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The Journal of Neuroscience, March 1, 2003, 23(5):1584
BRIEF COMMUNICATION
Opposing Roles of D1 and D2 Receptors
in Appetitive Conditioning
Yaniv S.
Eyny and
Jon C.
Horvitz
Department of Psychology and Program in Neurobiology and Behavior,
Columbia University, New York, New York 10027
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ABSTRACT |
Previous studies have shown that D1
receptor blockade disrupts and D2 receptor blockade
enhances long-term potentiation. These data lead to the
prediction that D1 antagonists will attenuate and
D2 antagonists will potentiate at least some types of
learning. The prediction is difficult to test, however, because
disruptions in either D1 or D2 transmission
lead to reduced locomotion, exploration, and response execution and are
therefore likely to impair learning that requires behavioral responding
(including exploration of an environment) during the learning episode.
Under a paradigm that minimizes motor requirements, rats were trained
to enter a food compartment during pellet presentation. Animals then
received tone-food pairings under the influence of D1
antagonist SCH23390 (0, 0.4, 0.8, and 0.16 mg/kg) or D2
antagonist raclopride (0, 0.2, 0.4, and 0.8 mg/kg). An
additional group received unpaired presentations of tone and food. On a
drug-free test day 24 hr later, animals that had been under the
influence of SCH23390 (like animals that had received unpaired
presentations of tone and food) showed reduced head entries in response
to the tone, whereas animals that had been under the influence of
raclopride showed increased head entries in response to the tone
compared with vehicle controls. These data demonstrate that, under a
conditioned approach paradigm, D1 and D2 family
receptor antagonists disrupt and promote learning, respectively, as
predicted by the effects of D1 and D2 receptor blockade on neuronal plasticity.
Key words:
dopamine; learning motivation; plasticity; conditioning; D1; D2; rat
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Introduction |
Long-term potentiation (LTP) is
blocked by D1 antagonists (Calabresi et al.,
2000 ; Kerr and Wickens, 2001) and is enhanced by
D2 antagonists and in D2
receptor knock-out mice (Calabresi et al., 1997; Yamamoto et al.,
1999). These opposite effects of D1 and
D2 receptor blockade on LTP appear to result from
their opposing effects on those intracellular cascades within striatal neurons that lead to dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) phosphorylation. D1
receptor binding causes a G-protein-mediated increase in the activity
of adenylyl cyclase, increased cAMP formation, stimulation of protein
kinase A, and phosphorylation (i.e., activation) of DARPP-32 (Hemmings
et al., 1984; Nishi et al., 1997). D2 binding
produces the opposite effect on DARPP-32 activation, both by reducing
adenylyl cyclase activity and through a mechanism that involves
calcineurin activation (Nishi et al., 1997; Greengard et al., 1999). It
is known that the activation and deactivation state of DARPP-32
critically mediates the facilitative and inhibitory effects of
D1 and D2 binding on LTP
induction, respectively (Calabresi et al., 2000; Centonze et al.,
2001). Thus, via opposing effects on the activation state of DARPP-32, D1 activity promotes and D2
activity restricts LTP.
As predicted on the basis of its role in striatal plasticity,
D1 receptor activity plays an important role in
learning (Beninger and Miller, 1998; Smith-Roe and Kelley, 2000; Azzara
et al., 2001; Baldwin et al., 2002). Although a large number of studies
demonstrate that D1 receptor blockade disrupts
appetitive learning, the effects of D2 receptor
blockade are more difficult to interpret because of the profound
motor impairments typically produced by D2
antagonists (Beninger and Miller, 1998).
A critical methodological consideration in such studies concerns the
fact that dopamine (DA) (both D1 and
D2) antagonists increase response latencies
(Horvitz, 2001). Imagine that rats are presented a number of pairings
of a conditioned stimulus (CS) that signals delivery of an
unconditioned food stimulus (US) and that drugged animals fail to show
normal increases in responsiveness to the CS with repeated trials. The
reduced responsiveness to the CS could reflect motor suppression,
disrupted learning, or a combination of the two effects. Although
animals might be tested for appetitive responses to the CS on the
following day, after the drug effects had subsided, it would remain
critical to demonstrate that, on the acquisition day, drugged animals
had received the food with normal latency. If drug-induced motor
suppression increased the animal's latency to retrieve food after CS
presentation on the acquisition day, drugged animals would have an
artificially increased CS-US interval, which could itself impair the
acquisition of the CS-US association. In this case, the reduced
learning would not be attributable to a direct effect of the drug on
the learning process but rather to a drug-induced motor deficit that
changed the nature of the CS-US relationship. We report here that,
using an appetitive head-entry paradigm that ensures normal CS-US
exposure during learning trials, D1 and
D2 antagonists produce opposite effects on
learning and that these learning effects mirror those predicted by
studies of D1 and D2
antagonist effects on LTP.
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Materials and Methods |
Subjects
One hundred twenty-one Sprague Dawley rats (275-300 gm) were
obtained from Charles River Laboratories (Kinsington, NY).
Animals were housed in pairs within Plexiglas cages (22 × 22 × 46 cm) mounted on a rack within an animal colony, with food and
water available ad libitum. The colony was maintained at
~23°C, with a 12 hr light/dark cycle (lights on at 8:00
A.M.). Animals were handled and gentled during their first 2 weeks of arrival and were then placed on a 23 hr food deprivation
schedule for 3 additional days before the experiment began. Animals
were maintained on this food-restricted diet for the remainder of the experiment.
Apparatus
Behavioral test sessions were conducted in conditioning chambers
(29 × 29 × 25 cm; Coulbourn Instruments,
Allentown, PA), individually housed within sound- and light-attenuated
enclosures. Two walls of the chamber were Plexiglas; the other two were
metal. A house light was located at the top center of one of the metal walls, 2 cm below the ceiling of the chamber. Recessed within the
bottom center of this wall, 2 cm above the chamber floor, was a food
compartment (4 × 3 × 2.5 cm) into which food pellets (F0021, 45 mg; Bioserve, Frenchtown, NJ) were delivered. Activation of
the food magazine produced a 400 msec 78 dB sound immediately before
pellet delivery. A speaker (8 × 7.5 cm) was located adjacent to
the food compartment (2 cm above the chamber floor). When activated, the speaker generated a 6 sec duration 1500 Hz tone (80 dB measured from the center of the chamber, 5.5 cm above the floor). An infrared photo emitter and detector, located on the sides of the food
compartment, was interrupted by the animal's head entry and signaled
to the computer the presence of the animal's head within the food
compartment. Locomotor activity was recorded with an activity monitor
that detected the movement of infrared body heat across small
compartments of a ceiling-mounted lens (Pitts and Horvitz, 2000;
Horvitz et al., 2001). The computer (a Dell Pentium running Coulbourn
L2T2 data acquisition software) recorded the time of head
entries, head withdrawals, pellet deliveries, locomotor counts, and
tone presentations with 0.05 sec resolution.
Drug
Selective D1 receptor antagonist SCH23390
(SCH) (Iorio et al., 1983) and D2 receptor
antagonist raclopride (RAC) (Hall et al., 1988) (obtained from Research
Biochemicals, Natick, MA) were dissolved in isotonic saline.
Intraperitoneal injections of SCH23390 or raclopride were delivered in
a volume of 1 ml/kg body weight.
