Evidence for a role of the N-methyl-D-aspartate (NMDA) receptor in cortical spreading depression in the rat

The neurotransmitter glutamate activates the N-methyl-D-aspartate (NMDA), quisqualate and kainate receptors. It has been proposed, but also disputed, that local release of glutamate would play a pivotal role in cortical spreading depression (SD). We tested this hypothesis by investigating the influence of NMDA antagonists on SD, using the non-competitive NMDA antagonists ketamine, phencyclidine (PCP) and MK-801 and the competitive NMDA antagonist DL-2-amino-7-phosphonoheptanoate (2-APH), injected intraperitoneally in rats anesthetized with alfentanil. SD was elicited by cathodal DC-stimulation of the frontal cortex. SD propagation was followed using two ion-sensitive microelectrodes placed in the parietal and occipital cortex. The NMDA antagonists increased SD threshold, decreased the propagation velocity and decreased the duration of the accompanying extracellular DC, K+ and Ca2+ changes at the following doses: 40 mg/kg ketamine, 10 mg/kg PCP, 0.63 mg/kg MK-801, 10 and 40 mg/kg 2-APH. With each NMDA antagonist failure of SD propagation between both microelectrodes could be observed. SD elicitation (or propagation) was inhibited completely with 80 mg/kg ketamine, 3.1 mg/kg MK-801 and 160 mg/kg 2-APH. These NMDA antagonists have also anticonvulsant properties. None of these effects on SD were observed with high doses of other anticonvulsants such as 80 mg/kg phenytoin or 40 mg/kg diazepam. These experiments indicate that endogenous release of excitatory amino acids and their action on the NMDA receptor play an important role in the initiation, propagation and duration of SD.     

Maturation of locomotor and Fos responses to the NMDA antagonists, PCP and MK-801

Antagonists at the N-methyl-D-aspartate (NMDA)-type glutamate receptor, such as phencyclidine (PCP) and dizocilpine (MK-801), are well-known to evoke increases in locomotor activity in adult rats and mice. However, little is known about the effects of NMDA antagonists on locomotor activity as a function of development. The present study examined locomotor responses to PCP or MK-801 in male rats of varying ages and found that prepubertal rats were more sensitive to the locomotor-elevating effects of PCP (1.5 mg/kg and 3. 0 mg/kg, s.c.) than were adults. Locomotor responses to MK-801 (0.1 and 0.2 mg/kg, s.c.) were not dependent on age. The age-dependent response to PCP may be related to developmental events in the motor cortex, since more Fos-immunoreactive neurons were observed in the motor cortex of prepubertal animals after PCP administration relative to adult animals. An opposite pattern of age-dependent Fos responses was observed in the posterior retrosplenial cortex. The results suggest that locomotor responses to NMDA antagonists can be influenced in an age- and drug-dependent manner and that maturational events in the motor cortex may modify responses to PCP.     

Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and alpha2-adrenergic agonists.

N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists (eg MK-801, ketamine, phencyclidine [PCP]) injure cerebrocortical neurons in the posterior cingulate and retrosplenial cortex (PC/RSC). We have proposed that the neurotoxic action of these agents is mediated in part by a complex polysynaptic mechanism involving an interference in GABAergic inhibition resulting in excessive release of acetylcholine (ACh). Previously we have found that the systemic injection of GABAergic agents and alpha2-adrenergic agonists can block this neurotoxicity. In the present study we tested the hypothesis that NMDA antagonists trigger release of ACh in PC/RSC and that this action of NMDA antagonists is suppressed by GABAergic agents or alpha2-adrenergic agonists. The effect of MK-801 and ketamine on PC/RSC ACh output (and the ability of pentobarbital, diazepam and clonidine to modify MK-801-induced ACh release) was studied in adult female rats using in vivo microdialysis. Both MK-801 and ketamine caused a significant rise in PC/RSC ACh output compared to basal levels. Pentobarbital, diazepam and clonidine suppressed MK-801's effect on ACh release. Exploratory studies indicated that the site of action of these agents was outside of the PC/RSC. The microdialysis results are consistent with several aspects of the circuitry proposed to mediate the neurotoxic action of NMDA antagonists.     

