Injection Of MK-801 Research Articles

Valproate prevents the induction and the expression of MK-801 sensitization

Repeated administration of psychostimulants such as amphetamine, cocaine, and methylphenidate has been shown to induce behavioral sensitization. Sodium valproate, an anticonvulsant agent that enhances GABA activity, and dizocilpine (MK-801), a non-competitive NMDA receptor antagonist, can block the sensitization elicited by psychostimulants. MK-801 also has been demonstrated to sensitize to itself. The objective of the present study was to determine whether valproate disrupts the behavioral sensitization elicited by MK-801. Male Sprague–Dawley rats were given a regimen of repeated MK-801 injections (0.3 mg/kg, i.p.) that produced behavioral sensitization. They were also given valproate, at a dosage (50 mg/kg, i.p.) that prevented behavioral sensitization to stimulants, either during or after multiple MK-801 injections. After the washout period, animals were then re-challenged with MK-801 to determine whether valproate disrupted the behavioral sensitization elicited by MK-801. An activity monitoring system recorded horizontal activity, total distance, and vertical activity of the animals following drug treatment. Results of their locomotor responses demonstrated that valproate disrupted the development/induction and the expression of sensitization to MK-801, as it did to methylphenidate.

The effects of NMDA receptor antagonist MK-801 on lipid peroxidation during focal cerebral ischemia in rats

The effect of MK-801 on ischemic neuronal damage was studied in a rat model of permanent focal cerebral ischemia in terms of ipsilateral and contralateral cortical and cerebellar tissue lipid peroxides. Forty-five male Swiss Albino rats were assigned into one of four groups: sham operated as controls, subjected to right middle cerebral artery occlusion (MCAO) or injection of MK-801 (0.5 mg/kg ip) either 30 min before or just after right MCAO. Changes in lipid peroxides were expressed as nmol malondialdehyde (MDA) and conjugated diene (CD)/mg protein. MDA values after 60 min of ischemia relative to contralateral cortex and CD levels in 0, 10 and 60 min after ischemia were found to be higher in ipsilateral cortex than those in contralateral cortex. On the other hand, contralateral cerebellar MDA levels in 0 and 60 min of ischemia and CD levels in 0, 10 and 60 min after ischemia were found to be higher than those in ipsilateral cerebellum. Pharmacological inhibition of glutamate receptor by MK-801 before or just after permanent MCAO decreased significantly the MDA and CD levels in both cortex and cerebellum. Although no significant differences found in MDA values between rats pre- and posttreated with MK-801, CD levels in posttreated group seemed significantly lower than those in pretreated group. On the whole, these results suggest that MDA and CD represent early biochemical marker of lipid peroxidation in ischemic tissues, reflecting the radical-mediated tissue damage.

Effects of diltiazem and MK-801 on morphine analgesia and pharmacokinetics in mice

The effects of diltiazem, an L-type calcium channel blocker, and MK-801, a non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist on morphine analgesia and pharmacokinetics were examined in mice. Mice received a subcutaneous injection of morphine (3.2 mg/kg) 30 min after a subcutaneous injection of diltiazem or MK-801. Diltiazem (20–60 mg/kg) potentiated morphine analgesia and increased serum morphine levels in a dose-dependent manner. MK-801 (0.3 mg/kg) significantly attenuated morphine analgesia but had no significant effect on serum or brain morphine levels. These results suggest that a modification of morphine metabolism is involved, at least in part, in the ability of diltiazem to enhance morphine analgesia, whereas MK-801 attenuates morphine analgesia without affecting morphine pharmacokinetics.

Role of nitric oxide synthase inhibitors and NMDA receptor antagonist in nicotine-induced behavioral sensitization in the rat

