(Stroke. 2000;31:976.)
© 2000 American Heart Association, Inc.
Original Contributions |
1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl)-Piperidine Affords Neuroprotection From Focal Ischemia With Prolonged Reperfusion
From the Departments of Anesthesiology/Critical Care Medicine (I.H., A.B., A.B.S., A.C.D., P.D.H., R.J.T., J.R.K.) and Neurology (A.B., J.R.K.), Johns Hopkins University School of Medicine, Baltimore, Md, and National Institute on Drug Abuse (E.D.L.), Baltimore, Md.
Correspondence to Jeffrey R. Kirsch, MD, Blalock 1412, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-4963. E-mail jkirsch{at}jhmi.edu
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Abstract |
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Background and Purpose—We previously showed that the intravenous administration of the potent
1-receptor ligand
4-phenyl-1-(4-phenylbutyl)-piperidine (PPBP) provides neuroprotection
against transient focal cerebral ischemia and that the
protection depends on treatment duration. We tested the hypothesis that
PPBP would provide neuroprotection in a model of transient focal
ischemia and 7 days of reperfusion in the rat as assessed with
neurobehavioral outcome and infarction volume. Methods—Under the controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) with the intraluminal suture occlusion technique. We used laser Doppler flowmetry to assess MCAO. At 60 minutes after the onset of ischemia, rats were randomly assigned to 1 of 4 treatment groups in a blinded fashion and received a continuous intravenous infusion of control saline or 0.1, 1, or 10 µmol · kg-1 · h-1 PPBP for 24 hours. Neurobehavioral evaluation was performed at baseline (3 to 4 days before MCAO) and at 3 and 7 days of reperfusion. Infarction volume was assessed with triphenyltetrazolium chloride staining on day 7 of reperfusion in all rats.
Results—Triphenyltetrazolium chloride–determined infarction volume of ipsilateral cortex was smaller in rats treated with 10 µmol · kg-1 · h-1 PPBP (n=15, 68±12 mm3, 18±3% of contralateral structure, P<0.05) (mean±SEM) compared with corresponding rats treated with saline (n=15, 114±11 mm3, 31±3% of contralateral structure). PPBP did not provide significant neuroprotection in the caudoputamen complex. Although MCAO was associated with several alterations in behavior, the treatment with PPBP had no effect on behavioral outcomes.
Conclusions—The data demonstrate that the potent
1-receptor ligand PPBP decreases cortical infarction
volume without altering neurobehavior after transient focal
ischemia and prolonged reperfusion in the rat.
Key Words: cerebral infarction • cerebral ischemia, focal • excitotoxicity • ligands • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Numerous studies have demonstrated that
site–mediated drug effects modulate glutamate receptor function,
neurotransmitter release, behavior, and cognition.1 2
Furthermore, there is mounting experimental evidence from in vitro and
in vivo studies that -receptors play a role in the modulation of
ischemic neuronal injury. Several possible mechanisms
for this neuroprotection have been postulated; they include inhibition
of presynaptic glutamate release,3 buffering of
postsynaptic glutamate-evoked Ca2+ influx,
modulation of neuronal responses to pharmacological
N-methyl-D-aspartate (NMDA) receptor
stimulation,4 5 inhibition of dopamine
release,6 prevention of cortical spreading
depression,7 and attenuation of basal and
NMDA-evoked nitric oxide production in vivo.8
We previously demonstrated that the short-term administration of the
potent and highly selective 1-receptor ligand
4-phenyl-1-(4-phenylbutyl)-piperidine (PPBP) prevents early brain injury in rat9 and cat 10 models
of transient focal ischemia. However, prolonged continuous
infusion with PPBP, beyond 24 hours, provides no neuroprotection after
transient focal ischemia in the rat.11 We
postulated that this may be due to neurotoxicity secondary to prolonged
interaction with the NMDA/receptor complex and undesirable suppression
of glutamate-triggered events that subserve vitally important
metabolic, neurotransmitter, and neurotrophic
functions.12 However, we did not observe cytotoxic effects
histopathologically with prolonged treatment with PPBP in naive
rats,12 as has been shown with NMDA antagonist
toxicity.13