AMPA receptor antagonism attenuates MK-801-induced hypermetabolism in the posterior cingulate cortex

The effect of pretreatment with an AMPA receptor antagonist, NBQX, on MK-801-induced alterations in glucose use was examined using [¹⁴C]-2-deoxyglucose autoradiography. NBQX (7 mg/kg) had minimal effect on glucose utilisation in all anatomical regions examined. The intravenous administration of MK-801 (0.2 mg/kg) induced increases in glucose use in the limbic system and cingulate cortex. MK-801 reduced glucose utilisation in the sensory motor and auditory cortices. Pretreatment with NBQX attenuated the MK-801-induced hypermetabolism in the posterior cingulate cortex. The decreases in glucose utilisation induced by MK-801 were not exacerbated by the pretreatment with NBQX. The interaction between NBQX and MK-801 suggests a possible method of attenuating some of the adverse effects of the non-competitive NMDA receptor antagonists in the posterior cingulate cortex.     

Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl-D-aspartate induced neurotoxicity in an in vivo perinatal rat model

Three non-competitive antagonists (MK-801, TCP, PCP) and one competitive antagonist (CPP) of N-methyl-D-aspartate (NMDA) receptors, were compared for their ability to antagonize neurotoxic actions of NMDA injected into the brains of 7-day-old rats. Unilateral intracerebral injection of NMDA (25 nmol/0.5 microliters) into the corpus striatum of pups consistently produced severe confluent neuronal necrosis in the striatum extending into the dorsal hippocampus and overlying neocortex. The distribution of damage corresponded to the topography of NMDA type glutamate receptors in the vulnerable regions. With this lesion in developing brain, the weight of the injected hemisphere 5 days later can be used as a quantitative measure of brain injury. Intraperitoneal administration of MK-801 (0.02-42.0 mumol/kg), TCP (3.5-54.0 mumol/kg), PCP (1.0-41.0 mumol/kg), and CPP (1.0-60.0 mumol/kg) 15 min after NMDA injection had prominent dose-dependent neuroprotective effects. MK-801 was 14 times more potent than other compounds tested and the 50% protective dose (PD50, that dose which reduced damage by 50% relative to untreated NMDA-injected controls) was 0.63 mumol/kg. Corresponding values for CPP, PCP, and TCP were 8.84, 10.85, and 24.05 mumol/kg respectively. The lowest dose of MK-801 that provided significant protection was 0.2 mumol/kg (0.04 mg/kg, 37.9 +/- 4.6% protection). Four mumol/kg (0.8 mg/kg) of MK-801 completely protected against NMDA-mediated damage. The study provides the first direct in vivo comparison of the neuroprotective abilities of these compounds. Systemic administrations of MK-801, TCP, PCP, and CPP all limit NMDA-induced neuronal injury in this model. The susceptibility of the immature brain to the neurotoxicity of NMDA provides a sensitive, reproducible, and quantitative in vivo system for comparing the effectiveness of drugs with protective actions against excitotoxic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Post-lesion administration of the NMDA receptor antagonist MK-801 does not impair motor recovery after unilateral sensorimotor cortex injury in the rat

Although treatment with N-methyl-D-aspartate (NMDA) receptor antagonists reduce neuronal loss after cerebral infarction and brain trauma in laboratory animals, there is little data concerning the effects of these drugs on behavioral recovery. Because NMDA receptor antagonists impede certain kinds of learning, and because motor recovery after sensorimotor cortex injury in the rat is dependent on post-lesion experience, we hypothesized that treatment with MK-801 after focal brain injury would be detrimental. Groups of rats were first trained to traverse a narrow elevated beam and then subjected a right sensorimotor cortex suction-ablation lesion. In the first experiment, 24 h later, each rat received a single dose of either saline or the NMDA receptor antagonist MK-801 (0.5, 1.0, or 2.0 mg/kg). Beam-walking recovery was measured over the next 12 days. In a second experiment, rats were given 3 doses of MK-801 (0.5 mg/kg) at 24 h intervals beginning 24 h after cortex injury. In a third experiment, lesioned and sham-operated rats were allowed to recover for 12 days and then given MK-801 (0.5 mg/kg). Despite obvious behavioral effects of the drug, there was no overall difference in beam-walking performances among the treatment groups in any of the experiments. If 're-learning' is involved in motor recovery after cortex injury, the present results suggest that the process is not susceptible to permanent disruption by the early or late administration of an NMDA receptor antagonist.     

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine

Summary Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK-801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.     

Antagonism of ceruletide, a cholecystokinin analog, to the neurochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and MK-801, on regional dopaminergic neurons in the rat brain.