Repeated injections of nicotine are well known to produce progressively larger increases in locomotor activity, an effect defined as behavioral sensitization. This study was carried out to investigate the role of nitric oxide (NO) and N-methyl- d-aspartate (NMDA) receptors in nicotine-induced behavioral sensitization. Rats were given repeated injections of nicotine (0.4 mg/kg, s.c., twice daily for 7 days) followed by one challenge injection on the fourth day after the last daily injection. Systemic challenge with nicotine produced a much larger increase in locomotor activity in nicotine-pretreated rats. Rats were pretreated with the nonselective nitric oxide synthase (NOS) inhibitor, N G-nitro-arginine-methyl-ester ( l-NAME; 75 mg/kg, i.p.), the selective constitutive NOS inhibitor, N-nitro- l-arginine ( l-NNA; 15 mg/kg, i.p.), the prototypical selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) or NMDA receptor antagonist, MK-801 ((5 R,10 S)-(+)-5-Methyl-10,11-dihydro-5 H-dibenzo[a,d] cyclohepten-5,10-imine; 0.3 mg/kg, i.p.), 30 min before injections of nicotine during a 7-day development or a 3-day withdrawal phase after which challenged with nicotine on day 11. Pretreatment with l-NAME, l-NNA and MK-801, but not aminoguanidine, blocked the development of nicotine-induced sensitization to subsequent nicotine challenge. Injections of MK-801 twice daily during 3-day withdrawal periods after a 7-day induction period of nicotine attenuated nicotine-induced behavioral sensitization, whereas injections of l-NAME, l-NNA or aminoguanidine had no effects on the expression of sensitization produced by repeated nicotine. This study demonstrates that NMDA receptors can play a major role in the expression as well as development of nicotine-induced behavioral sensitization, and that NO is also involved in the development, but not critically involved in the expression of behavioral sensitization to nicotine.

Behavioral effects of MK-801 on reserpine-treated mice

The effects of dizocilpine (MK-801), a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, were studied on dopamine-related behaviors induced by reserpine treatments. This study focuses on behavioral syndromes that may used as models for Parkinson's disease, or tardive dyskinesia, and its response after glutamatergic blockage. Reserpine (1 mg/kg), administered once every other day for 4 days, produced increases in orofacial dyskinesia, tongue protrusion and vacuous chewing in mice, which are signs indicative of tardive dyskinesia. Reserpine also produced tremor and catalepsy, which are signs suggestive of Parkinson's disease. MK-801 (0.1 mg/kg), administered 30 min before the observation test, prevented the vacuous chewing movements, tongue protrusions and catalepsy induced by reserpine. However, MK-801 injection produced a significant increase of tremor in reserpine-treated mice. Reserpine (1 mg/kg), administered 90 min before the test and followed by apomophine injection (0.1 mg/kg) 5 min before the test, did not produce oral dyskinesia in mice. On the other hand, reserpine induced increases in tremor and catalepsy compared to control mice. MK-801 (0.1 mg/kg) administration attenuated the catalepsy and tremor induced by reserpine. Pretreatment with reserpine (1 mg/kg) 24 h before the observation test produced increases in vacuous chewing movements and tongue protrusion, as well as increases in tremor and catalepsy, whereas MK-801 (0.1 mg/kg) injection 90 min before the test reversed the effects of reserpine. These results show that reserpine produces different and abnormal movements, which are related to dose and schedule employed and can be considered as parkinsonian-like and tardive dsykinesia signs. The glutamatergic blockage produced by NMDA can restore these signs, such as vacuous chewing movements, tongue protrusions, catalepsy and tremor according to the employed model.

Disruption of sensitization to methylphenidate by a single administration of MK-801

Blockade of sensitization to methylphenidate by a single injection of MK-801 was investigated using a computerized activity monitoring system. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. After 2 days of baseline recording and a saline injection on day 3, the rats were randomly divided into four experimental groups. All received 2.5 mg/kg of methylphenidate (s.c.) once a day from days 4 to 9, then after five days of no treatment, they were re-challenged with 2.5 mg/kg of methylphenidate on day 15. One group received only methylphenidate, while the other three groups also received a single i.p. injection of MK-801 (0.30 mg/kg) either 24 h (day 3) or 1 h prior to the first of the six methylphenidate injections (day 4), or 1 h prior to the second methylphenidate injection (day 5). A single injection of MK-801 on day 4 (1 h prior to methylphenidate) blocked the development of sensitization to methylphenidate, since a sensitized response could not be elicited six days after cessation of repeated methylphenidate administration (day 15). However, sensitization to methylphenidate still occurred in the groups receiving MK-801 (0.30 mg/kg) on day 5, indicating that the mechanism by which a single injection of MK-801 disrupts sensitization to methylphenidate is sensitive to timing and is not a direct long-term effect. In conclusion, a single injection of MK-801 persistently blocks the development of sensitization to methylphenidate only if it is given with methylphenidate on the first day of the repetitive treatment phase.

NMDA receptor antagonists impair memory for nonspatial, socially transmitted food preference.