Procedure
Magazine training. Rats were acclimated to the
conditioning chamber for a single 30 min session during which no food
pellets were delivered. On the following day, animals began the first of 17 daily magazine training sessions. Seconds after placement in the
chamber, the onset of a house light signaled the start of the session
and remained illuminated until the session ended. During each session,
rats received 28 pellets (trials) delivered individually into the food
compartment on a variable time 70 sec (VT 70) schedule (with a minimum
interpellet interval of 30 sec). Rats received 17 d of this
magazine training. We found previously that this amount of pretraining
protects animals from the otherwise disruptive effects of SCH23390 and
raclopride on latencies to retrieve pellets (Choi et al., 2000; Horvitz
and Eyny, 2000). The latency to enter the food compartment during
pellet presentation was measured on each of these magazine training days.
Conditioning-drug treatment. On the following day (day 18),
28 pellets were delivered on a VT 116 sec schedule (with a 50 sec
minimum interpellet interval), and a tone (6 sec duration) was
presented 3 sec before each pellet delivery. Pilot studies showed that
these parameters for CS duration, CS-US interval, and intertrial
interval produced robust conditioning. On this day, animals were
pretreated with vehicle (VEH/PAIRED; n = 24), 0.04 (n = 12), 0.08 (n = 10), or 0.16 (n = 10) mg/kg of the D1 antagonist SCH23390 (SCH/PAIRED), or 0.2 (n = 9), 0.4 (n = 9), or 0.8 (n = 9) mg/kg of the
D2 antagonist raclopride (RAC/PAIRED) 30 min before the tone-food conditioning session. In
addition, an UNPAIRED group received vehicle injections 30 min before
a session in which 28 pellets were presented on the same schedule as
for the paired groups. For this group, the 28 tone presentations occurred randomly throughout the session, with the constraint that they
never occurred within 13 sec before or after pellet delivery. For all
groups, the time of each head entry, head withdrawal, pellet delivery,
and tone presentation was recorded. In addition, locomotor counts
were recorded throughout the session.
Test day. On the following day (day 19), all animals
received a test session during which the 6 sec tone was presented on a
schedule identical to that of the previous day, with the exceptions that animals were drug free and no food was delivered. The time of each
head entry, head withdrawal, and tone presentation was recorded for
each animal.
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Results |
Individual ANOVAs were conducted on SCH (0, 0.04, 0.08, and 0.16 mg/kg) and RAC (0, 0.2, 0.4, and 0.8 mg/kg) data. Over the course of
the 17 d magazine training sessions, the mean latency to retrieve
food pellets decreased from ~6.7 ± 1.0 on day 1 to 0.7 ± 0.1 sec on day 17 (Fig. 1). On day 18, neither SCH nor RAC disrupted latencies to enter the food compartment
during pellet presentation (F(3,52) = 0.40, p = NS; F(3,47) = 0.51, p = NS, respectively), in accordance with
previous findings that latencies to respond to an overtrained food cue
are relatively invulnerable to neuroleptic challenge (Choi et al.,
2000; Horvitz and Eyny, 2000). It is critical that latencies in
neuroleptic-treated animals were normal during the conditioning
session, because it ensured that all animals received the same number
of CS-US pairings and that drug treatment groups experienced normal
CS-US intervals. Figure 2 illustrates
the head-entry behavior of three individual rats under vehicle, SCH, or
RAC treatment during these conditioning trials. Note the intact
latencies to enter the food compartment during pellet presentation in
the neuroleptic-treated rats.
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Figure 1.
Latency to enter the food compartment during food
presentation during 17 d of magazine training.
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Figure 2.
Head entries during the 10 sec before CS onset,
the 6 sec CS, and the 16 sec after CS offset. Food was delivered 3 sec
after CS onset. The figure shows head entries for three representative
rats, one in the vehicle group (top), one in SCH at 0.16 mg/kg (middle), and one in raclopride at 0.4 mg/kg
(bottom). Horizontal bars indicate the
presence of the rat's head in the food compartment during each of the
28 conditioning trials (with successive trials represented from
bottom to top). Note the normal latencies
to respond to food presentation in SCH- and RAC-treated rats.
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Although the neuroleptics did not increase latencies to enter the food
compartment during pellet delivery, SCH and RAC reduced the duration of
time for which the animal's head was in the food compartment from the
onset of the CS period to the time of food delivery
(F(3,52) = 4.02, p < 0.05; F(3,47) = 2.87, p = 0.05, respectively). However, because day 18 behavior is assessed in DA antagonist-treated animals, it is not
possible to know whether the reduced behavioral responding reflects
learning deficits, drug-induced motor suppression, or a combination of
the two. Both D1 (Fowler and Liou, 1994; Aberman
et al., 1998) and D2 (Fowler and Liou, 1994;
Aberman et al., 1998; Horvitz and Eyny, 2000) antagonist drugs are
known to suppress motor behavior. As can be seen in Figure
3, SCH23390 and raclopride both reduced
locomotor activity during the day 18 tone-food conditioning trials
(F(3,52) = 4.29, p < 0.01; F(3,47) = 4.96, p < 0.005, respectively).
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Figure 3.
Both SCH23390 and raclopride reduced locomotor
activity on tone conditioning-drug treatment day
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To examine whether DA receptor blockade affects learning, it was
necessary to examine the learned behavior during a drug-free test day.
Figure 4 shows the probability of an
animal's head being inside the food compartment during consecutive 100 msec bins throughout the 10 sec pre-CS baseline, the 6 sec CS period,
and a 16 sec post-CS period. Separate one-way ANOVAs examined the
effects of (1) paired versus unpaired CS-US pairings, (2) SCH23390
dose, and (3) raclopride dose on mean head-in duration during baseline and CS periods. Animals that had received UNPAIRED presentations of CS
and food showed reduced CS period head-in durations compared with
PAIRED CS-food controls during the drug-free test session (F(1,35) = 7.90, p < 0.01). As can be seen in the top panel of Figure 4,
CS-period head-in durations were also reduced in animals that had been
under the influence of D1 antagonist SCH during the CS-food conditioning trials 24 hr earlier
(F(3,52) = 3.25, p < 0.05). Post hoc LSD tests revealed that only the high dose (0.16 mg/kg SCH) group showed significant reductions in CS-period head
duration compared with vehicle controls (p < 0.05). In contrast, animals that were under the influence of RAC during
conditioning-drug treatment trials showed increased test day head-in
durations during the CS period relative to vehicle controls
(F(3,47) = 6.56, p < 0.01) (Fig. 4, bottom). All raclopride groups showed
enhanced CS period head-in durations compared with vehicle controls
(p < 0.05 for each of the RAC doses). These
opposite effects of SCH and RAC on conditioned responding do not
reflect general changes in behavioral responsiveness, because neither
SCH nor RAC affected head-in durations during the baseline period 10 sec before CS presentation (F(3,52) = 2.35, p = NS; F(3,47) = 1.39, p = NS, for SCH and RAC, respectively), and
neither did SCH or RAC treatment (administered on day 18) affect
locomotor scores during the test session
(F(3,52) = 0.731, p = NS; F(3,47) = 0.38, p = NS, for SCH and RAC, respectively).
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Figure 4.
Performance of each treatment group during day 19, the drug-free test session. The y-axis shows mean
proportion of trials during which rats' heads were in the food
compartment for each successive 100 msec bin during the 10 sec before
tone onset ( 10 to 0), the presentation
of the tone (0-6), and the 10 sec after tone
offset (6-16). As can be seen, rats that had
received UNPAIRED presentations of CS and food showed reduced CS period
head-in durations compared with paired CS-food controls. Animal that
were under the influence of the highest SCH23390 dose during tone-food
pairings also showed a reduced CS head-in probability. Animals that
were under the influence of RAC during the tone-food pairings showed
increased CS head-in probabilities compared with vehicle controls on
test day.