In the present study, we investigated the effects of ceruletide (CL), a cholecystokinin analog, on the neurochemical response to non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine (PCP) and MK-801, of the dopaminergic neuron systems in the discrete regions of the rat brain. Systemically administered PCP (7.5 mg/kg, i.p.) or MK-801 (1.0 mg/kg, i.p.) produced significant increases in the tissue contents of dopamine metabolite, homovanillic acid (HVA), in the prefrontal cortex, the nucleus accumbens and the olfactory tubercle but not in the nucleus caudatus putamen after 60 min. The effects of NMDA receptor antagonists in the nucleus accumbens and the prefrontal cortex were partially antagonized by pretreatment with CL (80 and 400 micrograms/kg, i.p., at 60 min prior to the drugs). While CL alone decreased the dopaminergic metabolism only in the nigrostriatal pathways in naive rats, the present results indicated that CL also attenuates the activities of the meso-limbic and meso-cortical dopaminergic neuron systems when these are enhanced by either PCP or MK-801.     

Anticonvulsant action of a non-competitive antagonist of NMDA receptors (MK-801) in the kindling model of epilepsy

Anticonvulsant action of MK-801, a novel non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors, was investigated in the kindling model of epilepsy in rats. The results obtained were as follows. (1) Both the seizure stage and afterdischarge duration of previously kindled seizures from the amygdala were significantly suppressed following systemic injection of MK-801 (0.25–4 mg/kg) in a dose-dependent manner. The maximum effects were observed between 2 and 4 h after the injection. (2) The MK-801 also showed significant anticonvulsant effedts on kindled seizures from the frontal cortex and the ventral and dorsal hippocampus. The efficacy however, significantly differed between these kindled sites. (3) Daily treatment of MK-801 (0.25 and 1 mg/kg) prior to each electrical stimulation of the amygdala significantly retarded kindling seizure development and increased the total amount of afterdischarge (accumulated AD) required to reach the first stage 5 seizure. During drug sessions of 1 mg/kg MK-801 for 19 days, all rats showed only partial seizures and the growth of afterdischarge was strongly prevented. (4) Pretreatment with reserpine did not antagonize the anticonvulsant effects of MK-801 on previously kindled seizures from the amydala, suggesting that the effects may not be mediated by catecholaminergic systems. These results indicate that MK-801 has potent anticonvulsant actions on kindled seizures from both limbic and cortical foci, the NMDA system may play a critical role in the seizure-triggering mechanism of kindling. The possible application of NMDA antagonists in clinical epilepsy is suggested.     

The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression.

We examined the effect of blockade of N-methyl-D-aspartate (NMDA) and non-NMDA subtype glutamate receptors on anoxic depolarization (AD) and cortical spreading depression (CSD). [K+]e and the direct current (DC) potential were measured with microelectrodes in the cerebral cortex of barbiturate-anesthetized rats. NMDA blockade was achieved by injection of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate [MK-801; 3 and 10 mg/kg] or amino-7-phosphonoheptanoate (APH; 4.5 and 10 mg/kg). Non-NMDA receptor blockade was achieved by injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX; 10 and 20 mg/kg). MK-801 and APH blocked CSD, while NBQX did not. In control rats, the latency from circulatory arrest to AD was 2.1 +/- 0.1 min, while the amplitude of the DC shift was 21 +/- 1 mV, and [K+]e increased to 50 +/- 6 mM. All variables remained unchanged in animals treated with MK-801, APH, or NBQX. Finally, MK-801 (14 mg/kg) and NBQX (40 mg/kg) were given in combination to examine the effect of total glutamate receptor blockade on AD. This combination slightly accelerated the onset of AD, probably owing to circulatory failure. In conclusion, AD was unaffected by glutamate receptor blockade. In contrast, NMDA receptors play a crucial role for CSD.     

The effect of glutamate antagonists on c-fos expression induced in spinal neurons by irritation of the lower urinary tract

Chemical irritation of the lower urinary tract (LUT) of the rat increases the expression of c-fos in neurons in the dorsal horn, dorsal commissure and intermediolateral region of the spinal cord. The role of glutamatergic synapses in this response was examined using two glutamate receptor antagonists, MK-801 (an NMDA antagonist) and CNQX (an AMPA antagonist). In rats with an intact spinal cord, MK-801 (3.5 mg/kg, i.v.) administered 15 min before bladder irritation decreased (50–60%) the number of c-fos-positive cells in all regions of the cord. A smaller dose of MK-801 (0.8 mg/kg, i.v.) was ineffective. In spinal transected rats (4–7 days prior to the experiment) MK-801 (3.5 mg/kg, i.v.) decreased c-fos expression only in the medial dorsal horn. CNQX (1.2 mg/kg, i.v.) was ineffective in both preparations. These results indicate that activation of NMDA receptors at glutamate synapses in the central nervous system may play a role in the processing of nociceptive input from the LUT and may also be involved in reflex pathways mediating micturition.     