Rats avoid unfamiliar foods and learn to prefer those that they smell on the breath of conspecifics. Hippocampal lesions produce rapid forgetting of this socially acquired memory. The authors report that NMDA receptor antagonists impair this memory. Rats given CPP were trained in the social transmission of food preference task. Normal rats showed robust memory 72 hr later. CPP-injected rats performed normally 24 hr, but randomly 72 hr, after training. Spatial context was irrelevant: Rats trained and tested in different rooms performed the same as rats trained and tested in 1 room. MK801 and intrahippocampal injections of APV produced amnestic effects similar to CPP. Thus, NMDA receptor activation is crucial for the persistence of socially acquired, hippocampus-dependent, nonspatial memory.

Social contacts and production of 50-kHz short ultrasonic calls in adult rats.

The goal of the study was to provide evidence that the production of 50-kHz calls by adult rats is driven by potential or direct social contacts. The calls have been studied during daily visits to a cage by single or paired rats. Repeated exposure of rats to the cage frequently visited by other rats or direct contact between rats significantly increased the number of 50-kHz calls. The increase in production of 50-kHz calls was reduced by 78% after intrapreoptic-anterior hypothalamic injection of MK-801, an N-methyl-D-aspartate-type glutamate receptor antagonist. Calls emitted in all situations had a similar acoustic profile. It was found that 50-kHz calls were produced in anticipation of, and/or during, direct social contacts among adult rats and were predominantly initiated by olfactory stimuli. The calls seem to express an appetitive behavioral state in which the central glutamatergic mechanism is implicated.

Depolarization induces insulin-like growth factor binding protein-2 expression in vivo via NMDA receptor stimulation.

The effect of depolarization and N-methyl-D-aspartate (NMDA) receptor blockade on insulin-like growth factor-I (IGF-I), IGF binding protein-2 (IGFBP-2) and IGFBP-4 expression was analysed in vivo. Depolarization was induced in adult rat brains by applying 3 M KCl to the exposed cortex for 10 min. A subgroup of animals also received daily injections of MK-801. Four days after KCl exposure, the brains were analysed by in situ hybridization, immunohistochemistry and TUNEL. A significant upregulation of IGFBP-2 mRNA and protein was detected in astrocytes after KCl exposure This upregulation was reduced by MK-801 treatment. No alterations in IGF-I or IGFBP-4 mRNA levels were noted. We did not detect TUNEL positive cells, morphological signs of necrosis or apoptosis, or neuronal loss in the depolarized zone. Taken together, these findings indicate that upregulation of IGFBP-2 by depolarization is mediated by NMDA receptors, and, as no neuronal damage was detected, astrocytic NMDA receptors may be responsible for this upregulation.

NMDA-type glutamatergic modulation in dopaminergic activation measured by apomorphine-induced cage climbing behaviors.

The present study examined the hypothesis that NMDA, AMPA/Kainate, and metabotropic (mGlu) glutamate receptors contribute to a behavioral stimulation induced by activation of dopamine receptors by comparing responses in apomorphine-induced cage climbing behaviors in mice. MK-801, CNQX, and MCPG were served as the NMDA receptor, AMPA/Kainate receptor, and mGlu receptor antagonist, respectively, to elucidate the glutamatergic modulation in apomorphine-induced dopaminergic activation in mice. Drugs were administered intracerebroventricularly (i.c.v.) into the mouse brain 15 min before the apomorphine treatment (2 mg/kg, s.c.). I.c.v. injection of MK-801 inhibited the apomorphine-induced cage climbing behavior dose-dependently. However, treatments with CNQX and MCPG did not any significant change in apomorphine-induced cage climbing behavior in mice. These results suggest that stimulation of NMDA type of glutamate receptors could contribute to the dopaminergic stimulation, but not AMPA/Kainate and mGlu type glutamate receptors.

MK801 suppresses the l-DOPA-induced increase of glutamate in striatum of hemi-Parkinson rats

In vivo microdialysis in freely moving rats was used to investigate the influence of the indirect dopamine receptor agonist levodopa ( l-DOPA), alone and combined with the N-methyl- d-aspartate (NMDA) receptor antagonist dizocilpine (MK801), on extracellular glutamate levels in the striatum of intact and 6-hydroxydopamine-lesioned rats. l-DOPA (25 mg/kg i.p. after benserazide 10 mg/kg i.p.) increased extracellular glutamate levels in the striatum of both intact and dopamine-depleted rats. A prior injection of MK801 (0.1 and 1.0 mg/kg i.p.) did not alter the l-DOPA-induced glutamate release in the striatum of intact rats. In contrast, the l-DOPA-induced increase in glutamate in the striatum of 6-hydroxydopamine-lesioned rats was suppressed by MK801 (0.1 mg/kg i.p.). The data presented here suggest that NMDA receptors do not play a role in the l-DOPA-induced increase in striatal glutamate in intact rats but are involved in the glutamate release in the dopamine-depleted striatum. The suppression of this increase by prior administration of MK801 could represent a neuroprotective effect.

Expression of c-Fos, Fos B, Jun B, and Zif268 transcription factor proteins in rat barrel cortex following apomorphine-evoked whisking behavior

Apomorphine-evoked expression of transcription factor proteins: c-Fos, Fos B, Jun B, and Zif268 (also named Krox-24, NGFI-A, Egr-1), was investigated in rat somatosensory (barrel) cortex. The effect of the N-methyl- D-aspartate receptor antagonist MK-801 on their expression was also analyzed. Apomorphine is a dopamine receptor agonist, eliciting motor activity, including enhanced whisking leading to the activation of vibrissae representation in the barrel cortex. Rats had their whiskers clipped on one side of the snout. The Zif268 levels were markedly reduced by this procedure alone. In contrast, apomorphine (5.0 mg/kg) evoked marked c-Fos elevation, less pronounced changes in Jun B and Zif268 and no change in Fos B. The greatest apomorphine-evoked c-Fos accumulation was observed in layers IV and V/VI of non-deprived barrel cortex and was not significantly influenced by MK-801 injection at 0.1 mg/kg. A higher dose of MK-801 (1.0 mg/kg) produced abnormalities in locomotor behavior and diminished c-Fos levels on the non-deprived side to the ones observed in the sensory stimulus-deprived cortex. We conclude that the response of the somatosensory cortex is selective with respect to both the gene activated and its cortical layer localization. Furthermore, sensory stimulation provides a major but not the only component to apomorphine-evoked barrel cortex gene activation.

Effect of orally administered guanosine on seizures and death induced by glutamatergic agents

Intraperitoneal guanosine has been shown to prevent quinolinic acid-induced seizures in mice. In this study, we investigated the effect of orally administered guanosine on seizures induced by the glutamate agonists quinolinic acid and kainate, and the endogenous glutamate releaser α-dendrotoxin. Guanosine (7.5 mg/kg, per os), administered 75 min in advance, prevented 70% of seizures induced by i.c.v. quinolinic acid, being as efficient as the NMDA channel blocker MK-801 administered intraperitoneally. Guanosine was ineffective against kainate-induced seizures, but significantly reversed the potentiation of seizures and death caused by the concomitant injection of MK-801. Guanosine also significantly prevented seizures and death induced by i.c.v. α-dendrotoxin, whereas MK-801 and phenobarbital only prevented death. Altogether, our findings underscore the therapeutic potential of oral administration of guanosine for treating diseases involving glutamatergic excitotoxicity, including epilepsy.

NMDA receptor antagonism modifies the synergistic regulation of striatal tachykinin gene expression induced by dopamine D 1 and serotonin 2 receptor stimulation following neonatal dopamine depletion

Co-application of SKF-38393 (dopamine D 1 agonist; 1 mg/kg) and DOI (serotonin 2 agonist; 1 mg/kg) induced a synergistic increase in striatal preprotachykinin (PPT) mRNA levels in adult rats 60 days after neonatal intracerebroventricular injection of 6-hydroxydopamine. This magnitude of response was not observed in intact (vehicle-injected) rats and was restricted to the dorsomedial (DM, 333±25% of lesion) subregion of the anterior striatum, with smaller increases observed in the dorsolateral striatum (DL, 206±26% of lesion). A single i.p. injection of MK-801 (NMDA antagonist; 0.1 mg/kg) administered prior to dopamine D 1 (D 1) and serotonin 2 (5-HT 2) receptor co-stimulation suppressed the synergistic regulation of PPT mRNA expression in the DM striatum, but also produced a large increase in PPT message levels within the DL striatum (321±17% of lesion). These data suggest that the synergistic regulation of PPT mRNA within the DM striatum induced by D 1/5-HT 2 receptor co-stimulation in the dopamine lesioned rat is dependent on NMDA receptor activity. However, MK-801 may simultaneously potentiate striatal PPT mRNA expression by a separate mechanism due to the changed environment of the dopamine-depleted basal ganglia.

Effects of bilateral olfactory bulbectomy on N-methyl-D-aspartate receptor function: autoradiographic and behavioral studies in the rat.

Rat bilateral olfactory bulbectomy (OBX) serves as a useful model in the study of depression and the mechanisms of action of antidepressant treatments. Considering the evidence of NMDA receptors involvement in depression, the present study was undertaken in order to investigate the time-course effects of OBX on the NMDA receptor function. Following bilateral olfactory bulbectomy, rats display an increase in locomotor activity and changes in other types of behavior in a novel environment. Autoradiographic experiments using the noncompetitive NMDA antagonist [(125)I]-iodo-MK-801 as the labeling agent showed that this increase in behavioral activities corresponds to a decrease in [(125)I]-iodo-MK-801 binding in a number of brain regions. In most regions, this reduction reached significance by the third week following OBX. However, in some cortical areas-a nucleus of the thalamus (AV) and one of the amygdala (LA)-this reduction was already significant in the first or second week following OBX and lasted throughout the 4 weeks of the study. We also compared the behavioral modifications induced by a challenge injection of MK-801 (0.2 mg/kg i.p.) in OBX and sham-operated rats. This challenge is known to induce hyperlocomotion and a number of stereotypies in naive rats. These effects were drastically reduced in OBX as compared to sham-operated rats. These data are consistent with the above-mentioned decrease in cerebral binding of MK-801 to NMDA receptors.

MK-801 induced retrieval, but not acquisition, deficits for passive avoidance conditioning

Two experiments using a state-dependent retention (SDR) design determined whether MK-801 blocked the acquisition and retention of an avoidance response. In Experiments 1 and 2, rats were trained and tested 30 min after injections of either saline or MK-801 (0.05 and 0.10 mg/kg, respectively). Two minutes after training, subjects were immediately tested, and in both experiments, the avoidance response was acquired. The 24-h retention tests for Experiment 1 revealed that the data marginally supported a SDR interpretation. In Experiment 2, the dose of MK-801 was increased to 0.10 mg/kg, and the results showed that MK-801 rendered passive avoidance (PA) state-dependent. These experiments indicate that neither the 0.05 nor 0.10 mg/kg doses of MK-801 prevented acquisition of the avoidance response and that the latter dose rendered memory for PA training state-dependent. It is suggested that doses of MK-801 that did not impair PA learning can function as a cue state and influence expression of memory for PA.

Sensitization of prepulse inhibition deficits by repeated administration of dizocilpine

Repeated administration of psychoactive drugs results in a progressive enhancement of the behavioral effects of these compounds, a phenomenon termed sensitization. We tested whether repeated administration of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) induces sensitization of the disruptive effects of this compound on prepulse inhibition (PPI) of startle. Rats received nine daily i.p. injections of 0.1 mg/kg MK-801 in the startle cage and were tested for PPI, startle in the absence of prepulses and motor activity in the startle cage. Another group of rats received MK-801 in the home cage on 9 days without daily testing. Controls were injected with saline and tested daily, while a separate group of rats received saline in the home cage without daily testing. On day 10, all rats received saline injections and were tested. On day 11, all rats were injected with 0.1 mg/kg MK-801 and tested again. On day 12, all rats received 1 mg/kg dl-amphetamine i.p. and were tested for PPI, to assess a possible cross-sensitization. MK-801 had no effect on day 1 of testing but induced a PPI deficit after 6-9 days of daily treatment and testing in those rats that received the drug in the startle cage, but not in the home cage. Motor activity was increased after repeated treatment and testing. There was also a trend towards sensitization of enhancement of the startle magnitude by MK-801 in these rats. dl-Amphetamine reduced PPI in those rats that received daily MK-801 injections in the startle cage to a similar extent as saline injections. Since PPI is considered as a measure of sensorimotor gating, our data indicate that sensorimotor gating deficits induced by MK-801 are subject to a sensitization process. These findings may be relevant for current hypotheses relating schizophrenic symptoms to sensitization.

MK-801 Can Exacerbate or Attenuate Behavioral Alterations Associated With Neonatal Alcohol Exposure in the Rat, Depending on the Timing of Administration

Background: We have reported that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase. Methods: Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal-learning task were evaluated at PD 18 and PD 40, respectively. Results : Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective. Conclusion : These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.

MK‐801 Can Exacerbate or Attenuate Behavioral Alterations Associated With Neonatal Alcohol Exposure in the Rat, Depending on the Timing of Administration

We have reported that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase. Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal-learning task were evaluated at PD 18 and PD 40, respectively. Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective. These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.

Differential Interaction of Platelet-Activating Factor and NMDA Receptor Function in Hippocampal and Dorsal Striatal Memory Processes

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 μg/0.5 μl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 μg/0.5 μl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.