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.     

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.     

Memantine induces heat shock protein HSP70 in the posterior cingulate cortex, retrosplenial cortex and dentate gyrus of rat brain

High-affinity N-methyl-d-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock. protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.     

Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK-801) injures pyramidal neurons in rat retrosplenial cortex

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine, phencyclidine (PCP) and dizocilpine (MK-801), produce psychosis in people. In rodents they produce cytoplasmic vacuoles in injured retrosplenial cortical neurons that express HSP70 heat shock protein. This study examined possible circuits and receptors that mediate this neuronal injury. Bilateral, but not unilateral, injection of dizocilpine (5, 10, 15, 20 microg/microL per side) into the anterior thalamus induced HSP70 protein in pyramidal neurons in deep layer III of rat retrosplenial cortex 24 h later. In contrast, bilateral dizocilpine injections (5, 10, 15, 20 microg/microL per side) into the retrosplenial cortex or into the diagonal band of Broca did not induce HSP70. Bilateral injections of muscimol (0.1, 1, 10 microg/microL per side), a GABAA (gamma-aminobutyric acid) agonist, into the anterior thalamus blocked HSP70 induction in the retrosplenial cortex produced by systemic dizocilpine (1 mg/kg). Bilateral thalamic injections of baclofen (0.1, 1, 10 microg/microL per side), a GABAB agonist, were ineffective. Anterograde tracer studies confirmed that neurons in the anterior thalamus project to superficial layer III of the retrosplenial cortex where the dendrites of HSP70-immunostained neurons in deep layer III reside. Bilateral blockade of NMDA receptors on GABA neurons in the reticular nuclei of the thalamus is proposed to decrease GABA neuronal firing, decrease GABA release and decrease activation of GABAA receptors. This activates thalamic projection neurons that damage retrosplenial cortical neurons presumably via unblocked cortical glutamate alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate receptors. The increases of blood flow that occur in the thalamus and retrosplenial cortex of people that have psychosis produced by NMDA antagonists could be related to thalamic excitation of the retrosplenial cortex produced by these drugs.     

Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain

The mRNA expression pattern for four different immediate early genes was examined dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6 mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1 and 48 hours. cfos mRNA was induced in cortical areas at early times after either dose of PCP or of MK801; the change was especially prominent in cingulate and auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed (24–48 hour) suppression after PCP and MK801 in neocortical areas. PCP also caused cjun and junB mRNA induction in cortical areas at early times, with a distribution and time course similar to its effects on cfos mRNA. No alterations in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any delayed time (>6 hours) after PCP treatment, whereas suppression of zif268 expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA antagonist, showed a similar pattern of effects on cfos and zif268 mRNA expression. These functional consequences of a PCP- or MK801-induced reduction in NMDA-sensitive glutamate transmission may be relevant to an understanding of animal NMDA pharmacology and/or to clinical psychotomimetic side effects of antiglutamatergic treatments. Synapse 29:14–28, 1998. © 1998 Wiley-Liss, Inc.     

Rolipram, a Selective Phosphodiesterase Type-IV Inhibitor, Prevents Induction of Heat Shock Protein HSP-70 and hsp-70 mRNA in Rat Retrosplenial Cortex by the NMDA Receptor Antagonist DizociIpine

The non-competitive NMDA receptor antagonists, such as (+)-MK-801 (dizocilpine), cause the expression of heat shock protein HSP-70 and pathomorphological damage in the retrosplenial cortex of the rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is unknown. The present study was undertaken to examine the role of phosphodiesterase type IV in the expression of heat shock genes induced by dizocilpine. Heat shock protein HSP-70, which is known as a sensitive marker of neuron injury, was induced in the retrosplenial cortex of the rat brain 24 h after a single administration of dizocilpine (1 mg/kg). Pretreatment with the specific phosphodiesterase type IV inhibitor rolipram (2.5, 5 or 10 mg/kg, 15 rnin before dizocilpine) attenuated the expression of HSP-70 and hsp-70 mRNA induced by dizocilpine (1 mg/kg) in a dose-dependent manner. Furthermore, another phosphodiesterase type IV inhibitor, Ro 20–1724 (5 or 10 mg/kg, 15 min before dizocilpine), and a non-selective phosphodiesterase inhibitor, 3–isobutyl-1–methylxanthine (IBMX) (5 or 10 mg/kg, 15 min before dizocilpine), significantly attenuated the expression of HSP-70 protein and hsp-70 mRNA induced in the retrosplenial cortex by dizocilpine. However, the induction of the immediate early gene c-fos and microglial activation in the retrosplenial cortex after administration of dizocilpine was not attenuated by pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine). Moreover, histopathological study indicated that pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine) did not prevent the formation of vacuoles caused by treatment with dizocilpine. The present findings suggest that phosphodiesterase type IV may play a significant role in the expression of HSP-70 protein and hsp-70 mRNA in the rat retrosplenial cortex after administration of dizocilpine, and that phosphodiesterase type IV may not play a role in the neurotoxicity of NMDA receptor antagonists such as dizocilpine.     