YM90K, an AMPA Antagonist, Has No Neurotoxic Effects on Cerebrocortical Neurons in Rats

The neuroprotective properties of glutamate receptor antagonists arise from their ability to antagonize the excitotoxic actions of endogenous excitatory amino acids. However, J. W. Olney et al. (1989, Science 224: 1360-1362) have reported that MK-801, an N-methyl- -aspartate (NMDA) glutamate receptor antagonist, induced morphological damage in neurons in the cerebral cortex of rats. YM90K is a potent α-amino-3-hydroxy-5-methylisoxazole propionic acid receptor antagonist which has high neuroprotective efficacy against delayed neuronal injury. The purpose of this study was to investigate whether YM90K induces a vacuolar reaction in the cytoplasm of neurons similar to that seen after the administration of MK-801. All experiments were performed on female F344 rats. YM90K was administered by iv infusion for 3 h at the dose of 40 mg/kg/h. MK-801 was given by single sc injection at the dose of 1 mg/kg. All rats receiving MK-801 showed neuronal vacuolation. The affected neurons were recognized as medium-sized pyramidal-shaped neurons which were distributed between layers II and IV in the posterior cingulate and retrosplenial neocortices. Most of these vacuoles contained multiple small and round structures that appeared to be remnants of mitochondria. Other vacuoles were recognized as enlarged sER or those present within the bilaminar nuclear membrane. MK-801 also induced heat shock protein immunoreactivity in the same neurons. In contrast, no such pathomorphological changes could be detected in the YM90K-treated rats. The present results as well as recent reports that some NMDA receptor antagonists, including SL 82.0715 and L 687,414, which have different sites of action, did not induce these alterations suggest that the neurotoxicity of glutamates antagonists may be related to the receptor subtype with which they interact or the active site of each compound.     

Haloperidol prevents induction of the hsp70 heat shock gene in neurons injured by phencyclidine (PCP), MK801, and ketamine.

The non-competitive NMDA receptor antagonists, PCP (phencyclidine), MK801, and ketamine produce psychosis in humans and abnormal vacuoles in posterior cingulate and retrosplenial rat cortical neurons. We show that PCP (> or = 5 mg/kg), MK801 (> or = 0.1 mg/kg), and ketamine (> 20 mg/kg) induce hsp70 mRNA and HSP70 heat shock protein in these vacuolated, injured neurons, and PCP also induces hsp70 in injured neocortical, piriform, and amygdala neurons. The PCP, MK801, and ketamine drug induced injury occurs in 30 day and older rats, but not in 0-20 day old rats, and is prevented by prior administration of the antipsychotic drugs haloperidol and rimcazole. Since haloperidol and rimcazole block dopamine and sigma receptors, and since M1 muscarinic cholinergic receptor antagonists also prevent the injury produced by PCP, MK801, and ketamine, future studies will be needed to determine whether dopamine, sigma, M1, or other receptors mediate the injury.     

MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex.

MK-801 and ketamine are noncompetitive N-methyl-D-aspartate (NMDA) receptor blockers that decrease brain injury in animal models of focal and global ischemia. Recent reports, however, suggested that MK-801 itself can damage neurons. Here we show that MK-801 (0.1 to 5.0 mg/kg) and ketamine (40 to 100 mg/kg) typically induce heat shock protein HSP72 mainly in layer 3 neurons of the posterior cingulate and retrosplenial cortex of the rat. These HSP72-immunoreactive neurons contain abnormal cytoplasmic vacuoles visualized by electron microscopy. The HSP72 immunoreactivity is maximal at 24 hours with 1.0-mg/kg doses of MK-801 and disappears by 2 weeks. Based on these data, we propose: (1) MK-801 and ketamine injure selected neurons, which express HSP72 in response to that injury. (2) Since HSP72 is induced for 1 to 2 weeks, the prolonged psychological side effects of MK-801, ketamine, phencyclidine, and related drugs could be related to this injury. (3) The neuroprotective effect of MK-801 is probably not related to HSP72 induction. (4) HSP72 immunocytochemistry is useful for studying nonlethal neuronal injury from a wide variety of brain insults.     