Experimental pharmacological neuroprotection is rarely assessed at 3 to 4 days of reperfusion as an end point after transient focal ischemia. Furthermore, studies have predominantly used morphometric analysis of infarction volume as the primary outcome. Although improvements in complex behavior such as memory without histological correlation have been reported after global forebrain ischemia14 15 and traumatic brain injury,16 neuroprotective studies that correlate infarction volume and neurobehavior after focal ischemic stroke are limited. The purpose of the present study was to determine whether 24 hours of continuous infusion of PPBP affords neuroprotection by decreasing infarction volume and improves functional outcome (sensory capabilities, coordination, and anxiogenic effect) in a dose-specific manner after transient middle cerebral artery occlusion (MCAO) and 7 days of reperfusion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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General Preparation and Animal Surgery
The experimental protocol was approved by the Institutional Animal Care and Use Committee and conforms to the National Institutes of Health guidelines for the care and use of animals in research. Adult male Wistar rats weighing 260 to 340 g (n=103) were anesthetized with halothane (1.0% to 2.0%) in O2-enriched air (fraction of inspired O2 0.35% to 0.40%) to maintain the following conditions: arterial pH 7.35 to 7.40, PaCO2 35 to 45 mm Hg, and PaO2 100 to 160 mm Hg. With aseptic surgical techniques, the right femoral artery was cannulated to monitor arterial blood pressure and arterial blood gases. The right femoral vein was cannulated for the administration of drugs and fluids. After cannulation, both femoral arterial and venous catheters were tunneled subcutaneously, exteriorized in the posterior mid thorax, and suture fixed onto a swivel. The swivel allows for free movement of the rat in a cage and for continuous intravenous drug administration at a desired rate with an infusion pump. Rectal and temporalis muscle temperatures were monitored and maintained within a normothermic range with a heat lamp throughout the surgical procedures.
Focal Ischemia and Reperfusion
The adequacy of vascular occlusion was documented with laser
Doppler flowmetry (LDF). An area 2 to 3 mm in diameter
in the right parietal bone (2 mm posterior and 6 mm lateral
to bregma) was thinned for the placement of an LDF probe (model MBF3D;
Moor Instruments Ltd) as previously described.17 Transient
focal ischemia (2 hours) was produced with MCAO according to an
intraluminal suture technique as previously described18
with some modification.9 At the end of ischemia (2
hours), reperfusion was produced through withdrawal of the intraluminal
suture; this was associated with rapid restoration of the LDF signal.
Rats that did not demonstrate a significant reduction (to at least 40%
of baseline) during MCAO or rapid restoration of the LDF signal during
reperfusion were excluded from the study. LDF measurements were
obtained during 5-minute periods at 5, 15, 30, 60, 90, and 120 minutes
after MCAO and 15 minutes of reperfusion.
Treatment Groups
Rats were randomly assigned in a blinded fashion to 1 of 4
treatment groups receiving 0.1, 1, or 10 µmol ·
kg-1 · h-1 PPBP
(National Institute on Drug Abuse) or an equivalent volume of saline.
The infusion was initiated at 1 hour of MCAO and continued for 24
hours. Infusion volume was 20 mL at a rate of 0.5 mL/h for 24 hours.
Using HPLC, we have previously shown that PPBP remains stable in 0.9%
saline for 
96 hours at 37°C.11 At 15 minutes after the
onset of reperfusion, rats were allowed to emerge from
anesthesia and were provided ad libitum access to food and
water. On day 7 after MCAO, rats were deeply anesthetized with
5% halothane and decapitated. The brain was harvested and sliced into
seven 2-mm-thick coronal sections for staining with 1%
triphenyltetrazolium chloride (TTC) in
saline at 37°C for 30 minutes as previously described.9
Infarction volume was measured with digital imaging (Digital Camera 40;
Eastman Kodak Co) and analysis software (SigmaScan Pro;
Jandel). The infarcted area (unstained) was numerically integrated
across each section and over the entire ipsilateral hemisphere.
Infarction volumes were measured separately in the cerebral cortex and
caudoputamen and expressed as a percentage of the volume of
the ipsilateral side.