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.     

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.     

Regionally different effects of scopolamine on NMDA antagonist-induced heat shock protein HSP70

Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1–1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists.     

Acute phencyclidine neurotoxicity in rat forebrain: induction of haem oxygenase-1 and attenuation by the antioxidant dimethylthiourea

Phencyclidine and other N-methyl-d -aspartate receptor antagonists are toxic to pyramidal neurons in the posterior cingulate/retrosplenial cortex of rat brain. Previous studies have shown induction of heat shock protein 70 in affected neurons. In this study, expression of haem oxygenase-1, a heat shock protein induced by oxidative stress, was examined in rat forebrain after administration of a single intraperitoneal dose of phencyclidine (50 mg/kg). Northern and Western blot analyses of brain tissue extracts from phencyclidine-treated rats revealed a marked induction of haem oxygenase-1 mRNA and protein, respectively. Immunohistochemistry studies revealed that phencyclidine increased haem oxygenase-1 immunoreactivity primarily in posterior cingulate/retrosplenial, piriform and entorhinal cortices, striatum and hippocampus. Haem oxygenase-1 protein was induced in non-neuronal cells, mainly astrocytes. Some microglia expressing haem oxygenase-1 protein were also found in the posterior cingulate/retrosplenial cortex. Haem oxygenase-1 immunoreactive astrocytes and microglia were present in close proximity to the heat shock protein 70-positive neurons in the posterior cingulate/retrosplenial cortex following phencyclidine. Pretreatment of rats with 1,3-dimethylthiourea, an antioxidant, significantly reduced haem oxygenase-1 protein induction by phencyclidine. Thus, induction of haem oxygenase-1 in glia by phencyclidine appears to be mediated mostly by oxidative stress. Experiments with the amino cupric silver stain for neuronal degeneration revealed phencyclidine-induced neurotoxicity in the posterior cingulate/retrosplenial cortex. The number of affected neurons was significantly reduced after 1,3-dimethylthiourea pretreatment. This suggests that the neurotoxicity of N-methyl-d -aspartate antagonists is due in part to the oxidative stress and may be amenable to therapeutic interventions.     

Expression of cyclooxygenase-2 mRNA in rat retrosplenial cortex following administration of phencyclidine

The effect of NMDA receptor antagonist phencyclidine (PCP) on expression of cyclooxygenase (COX)-2 mRNA in the rat brain was studied. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of COX-2 mRNA and heat shock gene hsp-70 mRNA, a marker of neuronal injury, in the retrosplenial cortex, in a dose-dependent manner. These results suggest that COX-2 may play a role in the neurotoxicity of NMDA receptor antagonists.     

Effects of sigma ligands on the ability of rimcazole to inhibit PCP hsp70 induction

Phencyclidine (PCP) can result in schizophrenia-like behavior. It binds at the PCP site on the NMDA-receptor calcium channel and at the sigma receptor. PCP also induces the heat shock gene hsp70 in retrosplenial cortex neurons. An antipsychotic drug, rimcazole, inhibits PCP hsp70 induction. Rimcazole binds predominately to sigma-2 sites. It is hypothesized that sigma ligands without antipsychotic properties and with some sigma-2 affinity should partially reverse the effects of rimcazole. (+)-3-PPP, (+)-cyclazocine, and (+)-pentazocine bind predominately to sigma-1 sites. (+)-3-PPP is also a modest sigma-2 ligand. Female Sprague-Dawley rats (200–260 g) were injected intraperitoneally (IP) with (+)-3-PPP (50 mg/kg), rimcazole (60 mg/kg) and, after 5 min, with PCP (40 mg/kg). Brains were sectioned (100 μm) and presence of the hsp70 gene protein product, HSP70, was determined immunocytochemically. (+)-3-PPP significantly (p < 0.05) diminished the ability of rimcazole to inhibit PCP hsp70 induction in the retrosplenial cortex. (+)-Cyclazocine (15mg/kg, IP) and (+)-pentazocine (80mg/kg, IP) given in an analogous manner did not diminished the ability of rimcazole to inhibit PCP hsp70 induction.     

Increased expression of zif268 mRNA in rat retrosplenial cortex following administration of phencyclidine

Phencyclidine (PCP) has been shown to cause neurotoxicity in rat retrosplenial cortex following a single administration, although the precise mechanism underlying PCP-induced neurotoxicity is unclear. Using in situ hybridization and immunohistochemistry, we studied the effects of PCP on expression of immediate early gene zif268 mRNA and zif268 protein in the rat brain. High constitutive levels of zif268 mRNA and zif268 immunoreactivity were observed in the brain of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of zif268 mRNA in the rat retrosplenial cortex, in a dose-dependent manner. However, the basal levels of zif268 mRNA in the other regions of cerebral cortex were decreased by administration of PCP. Emulsion-autoradiographical study suggested that marked expression of zif268 mRNA was observed in the layers III and IV of retrosplenial cortex where the neurotoxicity of PCP was detected. Furthermore, zif268 immunoreactivity in the layer IV of retrosplenial cortex was not changed by administration of PCP (25 mg/kg, i.p., 5 h), but that in the other layers of retrosplenial cortex was reduced by PCP. These results suggest that immediate early gene zif268 may, in part, play a role in the neurotoxicity of NMDA receptor antagonists such as PCP.     

MK-801 induces apoptotic neuronal death in the rat retrosplenial cortex: Prevention by cycloheximide and R(−)-2-Hexyl-N- Methylpropargylamine

MK-801 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which can prevent excitatory neuronal death. At higher concentrations, however, it can also induce neuronal death in the limbic system. This MK-801-induced selective neurotoxicity has been proposed as an animal model for dementia and psychosis. We have investigated the effects of the protein synthesis inhibitor cycloheximide and the neurorescue agent 2-hexyl-N-methylpropargylamine [R(−)-2HxMP] on MK-801-induced neuronal death in the retrosplenial cortex in the rat. Cycloheximide [2 mg/kg, subcutaneously (sc)] administered either 1 hr before, or after, injection of MK-801 (5 mg/kg, sc) prevented almost completely neuronal shrinkage and nuclear condensation of the granular retrosplenial cortex as assessed by hematoxylin-eosin staining. The results suggest that the MK-801-induced neuronal death was apoptotic. This neurorescue effect by cycloheximide was time dependent: after 4 hr the effect was reduced to about 50% and by 8 hr had disappeared. R(−)-2HxMP (0.25 mg/kg, sc), which does not inhibit protein synthesis in vitro, was also found to be effective at preventing MK-801-induced neuronal death. © 1996 Wiley-Liss, Inc.     

FOS expression in the brainstem and cerebellum following phencyclidine and MK801

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine (PCP) and dizocilpine maleate (MK801) cause nystagmus, tremor, and cerebellar ataxia at toxic doses. We have shown that PCP but not MK801 is toxic to rat cerebellar Purkinje cells. To study the mechanism and pathways of PCP and MK801 action, Fos protein expression was examined in the cerebellum and functionally related nuclei of the brainstem. PCP, 1–50 mg/kg i.p., induced Fos immunostaining in neurons of the inferior olive, cerebellar granule cell layer, and deep cerebellar and vestibular nuclei. At higher doses, PCP, 25–50 mg/kg, induced dense Fos immunoreactivity throughout the inferior olive except for rostral parts of medial accessory olive and caudal parts of principal olive. At lower doses of PCP, 1–10 mg/kg, Fos positive cells in inferior olive were concentrated in the subnucleus β. In the cerebellum Fos positive granule cells were arranged in patches distributed throughout the cerebellar cortex following PCP, 1–50 mg/kg. Rare Fos positive Purkinje cells were observed adjacent to these patches. At the highest dose of PCP tested (50 mg/kg), Fos was expressed in the fastigial, interpositus, and dentate nuclei, and in vestibular nuclei, most prominently in the medial vestibular nucleus. At lower doses, Fos was expressed mainly in medial cerebellar output nuclei and in vestibular nuclei. MK801, 0.2–10 mg/kg i.p., induced Fos expression in the same regions as PCP. However, MK801-induced Fos expression in inferior olive was localized primarily to subnucleus β. No apparent differences in the number or distribution of Fos positive neurons were observed at MK801 doses of 0.2–10 mg/kg. MK801 also induced Fos expression in fastigial and vestibular nuclei, but not in lateral (interpositus and dentate) cerebellar nuclei. MK801, 0.2–10 mg/kg, induced patchy Fos expression in cerebellar granule cells that was similar to PCP. These results support our earlier observations that PCP and MK801 have different actions in the cerebellum, although they both cause ataxia and indistinguishable behavioral symptoms. That high doses of PCP induce substantially more Fos expression in inferior olive than MK801 suggests that its toxicity to Purkinje cells is at least partially the result of excessive activity of climbing fibers, the excitatory neural input that arises from the inferior olive and synapses on Purkinje cell dentrities. © 1996 Wiley-Liss, Inc.     

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.     

Protective effect of LY379268, a selective group II metabotropic glutamate receptor agonist, on dizocilpine-induced neuropathological changes in rat retrosplenial cortex

In the present study, we examined the effects of LY379268, the group II metabotropic glutamate receptor (mGluR) agonist, on the neuropathological changes in the rat retrosplenial cortex induced by noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). Administration of LY379268 (1, 3, 10 mg/kg, i.p.) reduced dizocilpine (0.5 mg/kg, i.p.)-induced neuropathological changes in the retrosplenial cortex, in a dose-dependent manner. Co-administration of LY379268 (10 mg/kg, i.p.) with group II mGluR antagonist LY341495 (5 mg/kg, i.p.) blocked the effects of LY379268. Furthermore, LY379268 (10 mg/kg, i.p.) significantly reduced the expression of heat shock protein HSP-70, a marker of reversible neuronal injury, in the rat retrosplenial cortex after administration of dizocilpine (0.5 mg/kg, i.p.). Moreover, pretreatment with LY379268 (10 mg/kg, i.p.) significantly suppressed the increase in extracellular acetylcholine (ACh) levels in the retrosplenial cortex induced by administration of dizocilpine (0.5 mg/kg, i.p.). These results suggest that LY379268 has a protective effect on the neurotoxicity in the rat retrosplenial cortex after administration of NMDA receptor antagonists such as dizocilpine.     

Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801

Summary The akinesia induced by reserpine in mice was effectively reversed by the dopamine D₁ receptor agonists SKF 38393 (5–30 mg/kg IP) and CY 208-243 (1–5 mg/kg IP), and by the mixed D₁/D₂ agonist pergolide (5 mg/kg SC), but less well by the D₂ agonists lisuride, PHNO, LY 171555 and RU 24213 (each at 5 mg/kg SC) and not at all by the NMDA receptor antagonist MK 801 (0.1–10 mg/kg IP). MK 801 potentiated D₁-dependent locomotion, but always suppressed rearing and grooming. D₂-dependent locomotion was inhibited by MK 801. The D₂ agonist RU 24213 was antagonised by as little as 6.25 g/kg MK 801, while PHNO and LY 171555 were antagonised by 0.1 mg/kg MK 801. Lisuride was not inhibited by up to 1.6 mg/kg MK 801.Importantly, all animals showed signs of incapacitation with MK 801 in certain elements of their behaviour, most notably ataxia and hind limb abduction. Thus whilst NMDA receptor blockade can facilitate the restoration of movement by dopamine D₁ (though not D₂) agonists in monoamine-depleted mice, the fluency of the motor response is adversely affected.     

Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist

Summary Amantadine has been shown to displace [³H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5–40 mg/kg IP) produced a modest dose-dependent sedation in dopamineintact mice, with a reduction in locomotion and other species-typical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5–80 mg/kg IP) effected a small incrase in motility in akinetic reserpine-treated mice by itself, but this response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D₂ agonist RU 24213 (5 mg/kg SC) and the mixed D₁/D₂ agonist apomorphine (0.5 mg/kg SC) in monominedepleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D₁ agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D₁-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs, from that of conventional glutamate blocking drugs.     

NMDA receptors mediate heat shock protein induction in the mouse brain following administration of the ibotenic acid analogue AMAA

Expression of inducible heat shock protein-70 (HSP-70) and hsp-70 mRNA were studied in the adult mouse brain following systemic administration of the ibotenic acid analogue (±)-2-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMAA), which is a potent N-methyl- d-aspartate (NMDA) agonist. At the dose of 20 mg/kg, AMAA produced excitatory behaviours in adult mice but overt convulsions were not seen. This treatment did not result in any detectable morphological brain damage at 4 days following administration. At 2.5 h and 5 h following treatment induction of hsp-70 mRNA expression was found in the pyramidal cell layers of CA1 and, to a lesser extent, CA3 fields of hippocampal Ammon's horn, amygdala, olfactory lobes, tenia tecta, hypothalamic nuclei and a superficial layer of cingulate, frontal and retrosplenial cortices. The presence of HSP-70 was detected by immunohistochemistry at 24 h following drug administration in those regions previously showing hsp-70 mRNA induction. AMAA-induced hsp-70 mRNA expression was prevented by pre-treatment with the non-competitive NMDA antagonist MK-801. These results suggest that NMDA receptors are involved in the stress response induced by AMAA.