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Discussion |
LTP is blocked by D1 receptor
blockade and enhanced by D2 receptor blockade
(for review, see Centonze et al., 2001). One might therefore expect
D1 and D2 receptor blockade
to produce opposite effects on learning, that is, for
D1 blockade to disrupt and
D2 blockade to facilitate learning. The present
results confirm this prediction. Animals under the influence of
D1 antagonist SCH23390 during the conditioning
session showed reduced test day responding to the CS compared with
vehicle controls. Animals that had been under the influence of
D2 antagonist raclopride showed enhanced test day
responding to the CS.
D1 antagonists have been shown previously
to disrupt appetitive learning (Beninger and Miller, 1998; Azzara et
al., 2001). However, for D2 antagonists, it has
been difficult to dissociate drug-induced associative deficits from
motor impairments (Hunt et al., 1994; Beninger and Miller, 1998). We
believe that a critical feature of the current experimental design was
that animals under the influence of varying doses of the
D1 and D2 antagonists (1) received an identical number of CS-US pairings, (2) received normal CS-US intervals, and (3) were tested drug free. To ensure that drugged
animals retrieved the food with normal latency, animals were
overtrained to respond to the sound of the food magazine and then, in
the presence or absence of the DA antagonists, were asked to transfer
this response to an earlier CS. The paradigm may therefore be best
described as a secondary conditioning paradigm.
Although the D2 antagonist promoted learning, it
is unlikely to have done so by increasing the incentive motivational
properties of the food; to the contrary, D2
antagonists attenuate the incentive motivational or response-energizing
properties of food (Ettenberg and Horvitz, 1990; Chausmer and
Ettenberg, 1997). It is possible that D1 and
D2 roles in neural plasticity and learning are
distinct from their roles in incentive motivational processes.
Consistent with this notion, intra-prefrontal D1
antagonists disrupt the acquisition of an operant response at doses
that do not affect free-feeding behavior (Baldwin et al., 2002).
A state-dependent learning hypothesis also fails to account for the
present results, particularly the improved learning observed in
D2 antagonist-treated animals. Given the opposing
effects of the D1 and D2
antagonist drugs on test day responses to the CS, any explanation that
makes recourse to an altered pharmacological state on conditioning day
is unlikely to account for the effects of both the
D1 and D2 antagonists on
test day performance.
Finally, differential effects of the drug on motor performance on
conditioning day cannot easily account for these results, because both
drugs had similar response-attenuating effects on head entries and
locomotion during the conditioning day. Although D1 and D2 antagonists both
exert suppressive effects on response expression (Fowler and Liou,
1994; Aberman et al., 1998; Horvitz and Eyny, 2000; Salamone and
Correa, 2002), they may produce opposing effects on the acquisition of
new learning.
D1 and D2 antagonists
produce opposite effects on striatal plasticity, with
D1 antagonists blocking (Calabresi et al., 2000; Kerr and Wickens, 2001) and D2 antagonists
enhancing (Calabresi et al., 1997; Yamamoto et al., 1999) plasticity.
The current results show that, under a learning paradigm that ensures
normal CS-US exposure in drug-treated animals,
D1 and D2 antagonists
produce opposite effects on learning and that these learning effects
mirror those predicted by D1 and
D2 antagonist effects on neuronal plasticity.
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FOOTNOTES |
Received Oct. 8, 2002; revised Dec. 11, 2002; accepted Dec 16, 2002.
This work was supported by National Institute on Drug Abuse Grant R29
DA11653 (J.C.H.). We gratefully acknowledge Melissa Donner, Joell
Lerebours, Derek Narendra, Jennifer Adis, Michael Grody, Kimberly
Fisher, and Gavin Williams for their invaluable assistance in the
execution of this experiment.
Correspondence should be addressed to Dr. Jon C. Horvitz, Department of
Psychology, Columbia University, 1190 Amsterdam Avenue, Room 406, New
York, NY 10027. E-mail: jon{at}psych.columbia.edu.
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TOP
ABSTRACT
Introduction