Neurobehavioral Testing
Baseline behavioral tests were conducted 3 to 4 days before MCAO
(baseline) and then repeated at 3 (day 3) and 7 days (day 7) after
MCAO. To assess the effect of repeated testing, a separate group of
experimentally naive animals (n=15) were subjected to a similar
behavioral testing protocol. The trials were scored by a single,
experimentally uninformed observer. The behavioral tests were conducted
in a quiet room, during the light phase (between 1 and 3 PM
Eastern Standard Time). Between trials, the apparatus were
cleaned with a 75% ethanol solution.
Visual Placement
For evaluation of visual acuity, the rats were suspended by
their tails and slowly lowered toward the edge of a laboratory bench
top. A positive score was recorded if the animal extended its
forepaws toward the bench top before contact.
Locomotor Balance and Coordination
Rats were placed at the center of a wooden bridge or pole that
was suspended 
60 cm above a foam pillow. Animals were tested in
random order with a 2-cm-wide square bridge, and a wooden pole with a
diameter of 2 cm. The latencies (seconds) to fall off the bridges and
pole were recorded. Animals that did not fall received a score of
120 seconds.
Turning on an Inclined Screen
A mesh screen, maintained at a 45o angle,
was used to assess strength and agility. Rats were placed in the middle
of the screen facing downward. The time required for each rat to
complete a 90o turn was recorded.
Turning in an Alley
The ability to turn in an alley was used as a measure of
coordinated muscle movement and agility. The width of the alley was 12
cm. The animals were placed in the alley facing the back wall. The time
that the animals required to turn around and face the open end of the
alley was recorded.
Latency to Fall From Wire
Forelimb strength and grasping ability were evaluated by
suspending the rats by their forelimbs on a wire. The wire was
stretched between 2 posts at a height of 60 cm. A foam pillow was
positioned beneath the apparatus. The time (seconds) until
the animal fell was recorded. A score of zero was assigned to
animals that did not grasp the wire or fell immediately. The trials
lasted a maximum of 90 seconds.
Elevated Plus-Maze
The elevated plus-maze was used to assess anxiogenic behavior.
The maze consisted of 4 intersecting arms and was constructed from
varnished wood and opaque black Plexiglas. The maze was elevated 1 m
above the floor. The arms of the maze were 45 cm long and 10 cm wide;
the closed arms had walls on 3 sides that were 20 cm high, and the open
arms did not have walls on any of the sides. At the beginning of the
test, the rat was placed in the center of the maze facing 1 of the open
arms. An observer, who was seated 1 m from the apparatus
at a height sufficient to observe the animal in all 4 arms of the maze,
recorded the number of entries into each arm of the maze and the
time spent in each arm. The time that the experimental animal spent
grooming was also recorded.
Statistical Analysis
All values are expressed as mean±SEM.
Physiological parameters were subjected
to repeated measures ANOVA. Differences in infarction volume and mean
residual LDF measurements among groups were determined with 1-way
ANOVA. Post-hoc analysis was performed with Dunnett’s test.
The criterion for statistical significance was P<0.05.
Behavioral data from the pole and wire were analyzed via ANOVA
for repeated measures. The experimental errors of the data were not
normally distributed, so the data were transformed
[log10(y+1)] before
analysis. Transformation was not successful in normalization of
the data from the 2-cm bridge, inclined screen, alley, and elevated
plus-maze, so these data were analyzed with Kruskal-Wallis
1-way ANOVA on ranks. If there was no significant treatment effect on
any of the test days, the groups were collapsed, and a Kruskal-Wallis
ANOVA on ranks was conducted across time with post-hoc comparisons with
the use of Dunn’s method. Data points that were >3 SDs from the mean
were removed before analysis (pole n=2, incline n=4, alley n=2,
wire n=4, elevated plus-maze n=3).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Mean arterial blood pressure, PaCO2, PaO2, pH, and temporalis muscle temperatures were within normal physiological ranges in all groups at baseline (preischemia), during ischemia, and after ischemia (postischemia) (Table 1
). Death occurred before the end
of the experimental protocol in 4 of 26 control rats treated with
saline, 2 of 21 rats treated with 0.1 µmol ·
kg-1 · h-1 PPBP, 2
of 19 rats treated with 1 µmol ·
kg-1 · h-1 PPBP,
and 4 of 21 rats treated with 10 µmol
· kg-1 · h-1
PPBP. The number of animals that were excluded because the residual LDF
signal did not decrease to 40% of baseline signal and did not remain
below this value during the period of MCAO were 7 saline-treated
control rats, 4 rats treated with 0.1 µmol ·
kg-1 · h-1 PPBP, 2
rats treated with 1 µmol ·
kg-1 · h-1 PPBP,
and 2 rats treated with 10 µmol ·
kg-1 · h-1 PPBP.