MK-801 prevents the development of behavioral sensitization during repeated morphine administration

Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 rng/kg) and horizontal locomotion at higher- doses, (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects. © 1994 Wiley-Liss, Inc.     

Effect of the noncompetitive NMDA antagonists MK-801 and ketamine on the spastic Han-Wistar mutant: a rat model of excitotoxicity

The neuroprotective effects of the NMDA antagonists MK-801 and ketamine were analyzed in a mutant strain of Han-Wistar rats which develop neurodegeneration in the hippocampus and cerebellum. Previous experiments have shown that the progressive neuronal degeneration observed in this mutant may be the result of a dysfunctional glutamatergic system. For MK-801 studies, mutants were injected in a chronic paradigm with (+)MK-801 or its weaker acting isomer (-)MK-801 at a dose of 1 mg/kg. Ketamine studies consisted of both acute (50 mg/kg once) and chronic (10 mg/kg multiple times) injection paradigms. MK-801-treated mutants exhibited longer life spans (8-23%) compared to saline-injected mutants. Ketamine-injected mutants in both paradigms also lived slightly longer (6-9%) than the saline mutants. Motor skill deterioration was monitored in an open-field test, and after 50 days of age the MK-801 and ketamine mutants displayed over 20% greater motor skill activity than the saline mutants. In the cerebellum, mutants treated with ketamine and both forms of MK-801 had 10-20% more Purkinje cells surviving at 55 days than the saline mutants. Further, the density of CA3c pyramidal hippocampal neurons in ketamine and MK-801-treated mutants as compared to saline mutants appeared to be greater upon qualitative analysis. This study shows that these mutants derive some protective effects from the NMDA antagonists MK-801 and ketamine, confirming glutamate-induced excitotoxicity as a possible cause of neuronal degeneration in this mutant strain of rat.     

Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat

Arginine vasopressin (AVP) is a peptide involved in social behaviors in rodents. To investigate the mechanism underlying the deficits in social behavior induced by blockade of N-methyl-D-aspartate (NMDA) receptors, this study examined the effect of noncompetitive NMDA antagonists on AVP receptor binding and social interaction in the rat. Subchronic phencyclidine (PCP) administration (2 mg/kg/day, 14 days, i.p.) significantly reduced the density of V1a receptor binding sites, labeled by an [125I]-Linear AVP antagonist, in several brain regions. Subchronic treatment with PCP or MK-801 (0.13 mg/kg/day, 14 days, i.p.) impaired social interactions in rats, as has been previously reported. These results suggest that NMDA antagonists have modulatory effects on the central vasopressinergic system and social interaction.     

The N-methyl-d-aspartate (NMDA) receptor glycine site antagonist ACEA 1021 does not produce pathological changes in rat brain

ACEA 1021 is a potent, selective N-methyl-

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-aspartate (NMDA) receptor glycine site antagonist under clinical evaluation as a neuroprotectant for stroke and head trauma. The potential of ACEA 1021 to produce morphologic changes in cerebrocortical neurons of the rat was assessed since it is known that noncompetitive (e.g., MK-801) and competitive (e.g., CGS 19755) NMDA receptor antagonists produce neuronal vacuolization and necrosis in the rat posterior cingulate/retrosplenial cortex. Male and female adult rats were treated intravenously with either vehicle (Tris) or 10 mg/kg or 50 mg/kg ACEA 1021. MK-801 (5 mg/kg, s.c.) served as positive control. Whereas MK-801 produced characteristic neuronal vacuolization and necrosis in the posterior cingulate/retrosplenial cortex, neither dose of ACEA 1021 had any effect on neuronal morphology. The absence of neuropathological changes in rats supports the further clinical evaluation of ACEA 1021 for stroke and head trauma, and suggests that glycine site antagonists may be devoid of neurotoxic potential.     

Haloperidol Prevents Ketamine- and Phencyclidine-Induced HSP70 Protein Expression but Not Microglial Activation

NoncompetitiveN-methyl- -aspartate (NMDA) receptor antagonists, including ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat. Ketamine also induces 70-kDa heat shock protein (HSP70) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia. HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20-day-old animals following ketamine (80 mg/kg, ip). Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80–140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adult rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity.