitive); j, ( 0 )-sulpiride
(sensitive); h, ( 0 )-sulpiride (not sensitive); n, saline
(not sensitive). Cd N., caudate nucleus; Put., putamen.
Effects of DA receptor antagonists on learned behavior
To examine the effects of iontophoresis of DA receptor
antagonists on learned behavior, reaction times of button
pushing movements after LED onset were measured in the
visually guided push button task in experiment 2. The average reaction time was 663.3 { 109.1 (SD) ms before administration of drugs, whereas it was 661.2 { 96.0 ms during
administration of D1-class antagonists and 674.8 { 109.2 ms
during administration of D2-class antagonists. The average
reaction times after the administration of D1-class and
D2-class antagonists were not significantly different from
those before the administration (P ú 0.05, paired t-test). It
was concluded that the reaction time of button pushing after
FIG . 9. Location of iontophoresis in experiment 2. Drawings of electrode tracks on the coronal sections of the left and
right hemispheres in monkey B. Symbols indicate the administration sites of DA receptor antagonists where TANs were
sensitive exclusively to D1-class ( m ), exclusively to D2-class ( j ), and to both D1- and D2-class ( ● ) receptor antagonists,
respectively. Filled symbols indicate sites where both D1- and D2-class antagonists were tested. Open symbols indicate sites
where only 1 antagonist was tested. Cd N., caudate nucleus; Put., putamen; AC, anterior commissure; GPe, external segment
of globus pallidus; GPi, internal segment of globus pallidus.
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nist. Responses of 2 TANs were suppressed by both D1and D2-class antagonists. On the other hand, 19 TANs
were examined 1st by D1-, then by D2-class antagonists.
For these cells, responses of nine TANs were suppressed
exclusively by D2-class antagonist, whereas none of these
TANs were suppressed exclusively by D1-class antagonist. In five of these TANs, both D1- and D2-class antagonists suppressed the responses. Thus D2-class antagonistdominant effects were observed in both sequences of application of antagonists. Nonetheless, it appears that both
D2- and D1-class DA receptor – mediated mechanisms
play an important role in the expression of acquired activities of TANs during performance of learned behavioral
tasks.
DA RECEPTOR MECHANISMS IN THE STRIATUM FOR LEARNING
LED onset was not affected by the application of either class
of DA receptor antagonists. Thus the observed effects of
DA receptor antagonists on the responses of TANs were not
because of altered task performance.
Control experiments
Localization of recording sites
The TANs were usually encountered at intervals of 300–
700 mm along the recording microelectrode tracks both in
the caudate nucleus and in the putamen. We sampled TANs
in both nuclei in the right hemisphere of monkey A in experiment 1, and in both nuclei in both hemispheres of monkey
B in experiment 2. The recording sites in the striatum covered about the dorsal two-thirds of the nuclei at the level
caudal to the anterior commissure. The locations at which
responses of TANs to sensory cues were influenced by the
application of D1-class and/or D2-class antagonists are indicated on the electrode tracks with different symbols in Fig.
8 (experiment 1) and Fig. 9 (experiment 2). No clear difference in the distribution in the striatum was observed between
TANs sensitive to D1-class antagonist and those sensitive
to D2-class antagonist in either monkey.
DISCUSSION
Nigrostriatal DA system enables TANs to express learned
activity primarily through D2-class receptor–mediated
mechanisms in the striatum
In the present study, the pause responses of 65% (26/40)
of TANs examined with iontophoretic application of DA
receptor antagonists were abolished by D2-class antagonist,
whereas micropressure application of the D2-class but not
D1-class antagonist abolished the responses of TANs. In 2 of
10 experiments using micropressure injection, we recorded 3
TANs beneath the injection site of DA receptor antagonist
in the same electrode track. After the application of 0.7 ml
of the D2-class antagonist, ( 0 )-sulpiride, the response of a
TAN 600 mm beneath the injection site was suppressed similarly to the response of the TAN at the injection site, whereas
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the response of another TAN 1,200 mm beneath the same
injection site remained.
These observations using alert behaving monkeys are entirely consistent with the results of recent pharmacological
and neurobiological studies on the striatal neurons. Dopaminergic afferents end directly on both the spiny projection
neurons and the cholinergic interneurons in the striatum
(Chang 1988; Freund et al. 1984; Kubota et al. 1987). Yelnik et al. (1993) reported that the cholinergic interneurons
in the primate striatum have large elongated dendrites extending up to 600 mm on an average. TANs are thought to
be the striatal cholinergic interneurons, based on their slow
tonic firing, morphology of cell soma and dendritic arbors
(Kawaguchi 1992; Wilson et al. 1990), and preferential distribution at striosome/matrix borders in the striatum (Aosaki
et al. 1995).
Striatal cholinergic interneurons have been reported to
contain D2-class DA receptors and to express the D2 DA
receptor gene (Zhou et al. 1993). In situ hybridization studies have shown that cholinergic interneurons express
D2- and/or D1-class receptor mRNA (Le Moine et al. 1991;
Weiner et al. 1991). Recent investigation by the use of
reverse transcription-polymerase chain reaction analysis
(RT-PCR) of dissociated striatal cells provided evidence
that cholinergic interneurons express primarily D2 and D1b
receptor mRNAs (Yan et al. 1997). These studies indicate
that most cholinergic interneurons in the striatum possess
D2-class DA receptors and some of them have both
D1-class and D2-class DA receptors.
Recently, Aosaki and Kawaguchi (1997) investigated the
actions of DA receptor agonists on the striatal cholinergic
interneurons in the slice preparation using whole cell patchclamp technique. Application of the D1-class agonist,
SKF38393, almost always induced an inward current, and
thus caused burst discharges of these neurons. On the other
hand, a D2-class agonist, quinpirole, induced an outward
current and suppressed spike discharges in one-half of them
and induced inward current and burst discharges in the other
half of them. In a study that used an acute dissociated cell
preparation (Yan et al. 1997), it was reported that activation
of D2 DA receptors in cholinergic interneurons reduces
N-type Ca 2/ current. This D2 receptor-mediated reduction of
N-type Ca 2/ current should not only attenuate the dendritic
invasion of initial segment spikes (Spruston et al. 1995) but
also attenuate the active augmentation of excitatory synaptic
events arising from cortical or thalamic sources (Bernander
et al. 1994; Kim and Connors 1993; Wilson 1993).
Thus it would be reasonable to assume that DA receptor
antagonists applied by micropressure in the present study
covered a spherical volume of striatal tissue with a radius
of ú600 mm, and thus covered not only the whole cell body
but also distal dendrites of TANs. Of 40 TANs that were
examined with iontophoresis of both D1- and D2-class antagonists, pause responses of 26 TANs to conditioned stimuli
were almost completely suppressed by the administration of
D2-class antagonist, whereas those of 10 TANs were abolished by D1-class antagonists. Therefore the nigrostriatal
DA system appears to play a fundamental role in the expression of acquired activities of TANs, primarily through
D2-class receptors and partly through D1-class receptors.
It has been demonstrated that local infusion of the dopa-
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As a control, saline was iontophoretically applied to confirm that the observed suppression of learned responses of
TANs by the application of DA receptor antagonists was
not induced by the electric current itself. In one neuron, the
iontophoretic administration of D2-class antagonist with a
current of /30 nA abolished the conditioned response of
the TAN (Fig. 7B, P ú 0.05). The conditioned response of
the TAN recovered in 14 min after the administration of
D2-class receptor antagonist (Fig. 7C). In the same neuron,
saline was subsequently applied with a current of /30 nA,
but the response of the TAN was not influenced (Fig. 7, D
and E, P õ 0.05). In all TANs examined in this way (n Å
4), iontophoretic application of saline with õ50 mA had no
significant effects on the responses of TANs to conditioned
stimuli. From these observations, it was concluded that the
very strong suppressive effects of DA receptor antagonists
on the responses of TANs were not artificially induced by
ejecting current but directly caused by the DA receptor antagonists.
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K. WATANABE AND M. KIMURA
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et al. 1995). If GABAergic striatal projection neurons containing SP send their axon collaterals to TANs that are supposed to be cholinergic (Bolam et al. 1983, 1986), administration of D1-class antagonist would diminish inhibitory
GABAergic neurotransmission to TANs. This could lead to
the suppression of the pause response of TANs by D1-class
antagonist. This mechanism may be responsible for the observation that sensory response of some TANs were significantly reduced by D1-class antagonist.
In this investigation, it was revealed that TANs express
learned activities primarily through D2-class and partly
through D1-class receptor–mediated mechanisms in the striatum. In this relevance, it is interesting to note the enabling
effects of D1 rather than D2 receptor stimulation on taskrelated activity in the cerebral cortex. Williams and Goldman-Rakic (1995) showed that D1 antagonists can selectively potentiate the ‘‘memory fields’’ of prefrontal neurons
that subserve working memory. This might reflect specificity
in the cellular mechanisms of DA receptors involved in
learning and memory of actions in different brain areas. On
the other hand, it remains to be studied which class of DA
receptors is involved in the acquisition of new activities in
both TANs and the other class of striatal neurons, phasically
active neurons (PANs), which are believed to be projection
neurons to the globus pallidus and substantia nigra.
Midbrain DA neurons and TANs may have contrasting
response plasticity during behavioral learning
Schultz and his colleagues reported a systematic rewardrelated response plasticity of midbrain DA-containing neurons in behaving monkeys (Ljungberg et al. 1992; Schultz
1986; Schultz et al. 1993). DA neurons were activated by
primary food and fluid rewards. But when the rewards were
predicted by a sensory stimulus used as a behavioral cue,
the DA neurons became responsive to visual or auditory
stimuli predictive of reward (Ljungberg et al. 1992). In
the striatum, the majority of TANs responded to a rewardassociated click, when animals were trained to associate sensory stimuli with reward. But when animals learned a visually guided push button task, TANs responded to the visual
trigger stimulus and showed no significant responses to the
reward-associated click. This suggests the interesting possibility that the TANs in the striatum exhibit responses to
behavioral events predictive of reward under the strong influence of inputs from the DA-containing neurons in the
substantia nigra pars compacta (SNc).
Nevertheless, the acquired activities of these two sets of
neurons have some contrasting profiles. The response of
DA-containing neurons, once acquired, seems to diminish
progressively with overtraining (Ljungberg et al. 1992;
Schultz et al. 1993). By contrast, the TANs, once having
acquired responses to the reward-predictive stimuli, maintained the responses even with prolonged overtraining, when
the conditioned behavior became highly automatized (Aosaki et al. 1994b). This contrasting property in activity suggests that nigrostriatal DA neurons and TANs are involved
in different aspects of mechanisms in behavioral learning.
That is, DA-containing neurons may transmit motivation- or
reinforcement-related information to the striatum with phasic
release of DA in the striatum through which TANs acquire
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minergic neurotoxin MPTP into the striatum abolishes pause
responses of TANs to reward-predictive stimuli that were
acquired through behavioral conditioning (Aosaki et al.
1994a). But an initial excitation preceding the pause remains
after MPTP infusion. Quite similarly, our study demonstrates
that application of specific DA receptor antagonists largely
reduced pause responses of TANs to stimuli that were predictive of reward, but the initial excitation remained. The
initial excitatory response of TANs thus must be mediated
through mechanisms that are not related or poorly related
to DA receptors. Aosaki et al. (1994a) demonstrated that
application of the DA receptor agonist, apomorphine, reinstated responses of TANs in striatum previously infused with
MPTP. The present results explain, at least partly, the mechanisms of action of the nigrostriatal DA system on TANs that
are working when animals are performing learned behavioral
tasks. First, the nigrostriatal DA system does not seem to
convey specific, sensory inputs to TANs, but rather to supply
control signals for TANs to express responses to inputs.
Second, the control of responsiveness of TANs by the nigrostriatal DA system seems to be mediated primarily through
D2-class, but partly through D1-class receptor mechanisms.
Therefore it can be concluded that the nigrostriatal DA system enables TANs to express learned activities primarily
through D2-class and partly through D1-class receptor–mediated mechanisms in the striatum.
Although we examined responses of striatal neurons to
conditioned stimuli in most neurons, we examined responses
of the neurons to nonconditioned stimuli as well in a considerable number of neurons. Only 4 of 20 TANs examined
responded to the nonconditioned stimulus, and there is no
significant pause response, although the initial excitation is
present, consistent with the results of Aosaki et al. (1994b)
that 10–20% of TANs respond to a solenoid click before
conditioning. Responses of most of the TANs to the conditioned stimuli thus must have been acquired through the
conditioning process. Therefore the present results strongly
suggest that tonic DA receptor stimulation enables the striatal neurons to express learned activities, although activity in
a small percentage (10–20%) of neurons may depend on
DA receptor stimulation independent of learning.
In the present study, the acquired responses of 11 of 41
(27%) TANs were almost abolished either exclusively by
D1- or by both D1- and D2-class antagonists applied with
iontophoresis. On the other hand, an effect of D1-class antagonist was observed in none of five microinjection applications, although the results of the two experiments were otherwise relatively consistent. This difference might at least
partly be explained either by the use of different D1-class
antagonists (both SCH23390 and cis-flupentixol in experiment 1; only SCH23390 in experiment 2) or by different
concentrations of the antagonists applied. Recent findings
showed that D1-class receptor agonists selectively facilitate
g-aminobutyric acid (GABA) –mediated inhibitory transmission of the strioentopeduncular neurons containing substance P (SP) (Ferre et al. 1996). This observation was
supported by other studies (Girault et al. 1986; Reid et al.
1990). On the other hand, the most consistent response of
TANs to sensory stimuli is the pause of tonic discharge,
which is presumably mediated by either inhibitory mechanisms or resetting of tonic background discharges (Aosaki
DA RECEPTOR MECHANISMS IN THE STRIATUM FOR LEARNING
responses to behavioral events predictive of reward. When
DA neurons lose their responsiveness through overtraining,
TANs might express activities encoding reward predictability in terms of the baseline release of DA in the striatum.
Because the main targets of TAN axons are nearby projection neurons in the striatum (Aosaki et al. 1995), the projection neurons would receive innervation by both the nigrostriatal DA neurons and TANs. Therefore the contrasting response plasticity of nigrostriatal DA neurons and TANs in
the striatum may constitute fundamental role in basal ganglia
mechanisms involved in acquisition and retrieval of purposeful behavior.
Possible origins of characteristic responses of TANs in the
striatum
Background discharges of TANs before and after
application of DA receptor antagonists
Background discharge rate of TANs was affected by neither D1- nor D2-class antagonists. In both experiments 1
and 2, the average discharge rates of TANs before administration of both D1-class and D2-class antagonists were not
significantly different from those after and during administration. These results are concordant with previous observations showing that there were no apparent changes of spontaneous discharge rates of TANs both in chronically MPTPinfused striatum and in acutely haloperidol-injected striatum
(Aosaki et al. 1994a). On the other hand, Rolls et al. (1984)
observed a decrease in spontaneous firing rates of primate
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striatal and prefrontal cortex neurons in response to iontophoretically applied DA, and drew their conclusion that DA
sets the baseline firing rate very low so that the DA can
control the signal-to-noise ratio of processing in the striatum.
It is not possible to compare directly the results of Rolls et
al. with the present observations, because they recorded the
activity of striatal projection neurons, but not TANs, and
because they did not examine effects of specific D1- and
D2-class antagonists.
The results of our study demonstrate that the nigrostriatal
DA system does not affect significantly the mechanisms for
characteristic tonic discharges of TANs in the striatum, but
specifically modulates responsiveness to conditioned inputs
mainly through D2- and partly through D1-class receptors.
We are grateful to Prof. C. Ohye for advice and constant encouragement,
to Dr. Ann M. Graybiel for valuable advice, to Drs. M. Inase and H.
Sato for technical advice, and to N. Matsumoto, Y. Ueda, T. Sato, and T.
Minamimoto for participation in a part of this study. We thank Dr. Edward
S. Ruthazer for correcting English expression of the manuscript.
This study was supported by grants from the Ministry of Education of
Japan (96L00201, 07408035, and 40118451) to M. Kimura.
Address for reprint requests: M. Kimura, Faculty of Health and Sport
Sciences, Osaka University, Toyonaka, Osaka 560, Japan.
Received 18 September 1997; accepted in final form 10 February 1998.
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