Thus, 15 rats in each group successfully completed the experimental
protocol. The residual LDF signal during MCAO was similar in all groups
(27±2% in saline-treated rats, 34±2% in 0.1 µmol ·
kg-1 · h-1
PPBP-treated rats, 30±2% in 1 µmol ·
kg-1 · h-1
PPBP-treated rats, and 30±2% in 10 µmol ·
kg-1 · h-1
PPBP-treated rats). On withdrawal of the monofilament, the LDF signal
returned rapidly to baseline values within 5 minutes in all groups.
After 15 minutes of reperfusion, LDF signal was 116±13% in saline
control rats, 104±8% in 0.1 µmol ·
kg-1 · h-1
PPBP-treated rats, 106±11% in 1 µmol ·
kg-1 · h-1
PPBP-treated rats, and 104±10% in 10 µmol ·
kg-1 · h-1
PPBP-treated rats.
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TTC-determined infarction volume measured at 7 days of reperfusion of
ipsilateral cortex was smaller in rats treated with 10 µmol
· kg-1 · h-1
PPBP (n=15, 68±12 mm3, 18±3% of
contralateral structure; P<0.05) (mean±SEM) than in
corresponding rats treated with saline (n=15, 114±11
mm3, 31±3% of contralateral structure)
(Figure). Infarction volume of the
caudoputamen complex was not statistically different
between saline control rats and PPBP-treated rats at the 3 different
doses.
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Behavioral Data
There were no significant behavioral differences
(P>0.05) between animals treated with PPBP or the vehicle
at any time point measured in any of the behavioral tests. However,
MCAO was associated with functional alterations in several of the
behavioral tests when pre-MCAO baseline performance was
compared with performance after 3 or 7 days of reperfusion
(Table 2). Latency to fall from
the pole was significantly longer at 7 days but not at 3 days post-MCAO
compared with baseline (F2,165=4.2,
P<0.05). Latency to fall from the 2-cm bridge was
significantly longer at 3 and 7 days after MCAO than at baseline
(H=25.4, df=2, P<0.01). Latency to turn on an
inclined screen was significantly longer at 7 days, but not at 3 days,
after MCAO than at baseline (H=16.5, df=2,
P<0.01). Latency to fall from the wire was significantly
longer at both 3 and 7 days after MCAO than at baseline
(F2,163=21.2, P<0.01). There
was a significant decrease in the total number of arm entries in the
elevated plus-maze at 3 days after MCAO (H=35.9, df=2,
P<0.01) and an increase in the amount of time spent
autogrooming in the maze on day 7
(F2,167=5.8, P<0.01) compared
with baseline. Because of the extreme MCAO-induced decrease in
locomotor (exploratory) behavior observed in the elevated plus-maze,
time spent in the open versus closed arms is not a valid measure of
anxiogenic-like behavior; therefore, these data are not
presented. There was no significant effect (P>0.05)
of MCAO on visual placement or turning in an alley.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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The main findings of the present study with a model of focal ischemia with prolonged reperfusion model in the rat are that (1) continuous 1-day intravenous infusion PPBP administered 1 hour from the onset of MCAO decreases cortical but not striatal infarction volume and that (2) PPBP treatment does not alter neurobehavioral outcome within a 7-day observation period. These data suggest that PPBP-associated neuroprotection is region specific but robust in the mature as well as early9 ischemic lesion.
