Departments of
Pharmacology (C.M.C., E.R.B., J.H.W.) and
Psychology
(J.H.W.), University of Michigan, Ann Arbor, Michigan
The effects of i.m. injections of (+)-HA-966, a glycine-site antagonist
at the N-methyl-D-aspartate (NMDA) subtype
of the glutamate receptor, its enantiomer (
)-HA-966, the competitive glutamate antagonist CGS-19755, the uncompetitive glutamate antagonists phencyclidine and dizocilpine, and the µ opioid agonist
morphine were evaluated in a repeated acquisition task in pigeons. All of the drugs produced dose-dependent decreases in rates of responding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to have
a greater effect on acquisition than did morphine at doses that did not
fully suppress responding. The rate suppression and learning impairment
produced by a large dose of (+)-HA-966 (100 mg/kg) were completely
prevented by coadministration of the glycine-site agonist
D-serine (560 mg/kg) but not by its enantiomer,
L-serine (1000 mg/kg). D-Serine, however,
produced incomplete antagonism of the effects of dizocilpine and
phencyclidine and failed to alter those of CGS-19755. These findings
provide evidence that reducing the activity of the NMDA subtype of the
glutamate receptor through pharmacological action at any of three sites
produces similar decrements in acquisition, and those produced through antagonism of the glycine site are differentially sensitive to the
glycine-site agonist D-serine.
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Introduction |
Activation
of the N-methyl-D-aspartate (NMDA)
subtype of glutamate receptors requires the presence of glycine at a
site on the receptor that is distinct from the site at which NMDA and glutamate bind (Corsi et al., 1996
). The actions of glycine at this
site are not blocked by strychnine, which makes them distinct from the
inhibitory actions of glycine on glycine-sensitive chloride channels
(Vannier and Triller, 1997). There are several similarities between
compounds such as (+)-3-amino-1-hydroxy-2-pyrrolidine (HA-966) and
7-chlorokynurenic acid (7CKA), which block binding of glycine at its
site on this glutamate receptor; compounds such as
cis-4-phosphonomethyl-2-piperidine carboxylic acid
(CGS-19755) and
DL-(E)-2-amino-4-methyl-5-phospono-3-pentenoic
acid, which are competitive antagonists at the glutamate binding site;
and noncompetitive antagonists such as phencyclidine and dizocilpine, which block the ion channel of the NMDA receptor. All, for example, have protective effects against the effects of central hypoxia and
ischemia (McDonald et al., 1989; McNamara and Dingledine, 1990;
Priestley et al., 1990; Wood et al., 1992), and all have anticonvulsant
effects (Croucher and Bradford, 1990, 1991; Singh et al., 1990;
Meldrum, 1994). The fact that the anticonvulsant effects of (+)-HA-966
and 7CKA are mediated through the glycine site was demonstrated by the
ability of i.c.v. administration of the glycine-site agonist
D-serine to prevent the anticonvulsant effects of
these antagonists but not those of an antagonist at the glutamate site
(Lu, 1994). A third common aspect is that both the glutamate site and
the glycine site on the NMDA receptor have been implicated in learning
and long-term memory. Morris et al. (1986) found that i.c.v.
administration of aminophosphonovaleric acid, a competitive antagonist
at the NMDA site, selectively impaired the ability of the rats to
acquire spatial information and prevented the induction of hippocampal
long-term potentiation, which may be associated with synaptic
plasticity relevant to acquisition of new behavior. The competitive
glutamate-site antagonists
DL-(E)-2-amino-4-methyl-5-phospono-3-pentenoic acid and
DL-(E)-2-amino-4-methyl-5-phospono-3-pentenoic
acid carboxy-ethylester have also been reported to cause decrements in
the performance of rats in a radial arm maze (Butelman, 1989; Bischoff
and Tiedtke, 1992). In operant repeated acquisition procedures, the
uncompetitive glutamate antagonists phencyclidine and dizocilpine
impaired acquisition in rats (Cohn and Cory-Slechta, 1992), monkeys
(Moerschbaecher et al., 1985; France et al., 1991), and pigeons
(Thompson and Moerschbaecher, 1982). Recent reports have identified
learning deficits produced by glycine-site antagonists. Intracoronary
administration of 7CKA blocked the ability of chicks to learn passive
avoidance (Steele and Stewart, 1993). This same glycine-site antagonist impaired the working memory of rats in a three- runway task, and this
impairment was prevented by the intrahippocampal administration of
D-serine (Ohno et al., 1994). The present
experiments were designed to compare the glycine-site antagonist
(+)-HA-966 with the glutamate-site competitive antagonist CGS-19755 and
the uncompetitive antagonists dizocilpine and phencyclidine with
respect to their ability to modify complex behavior in pigeons after
parenteral (i.m.) administration. A repeated acquisition task was used,
similar to those used in previous studies, to evaluate drug
interactions with learning and memory. In addition, the ability of
parenteral administration of the glycine-site agonist
D-serine to reverse the deficits produced by each
of these antagonists was evaluated to determine whether their similar
effects on acquisition and performance were mediated through a similar
or different site.
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Materials and Methods |
Subjects.
Eight experimentally naive White Carneau pigeons
(Palmetto, Sumter, SC), maintained at approximately 80% of their
free-feeding weight, constituted the study population. The pigeons were
individually housed in cages, with water and grit freely available, in
a colony room with a 12-h light/dark schedule (lights on at 7:00 a.m.). All animals had previously received phencyclidine-like compounds. Animals in these studies were maintained in accordance with the University Committee on the Use and Care of Animals, University of
Michigan and "Guidelines of the Committee on the Care and Use of
Laboratory Animals" of the Institute of Laboratory Animal Resources, National Health Council (Department of Health, Education and Welfare, publication no. NIH 85-23, revised 1983).
Apparatus.
Experiments were conducted in ventilated,
sound-attenuating chambers measuring 36 × 28 × 33 cm.
Operant conditioning boxes were located within each chamber and had
three translucent response keys, 2.4 cm in diameter, located on the
middle of one wall, 25 cm from the floor. The keys were 5 cm apart and
could be transilluminated by blue, red, green, or amber (red and green
lights simultaneously illuminated) 7-W lights located behind the wall.
Mixed grain was made available by means of a hopper that could be
raised to a position below the center response key and 10 cm from the
floor of the chamber. During food availability, the hopper was
illuminated by a 7-W white light. Execution of the experiments and data
collection were accomplished using an IBM model 70 PC and Med-State
software (Med Associates, Inc., East Fairfield, VT).
Repeated Acquisition Procedure.
Pigeons were trained to
acquire a four-link response chain under a second-order FR5 schedule
(Thompson, 1973). The terminal schedule was one in which all three keys
were illuminated red at the beginning of a trial. The pigeon could
respond on any of the three keys but only one was designated
"correct." A response on that key turned all three keys green. A
peck on one of the two "incorrect" red keys resulted in a 4-s
timeout during which the chamber was dark and key pecks had no
programmed consequences. After the timeout, the three lights were again
illuminated red; the same key was designated correct, and a response on
this key turned all the keys green. When all keys were green, a peck on the one correct green key turned all the keys amber. A peck on one of
the two incorrect keys darkened the chamber for 4 s, and then the
three green keys were again illuminated. In the presence of amber key
lights, a correct response turned all the keys blue and a correct
response in the presence of the blue key lights produced a 0.5-s flash
of the hopper light and restarted the cycle in red. On the fifth time
through the cycle (FR5), a correct response in the presence of the blue
light resulted in 4-s access to mixed grain. The sequence of light
colors was constant (red, green, amber, blue) each day. However, the
key that was designated correct in the presence of each light color was
changed from day to day, and the response-sequence made by the pigeon
had to be altered each day and match the newly programmed key sequence
to produce food.
Training the pigeons on this schedule was initiated by illuminating the
center key blue and presenting food as a consequence of a peck on this
key. Once the key peck response had been made and food presented, all
three keys were illuminated blue, and the pigeon was required to peck
the correct key to produce access to grain. Incorrect selection
resulted in a 4-s timeout followed by reillumination of the blue key
lights. Once the pigeon had pecked the correct blue key, the training
was continued by illuminating all keys amber and reinforcing correct
amber key selection by turning the keys blue. The key that had been
correct during previous exposure to the blue lights was still correct,
and a response on this key resulted in grain presentation. The training
continued to step backward in the key color presentation until a
correct response in the presence of the red key lights turned all keys green, a correct response in the presence of the green key lights turned all the keys amber, and a correct response in the presence of
the amber key lights turned all the keys blue. A correct response in
the presence of the blue key light resulted in grain presentation during the initial steps of training; the number of times the pigeon
was required to complete the four-color links in the chain was
gradually increased to five. Incorrect responses in any key color
produced a 4-s timeout and the subsequent reillumination of three keys
in the color in which the error had been made.
Sessions were typically run 6 days per week. Each session began with a
blackout period lasting approximately 5 min. During this blackout
period, key pecks had no programmed consequence. Sessions terminated
after pigeons received 60 reinforcers or 60 min had elapsed. Correct
key locations for each link color were changed on a daily basis
according to a schedule of three sets of six series (18 distinct
orders). The series were selected to be equivalent in several ways with
restrictions in their ordering across sessions (Thompson, 1973). An
example of a set of six chains is LRCR, CLRL, LRLC, RCRL, CLCR, and
RCLC, where L is left, R is right, and C is center. For all chains, the
first response requirement was in the presence of red stimulus lights,
the second was in the presence of green stimulus lights, the third was
in the presence of amber stimulus lights, and the last was in the presence of blue stimulus lights.
Pigeons were trained until a steady state of acquisition was reached.
This required that animals consistently receive at least 54 (90%) of
the available 60 food reinforcers while responding more rapidly than
0.5 responses/s, with a maximum of 33% errors during the entire
session. (Errors were designated as the number of incorrect key pecks
divided by the total number of key pecks multiplied by 100 and are
referred to as percent errors.) When an animal achieved this level of
acquisition, baseline data were collected for 8 to 10 days, and mean
values were calculated for the percent errors and response rate.
Drug evaluation was initiated when criteria were met for 5 consecutive
days. The error criterion was that the animal make no more or fewer
errors than 15% of its baseline error number. To meet the response
rate criterion, the number 0.18 was added and subtracted from the
session's response rate, and the established baseline rate had to fall
within these values. The 0.18 value is 15% of the typical high rate in
this procedure of 1.2 responses/s. After each drug test,
criterion-level performance had to be reached for 2 consecutive days
before subsequent testing.
Design.
Four or five pigeons were tested with each drug and
with saline. All drugs were administered in a single i.m. injection in a volume of 1 ml/kg b.wt. Dizocilpine (18-180 µg/kg) was given 20 min, phencyclidine (0.56-1.8 mg/kg) was given 10 min, CGS-19755 (0.32-3.2 mg/kg) was given 90 min, morphine (0.32-10 mg/kg) was given
10 min, and (+)-HA-966 (10-100 mg/kg) and its enantiomer ()-HA-966
(3.2-17.8 mg/kg), as well as D-serine (10-560 mg/kg) and
its enantiomer L-serine (1000 mg/kg), were given 30 min
before the start of the corresponding test session. The dose of
L-serine (1000 mg/kg) and the highest dose of
D-serine (560 mg/kg) used were chosen from pilot studies
that indicated that these were the largest behaviorally inactive doses
in these procedures.
Data.
The effects of drugs on individual animals' rates of
responding and percent errors are presented for each condition. In
addition, these values were averaged and are presented as mean ± S.E.M. Rates of responding were individually calculated as the total number of responses per time in the session, and percent errors represent the number of errors divided by the total number of responses
multiplied by 100 for one session. When no reinforcers were obtained in
a test session, no percent error value is reported for the individual animal.
Drugs.
Dizocilpine maleate (MK-801; Merck, Sharp and Dohme,
West Point, PA); morphine sulfate (Mallinckrodt, Inc., St. Louis, MO); phencyclidine, (+)-HA 966, and its enantiomer ()-HA 966 (National Institute on Drug Abuse); and D-serine and its enantiomer
L-serine (Sigma Chemical Co., St. Louis, MO) were dissolved
in physiological saline. Doses of dizocilpine and morphine are
expressed in their salt forms. CGS-19755 (Novartis Corp., Summit, NJ)
was dissolved in physiological saline and a minimum quantity of 0.1 N
NaOH. The solution was titrated to pH 6 to 8 with small quantities of lactic acid.
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Results |
Pigeons typically reached criterion-level performance of the
repeated acquisition procedure after 6 to 8 months of training. Values
of baseline percent errors and response rates were very similar across
animals. In baseline sessions, most errors were made as the first few
reinforcers were earned (i.e., reinforcers 1-3, or 5-15 correct sequences).
Comparison of NMDA Antagonists.
A detailed illustration of the
effects of the glycine-site NMDA antagonist (+)-HA-966 on accuracy and
rate of responding can be observed over the first 28 reinforcers earned
within a session by a single animal (Fig.
1). Although each dose caused this pigeon to make more errors compared with saline control (Fig. 1, top), only 56 mg/kg was associated with a large reduction in response rate (Fig. 1,
bottom). Dose of both 10 and 32 mg/kg had modest response rate-reducing
effects that were restricted to the early portion of the session (Fig.
1, bottom). After the administration of 10 mg/kg (+)-HA-966, error
accumulation declined by the 28th reinforcer (Fig. 1, top). This is
evident by the fact that only two errors were made in earning the 24th
through 28th reinforcer, indicating that the sequence was probably
acquired at this point in the session. In contrast, the animal made 23 errors in earning the 24th through 28th reinforcer after the
administration of 32 mg/kg (+)-HA-966. Similarly, no reduction in error
accumulation was observed after the administration of 56 mg/kg
(+)-HA-966; the animal stopped responding after making 174 errors,
earning six reinforcers. Thus, no evidence of acquisition of the
sequence was observed after the administration of 32 or 56 mg/kg
(+)-HA-966. Although this animal's rate of responding was different
with each dose of (+)-HA-966 for the first six reinforcers, cumulative
errors per reinforcer for the first six reinforcements were quite
similar across doses.
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Fig. 1.
Effects of (+)-HA-966 (10-56 mg/kg) on error
accumulation within a session: a record from a single animal (pigeon
8607). The first 28 reinforcers are shown. Ordinate, cumulative number
of errors (top) and response rates in responses per second per
reinforcement (bottom). Abscissa, number of reinforcers. Individual
points are represented for the first through the sixth reinforcer
(before the break) and are represented in groups of two reinforcers
thereafter.
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Data representing the effects of the enantiomers of HA-966 on percent
errors and response rates for each of five birds and their average in
the repeated acquisition program are shown in Fig.
2. Both enantiomers produced
dose-dependent increases in percent errors and decreases in rates of
responding. The ()-enantiomer was more potent in decreasing rates of
responding (Fig. 2, right bottom) and in increasing errors (Fig 2,
right top). There were substantial individual differences among the
pigeons with respect to their response to the HA-966 enantiomers, but
there was a general association between decreased rates of responding
and increased percent errors for the individual animals for both
enantiomers.
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Fig. 2.
Effects of (+)-HA-966 (10-100 mg/kg, left) and
()-HA-966 (3.2-17.8 mg/kg, right) on percentage of errors and
response rates in the repeated acquisition procedure. Ordinate, percent
errors (top) and response rates (bottom). Abscissae, dose of drug
(mg/kg). Larger open circles represent mean values (± S.E.M.). Smaller
symbols are single-animal data and represent an animal's behavior
during an entire session. The points above Sal indicate percentage of
errors and response rates after saline administration.
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In the repeated acquisition schedule, each of the three NMDA
antagonists, dizocilpine, phencyclidine, and CGS-19755, as well as the µ opioid morphine, produced dose-dependent increases in percent
errors and reduced response rates (Fig.
3). Morphine, however, produced fewer
errors at rate-decreasing doses, suggesting less effect of this drug on
acquisition behavior. At doses that produced a 50% decrease in rates
of responding, dizocilpine produced 62% errors, phencyclidine produced
39% errors, and CGS-19755 produced 50% errors. Morphine, in contrast,
at a dose that caused a 50% decrease in response rates, produced only
27% errors.
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Fig. 3.
Effects of dizocilpine (18-180 µg/kg, top left),
phencyclidine (0.56-1.8 mg/kg, bottom right), CGS-19755 (0.32-3.2
mg/kg, bottom left), and morphine (0.32-10 mg/kg, bottom right) on
percentage of errors (top for each treatment) and response rates
(bottom for each treatment) in the repeated acquisition procedure. The
large circles represent the mean ± S.E.M. from five animals, and
the smaller symbols represent the individual pigeon data. Some
individual data points are hidden within the larger average symbols.
These symbols indicate data from the same animals shown in Fig 2. The
points above Sal indicate percent errors and response rates after
saline administration.
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Coadministration of D-Serine With NMDA
Antagonists.
A dose of 100 mg/kg (+)-HA-966 produced marked
decreases in rates of responding, and marked increases in percent
errors, as shown in Fig. 2. Administration of increasing doses of
D-serine produced dose-dependent reversals in the percent
errors and response rate reductions caused by administration of 100 mg/kg (+)-HA-966 (Fig. 4, left). At the
largest dose of D-serine (560 mg/kg) coadministered with
100 mg/kg (+)-HA-966, the mean percent errors (Fig. 4, left top) and
response rates (Fig. 4, left bottom) were not substantially different
from saline control values. This dose of D-serine
administered alone had no effect on percent errors but slightly reduced
response rates. Unlike D-serine, L-serine did
not completely reverse the effects of (+)-HA-966 on percent errors and
response rates in the repeated acquisition procedure (Fig. 4, right).
Although percent errors after the coadministration of 1000 mg/kg
L-serine with 100 mg/kg (+)-HA-966 was moderately lower
than with 100 mg/kg (+)-HA-966 alone, this value was still much greater
than saline control (Fig. 4, right top). In addition,
L-serine only slightly reversed the profound reduction in
response rates caused by 100 mg/kg (+)-HA-966 (Fig. 4, right bottom).
Thus, the reversal by D-serine of the behavioral effects
caused by (+)-HA-966 was stereoselective.
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Fig. 4.
Effects of D-serine (56-560 mg/kg, left)
and L-serine (1000 mg/kg, right) coadministered with 100 mg/kg (+)-HA-966 on percent errors and response rates in the repeated
acquisition procedure. For L-serine, the data represent the
mean ± S.E.M. from five animals. For D-serine, the
large circles represent the mean ± S.E.M. from five animals, and
the smaller symbols represent the individual pigeon data. These symbols
indicate data from the same animals shown in Fig 2. Some individual
data points are hidden within the larger average symbols. The points
above Sal indicate percentage of errors and response rates after saline
administration. The points above Ser indicate percentage of errors and
response rates after administration of 560 mg/kg D-serine
alone. The points above (+)-HA indicate percentage of errors and
response rates after the administration of 100 mg/kg (+)-HA-966 given
alone. Ordinate, percentage of errors (top) and response rates
(bottom). Abscissae, treatment condition.
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A detailed illustration of the reversal by D-serine of the
effects caused by 100 mg/kg (+)-HA-966 on accuracy and rate of responding in the repeated acquisition procedure is shown over the
first 28 reinforcers averaged over all five animals (Fig. 5). The largest doses of
D-serine (560 mg/kg) restored both percent errors and
response rates to those observed after saline administration. The next
smallest dose of D-serine (320 mg/kg) also returned
response rates to predrug baseline levels (Fig. 5, bottom) but did not greatly modify the rate of error accumulation compared with
administration of 100 mg/kg (+)-HA-966 alone (Fig. 5, top).
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Fig. 5.
Effects of D-serine (320 or 560 mg/kg),
administered alone or with 100 mg/kg (+)-HA-966, on error accumulation
within a session. Numbers directly above the data points indicate the
number of animals contributing to the data after the administration of
100 mg/kg (+)-HA-966 (squares) when this number was less than five.
These animals did not earn more than five reinforcers in the 60-min
session due to low rates of responding. Diamonds represent data when
560 mg/kg D-serine was administered alone, and open circles
indicate rates and error accumulation after saline administration.
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Administration of a range of doses of D-serine along with a
dose of dizocilpine (180 µg/kg) that produced marked increases in
percent errors and decreases in response rates resulted in the partial
attenuation of the dizocilpine-induced impairments (Fig
6). The largest dose of
D-serine (560 mg/kg) was most effective in this regard
(Fig. 6, left). These effects, although modest and with considerable
interanimal variability, were reliably observed within animals over
three determinations per animal. The two smaller doses of
D-serine (100, 320 mg/kg) had very little effect on the dizocilpine-induced impairments. Coadministration of 1000 mg/kg L-serine with 180 µg/kg dizocilpine did not modify the
effects of dizocilpine (Fig. 6, right). D-Serine was less
effective in reversing deficits produced by another NMDA channel
blocker, phencyclidine (1.8 mg/kg) in the repeated acquisition
procedure (Fig. 7, left) and entirely
ineffective against comparable deficits caused by the competitive NMDA
antagonist CGS-19755 (3.2 mg/kg; Fig. 7, right).
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Fig. 6.
Effects of D-serine (100-560 mg/kg,
left) and L-serine (1000 mg/kg, right) coadministered with
0.18 mg/kg dizocilpine on percentage of errors and response rates in
the repeated acquisition procedure. The large symbols represent the
mean ± S.E.M. for five animals, and the smaller symbols represent
individual animal data. These symbols represent data from the same
animals shown in Fig 2. When fewer than five smaller symbols are shown,
the data are hidden by the larger average symbol. Single-animal data
points for 560 mg/kg D-serine coadministered with 0.18 mg/kg dizocilpine represent the average of three sessions. The points
above Sal indicate percentage of errors (top) and response rates
(bottom) after saline administration. The points above Ser indicate the
percent errors and response rates after the administration of 560 mg/kg
D-serine alone. The points above Dizo indicate percent
errors and response rates after the administration of 180 µg/kg
dizocilpine alone.
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Fig. 7.
The effects of D-serine (56-560 mg/kg)
coadministered with 1.8 mg/kg PCP (left) and 3.2 mg/kg CGS-19755
(right) on percentage of errors and response rates in the repeated
acquisition procedure. The larger symbols indicate the mean ± S.E.M. for five animals, and the smaller symbols indicate individual
data points. These symbols represent data from the same animals shown
in Fig. 2. Some individual data points are hidden within the larger
average symbols. The points above Sal indicate percentage of errors
(top) and response rates (bottom) after saline administration. The
points above Ser indicate the percent errors and response rates after
the administration of 560 mg/kg D-serine alone. The points
above Phen (left) indicate the effects of 1.8 mg/kg phencyclidine given
alone. The points above CGS (right) indicate the effects of 3.2 mg/kg
CGS-19755 given alone.
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Discussion |
Intramuscular administration of (+)-HA-966, an antagonist at the
glycine binding site of the NMDA subtype of the glutamate receptor,
caused a dose-dependent reduction in accuracy of responding and rates
of responding in a repeated acquisition task in pigeons. A similar
decrement was produced by dizocilpine and phencyclidine, drugs that
block the NMDA channel, and by CGS-19755, a competitive antagonist at
the glutamate binding site. Although a reduction in response rates was
often observed at doses that caused an impairment in acquisition,
rate-decreasing effects were not always accompanied by acquisition
impairments. Only the largest doses of (+)-HA-966, CGS-19755,
phencyclidine, and dizocilpine reduced response rates below the
criterion level of 0.5 responses/s. Intermediate doses of each NMDA
antagonist did not profoundly affect rates of responding, yet each
increased percent errors to greater-than-maximum criterion levels of
33%. The ()-enantiomer of HA-966, which is relatively less active as
a glycine-site antagonist (Pullan et al., 1990; Singh et al., 1990),
was 0.5 to 0.75 log unit more potent in suppressing rates of
responding, and nearly as effective in blocking acquisition of behavior
at doses just below those that stopped all responding. Morphine, which
has no clear interaction with NMDA receptor neurotransmission, produced
considerably less decrement in acquisition at doses that profoundly
suppressed rates, a result similar to that found by Thompson and
Moerschbaecher (1981).
These data suggest that blockade of ion transport through the NMDA
channel by pharmacological action at any of these three relevant
binding sites can produce a very similar reduction of acquisition of
learning in a relatively selective manner. Similar conclusions were
reached by Xu et al. (1995) in studies of the anterograde amnesia, fear
conditioning, and anticonvulsant effects of (+)-HA-966 and dizocilpine.
These data also provide further support for the notion that activation
of the NMDA subtype of glutamate receptors is an important aspect of at
least some types of learning.
It is unlikely that (+)-HA-966 was acting at a site on the NMDA
receptor other than the glycine site because systemic administration of
D-serine, an agonist at this glycine site, produced a
dose-dependent reversal of both the rate and learning impairments
caused by (+)-HA-966. At the largest dose of D-serine, the
reversal of (+)-HA-966-induced impairments was complete. When
coadministered with an effective dose of the uncompetitive antagonist
dizocilpine, the largest dose of D-serine returned both
acquisition and rate of responding to approximately 50% of control
values. Smaller doses had little effect. Modest improvements in
phencyclidine-impaired responding were observed but were not related to
D-serine dose, and D-serine had no effect on
impairments produced by CGS-19755. This indicates a specific
interaction of (+)-HA-966 on the glycine site to produce the decrements
in acquisition reported here.
Other investigators have found an interaction between
D-serine and glutamate channel blockers. Tanii et al.
(1994) reported that i.c.v. administration of D-serine
produced a dose-dependent but incomplete reversal of hyperactivity and
ataxia induced by phencyclidine in the rat; this reversal could be
prevented by administration of 7CKA. This suggests that our observation
of D-serine-induced partial antagonism of the
antiacquisition effects of phencyclidine and dizocilpine might be a
general phenomenon. The mechanism of this effect is unclear but might
involve D-serine-induced increases in the number of NMDA
channels that are operational, even in the presence of the channel blockers.
Although all of the NMDA antagonists produced similar impairments in
the repeated acquisition procedure, their differential sensitivity to
D-serine provides evidence that the learning impairments observed were produced by activity at different ligand-binding sites.
Similarly selective pharmacological interactions have been reported
previously after the central administration of D-serine. For example, i.c.v. administration of D-serine reversed the
inhibition of NMDA-induced convulsions caused by i.c.v. administration
of 7CKA and i.c.v. or i.p. administration of (+)-HA-966 in mice, but
was ineffective against the anticonvulsant effects of CGS-19755 (Lu,
1994). In pigeons, the response-rate decreasing effects of i.c.v.
administration of (+)-HA-966 or 7CKA, but not i.c.v. administration of
CGS-19755, were also reversed by i.c.v. administration of
D-serine (Lu, 1994).
Pharmacological characterization of the electrophysiological (Johnson
and Ascher, 1987; Kushner et al., 1988; Huettner, 1989; Vycklicky et
al., 1990) and in vitro binding (Mayer et al., 1989; Lerma et al.,
1990; Parsons et al., 1993) characteristics of glycine-site antagonists
has demonstrated that these effects are selectively mediated at glycine
sites associated with the NMDA receptor. Pharmacological characterization of glycine-site antagonists has not been well established using behavioral measures. In addition, systemic
bioavailability of glycine-site antagonists has not been previously
demonstrated using subconvulsive doses. The present findings provide
robust evidence that central glycine sites can be pharmacologically
manipulated by systemic administration of a glycine-site agonist and
antagonist and that the effects of blocking the NMDA receptor with a
glycine-site antagonist are similar to those produced by blocking this
receptor at either of two other sites.
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Abstract
Introduction