Effects on Infarction Volume
Focal ischemic injury volume is dependent on the temporal
end point of the study. Most previous studies of neuroprotection have
used morphometric analysis of infarction volume at 3 to 4 days
of reperfusion after transient focal ischemia as their end
point. Less is known about the outcome of these agents after prolonged
reperfusion. In our previous study,12 the continuous
infusion of PPBP ameliorated the effects of transient focal
ischemia at the dosage of 1 µmol ·
kg-1 · h-1 when
the infarction volume was assessed 4 days after MCAO. In the
present study, we assessed infarction volume at 7 days of
reperfusion after MCAO. Although some investigators19 have
demonstrated that brain infarction after mild transient focal
ischemia can develop in a delayed fashion (>3 days after the
original insult), others have shown that cerebral edema can cause an
artifactual increase in infarction volume as assessed with TTC
staining. Lin et al20 found that edema was maximal at 24
hours after MCAO with a subsequent reduction at 3 days. In addition,
the total volume of the infarcted cortex in the injured hemisphere was
smaller than the noninfarcted hemisphere at 7 days after MCAO. Other
variables, such as drug stability and penetration into the brain,
may influence infarction volume in studies that investigate
neuroprotective agents in focal ischemia. It has been shown
that PPBP penetrates the brain very readily when administered
intravenously with a slow in vivo clearance from the
brain.21 In addition, we previously demonstrated that PPBP
remains stable in solution for 96 hours at 37°C.11
Temperature is an important variable and modulator in
ischemic brain injury,22 and it is well
established that temperature affects outcome and infarction volume in
focal cerebral ischemia.23 24 In a previous study
in the cat, this neuroprotective effect of PPBP could not be explained
by either a more favorable redistribution of cerebral blood flow or an
effect on brain temperature.10 Small differences in brain
temperature during and immediately after a period of transient focal
ischemia can critically influence neuropathological
outcome.25 26 27 In our study, rectal and temporalis muscle
temperatures were monitored during preischemia, MCAO, and
immediate reperfusion (Table 1
). We9 10 28 and
others22 have demonstrated that -receptor ligands
afford neuroprotection without affecting body temperature. We attempted
to control temporalis muscle temperature during the acute experimental
period in our study, but we did not monitor temperature on a continuous
basis beyond the immediate reperfusion period. Thus, it is conceivable
that variations in body and brain temperature could have affected
infarction size in the experimental groups.
Behavioral Outcome
In the present study, transient MCAO was associated with
functional alterations in the outcomes of several behavioral tests
(Table 2). For example, rats exhibited a motor deficit as
measured by the number of arm entries made during a 5-minute test in
the elevated plus-maze. The number of arms entered decreased to 37% of
baseline on the third day after MCAO and recovered to 72% of
baseline by the seventh day after MCAO. Alterations in motor behavior
also were likely to be the cause of the significant increases in
latency to fall from a 2-cm bridge, to fall from the pole, and to turn
on an inclined screen that were observed after MCAO. During the
baseline testing on the 2-cm bridge and the pole, the rats explored the
entire length of the bridge and the pole; however, after MCAO, the rats
tended to remain where they were placed at the beginning of the trial.
Because they were moving less after MCAO, the rats were less likely to
misstep and fall, thus accounting for the increase in latency to fall
from the bridge and the pole after MCAO. After cerebral
ischemia, the latency to turn on the inclined screen also
increased as a result of slower initiation of movement after being
placed on the apparatus. Many factors could contribute to
the locomotor deficits that were observed in the ischemic rats,
including an increase in the prevalence of "sickness behaviors."
which commonly accompany an inflammatory response.29 30
Additional studies are necessary to determine whether rats subjected to
MCAO exhibit a generalized suppression in spontaneous locomotor
activity or whether the locomotor deficits are condition specific.
After MCAO, the latency to fall while suspended from a wire also was
3 times longer when tested several days after MCAO as opposed to
several days before surgery (baseline). The increase in latency to fall
is attributed to an abnormal grasp reflex in the forelimbs that most
likely resulted from damage to the frontal cortex during MCAO. Abnormal
grasp reflexes also have been identified in humans with cortical
damage.31 Repeated testing is not likely to be a
contributing factor to any of the MCAO-induced behavioral changes
described earlier, because the behavior of the experimentally
nonmanipulated animals did not change with repeated behavioral testing
in any of these measures. The only behavior that did change with
repeated testing in both the experimentally manipulated and the
nonmanipulated animals was the amount of time spent autogrooming in the
elevated plus-maze. Once spontaneous locomotor recovery has occurred in
rats that underwent MCAO, the use of additional behavioral tasks such
as passive avoidance or amphetamine-induced rotation to assess striatal
function may have revealed an effect of PPBP on behavioral outcome.
PPBP treatment was associated with histological protection in the cortex in the present study, but the compound did not offer protection from MCAO-associated behavioral deficits. However, the decreases in locomotor activity that were noted in the elevated plus-maze and on the bridge, pole, and screen prevented a clear assessment of anxiety, coordination, and balance in this study. It is possible that extension of the behavioral testing of the animals beyond 1 week may have allowed time for locomotor recovery to occur, which in turn would have allowed us to more accurately assess anxiety, coordination, and balance in the PPBP- versus vehicle-treated animals. Alterations in locomotor activity, coordination, balance, and anxiety are commonly identified confounding factors in the interpretation of data from complex behavioral and cognitive tests. Although the series of locomotor tests conducted in the present study do not specifically assess cortical or striatal function, they do indicate that the rats have significant sensorimotor deficits after MCAO that would prevent clear interpretation of the data from additional behavioral tests that could be used to assess cortical or striatal function. Taken together, the behavioral data presented in this study indicate that a recovery period of >7 days after MCAO will be necessary before the incorporation of complex behavioral and cognitive tests in future studies.
Although some studies of cerebral ischemia have reported a close correlation between histology and behavior,32 33 other studies have reported a dissociation between histology and sensorimotor behavior or cognitive function.14 15 34 35 36 37 Several factors could account for the lack of consistent correlation between histology and behavior, including the timing of the behavioral tests (as described earlier) and the use of histological techniques that provide low resolution. The most frequently used methods to quantify infarction volume after MCAO are not capable of measuring diffuse morphological changes,33 which could affect behavior. It is also possible that neurons that have been spared through pharmacological intervention are still not capable of functioning at the level of effective communication with other cells. In contrast, it is possible for the recovery of some sensorimotor functions to occur "spontaneously" several days after MCAO in the absence of accompanying histological improvement36 ; presumably, these behavioral improvements are due to compensatory changes that occur elsewhere in the brain. Clearly, until there is a better understanding of how histological changes affect behavior, it will be necessary to continue assessment of both histological and functional outcomes of potential treatments of stroke.
In conclusion, this study demonstrates that the continuous
intravenous infusion of the potent
1-receptor ligand PPBP improves
histological outcome after transient focal
ischemia and prolonged reperfusion without altering
neurobehavioral outcome.
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Acknowledgments |
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This work was supported in part by US Public Health Service National Institutes of Health grant NS-20020. Dr Bhardwaj is supported in part by an American Heart Association Clinician Scientist Award.
Received August 16, 1999; revision received December 1, 1999; accepted January 6, 2000.
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Editorial Comment
Department of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, Iowa City, Iowa
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Previous work has suggested that
-receptors may modulate
neuronal injury following ischemia. The goal of this study was
to examine the effect of 24-hour infusion of a
1-receptor ligand, 4-phenyl-1-(4-phenylbutyl) piperdine
(PPBP), on brain injury and neurological function in a model of focal
ischemia with relatively prolonged reperfusion (7 days). A
major strength of the study relates to its use of an array of
neurological tests. The results suggest that following focal ischemia with prolonged reperfusion, PPBP decreases cortical, but not caudoputamen, infarct volume. Despite the apparent selective reduction in brain injury, treatment with PPBP did not result in any detectable improvement in neurobehavioral outcome. Thus, the correlation between the degree of tissue injury, as determined by histological assessment of infarct volume, and neurological function was not perfect.
One limitation of this study is that it does not provide insight into the mechanism by which treatment with PPBP exerts a protective effect on infarct volume in this model. Possibilities include alterations in changes in gene expression that occur in response to ischemia as well as changes in neuronal activity, neurotransmitter release, or effects of glutamate (including effects on NMDA receptors).R1 R2 R3
Received August 16, 1999; revision received December 1, 1999; accepted January 6, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1. Maraca T, Lockhart BP. Neuroprotective and anti-amnesic potentials of sigma receptor ligands. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21:69–102.
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