Non-competitive N-methyl-D-aspartate Receptor Research Articles

Treadmill running induces striatal Fos expression via NMDA glutamate and dopamine receptors.

Several non-physiological stimuli (i.e. pharmacological or electrical stimuli) have been shown to induce Fos expression in striatal neurons. In this work, striatal Fos (i.e. Fos-like) expression was studied after physiological stimulation, i.e. motor activity (treadmill running at 36 m/min for 20 min). In rats killed 2 h after the treadmill session, Fos expression was observed in the medial region of the rostral and central striatum, and in the dorsal region of the caudal striatum. Fos expression was prevented by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg) or the D1 dopamine receptor antagonist SCH-23390 (0.1 mg/kg), but not by pretreatment with the D2 receptor antagonist eticlopride (0.5 mg/kg). Thirty-six hours after 6-hydroxydopamine lesion, a considerable reduction in treadmill-induced Fos expression was observed in both sides; however, Fos expression in the lesioned striatum was higher than in the contralateral intact striatum. Several weeks after unilateral 6-hydroxydopamine lesion of the nigrostriatal system, treadmill-induced Fos expression was significantly, but not totally, reduced in the lesioned striatum. Corticostriatal deafferentation also led to considerable reduction in treadmill-induced Fos expression. The present results indicate that exercise induces striatal Fos expression and that, under physiological stimulation, concurrent activation of D1 and NMDA receptors is necessary for such expression to occur. Reduction of Fos expression is practically absolute after acute blockage of these receptors, but not after lesions, possibly due partially to compensatory changes.

Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex

Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.

Behavioural pharmacology of the non-competitive NMDA antagonists dextrorphan and ADCI: relations between locomotor stimulation, anticataleptic potential and forebrain dopamine metabolism.

The effects of systemic administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonists dextrorphan (10-40 mg/kg, i.p.) and [+/-]-5-aminocarbony-10,11-dihydro-5H-dibenzo[a,d]cycloheptan++ +-5,10-imine (ADCI) (25-70 mg/kg, i.p.) on basal ganglia-mediated behaviour and on forebrain dopamine metabolism were investigated in rats. Dextrorphan increased locomotor activity but did not induce stereotyped sniffing. ADCI failed to produce any significant motor stimulant and motor depressant actions. Both dextrorphan and ADCI dose-dependently antagonized catalepsy induced by the D-1 dopamine receptor antagonist SCH 23390 or the D-2 dopamine receptor antagonist haloperidol. Only the highest doses of dextrorphan and ADCI increased dopamine metabolism in the prefrontal cortex and/or in the nucleus accumbens, but not in the dorsal striatum. Our results show that dextrorphan and ADCI produce some of the behavioural effects (antagonism of experimentally induced catalepsy) and neurochemical actions (regionally selective stimulation of dopamine metabolism) that have previously been observed in the prototypical non-competitive NMDA antagonist, dizocilpine. The failure of ADCI to induce hyperlocomotion and stereotypy suggests that anticataleptic doses of ADCI may be devoid of the psychotomimetic actions commonly associated with non-competitive blockade of NMDA receptor function.

Alterations in N-methyl- d-aspartate receptor binding in dystonic hamster brains

The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Previous pharmacological studies have shown that competitive and non-competitive N-methyl- d-aspartate (NMDA) receptor antagonists exert potent antidystonic activity in this model, indicating that abnormal NMDA receptor function may be involved in the pathophysiology of this movement disorder. Autoradiographic analysis of NMDA receptor density in 67 brain regions, using the ligand [ 3H] N-(1-[2-thienyl]cyclohexyl)3,4-piperidine, which binds to the phencyclidine (PCP) site in the ion channel of the NMDA receptor channel complex, revealed that NMDA receptor binding is not substantially altered in dystonic hamster brains compared to age-matched controls. Nevertheless, there was a tendency towards enhanced binding during a dystonic attack in several regions, including a 25% increase in the ventrolateral thalamic nucleus ( P<0.05), which may be associated with altered basal ganglia output. While the data do not indicate widespread abnormalities in the PCP site of the NMDA complex, they do not exclude the possibility of more pronounced changes at other regulatory binding sites of the NMDA complex or other types of glutamate receptors in dystonia.

Caroverine in Tinnitus Treatment

This study was performed to examine whether a single infusion of caroverine, a quinoxaline-derivative, can be used successfully in the treatment of inner ear tinnitus. Microiontophoretical experiments in guinea-pigs have shown that caroverine acted as a potent competitive a-amino-3-hydroxy-5-methyl-4-isoxazone-proprionic acid (AMPA) receptor antagonist and, in higher dosages, a non-competitive N-methyl-d-aspartate (NMDA) antagonist. According to our working hypothesis of the pathophysiology of inner ear tinnitus (cochlear-synaptic tinnitus), these forms of tinnitus occur when the physiological activity of the NMDA and AMPA receptors at the subsynaptic membranes of inner hair cell afferents is disturbed. In total, 60 patients with inner ear tinnitus of assumed cochlear-synaptic pathophysiology were included in the study: after computerized randomization, 30 were treated with caroverine and 30 with placebo. For a response to have occurred, tinnitus had to show a reduction in both subjective rating and psychoacoustic measurement (tinnitus matching). In the caroverine group, 63.3% responded to therapy immediately after the infusion. In the placebo group, none of the patients treated showed a significant response according to the defined success criteria. The results confirm our working hypothesis on the genesis of cochlear-synaptic tinnitus.

Effects of MK-801 and Pentobarbital on Cholinergic Terminal Damage and Delayed Neuronal Death in the Ischemic Gerbil Hippocampus

The present study covers both the effects of MK-801, a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, and pentobarbital on cholinergic terminal damage and delayed neuronal death (DND) in ischemic gerbil. To study the above effects, in vivo microdialysis, immunohistochemical, and morphological techniques were used. MK-801 (3 mg/kg) or pentobarbital (50 mg/kg) were injected intraperitoneally 1 h or 30 min before 5 min ischemia, respectively. Each estimation was then carried out 4, 7, or 14 days after ischemia. Ischemia induced a significant decrease in acetylcholine (ACh) release and a disappearance of choline acetyltransferase (ChAT)-immunoreactivity in the hippocampus in addition to inducing DND. On day 4, MK-801 protected ischemia-induced DND in the hippocampal CA1 subfield. However, MK-801 had no effect against the decrease in ACh release in spite of protection of the decrease in ChAT-immunoreactivity. On day 7 and 14, no protective effect of MK-801 was observed in all estimations. It became clear that the mechanism of cholinergic terminal dysfunction is different from that involved in pyramidal cell death, i.e., excitative neurotoxicity induced by overabundant extracellular glutamate. Pentobarbital also provided protection against DND. However, protective effects of pentobarbital on the decrease in ACh release and the low ChAT-immunoreactivity were incomplete. Our present study indicated a limitation on the efficacy of NMDA receptor antagonist and barbiturate against cerebral ischemia.

The Non-Competitive NMDA Antagonist MK-801 Increases Food Intake in Rats

A role for excitatory amino acids in the control of feeding behavior has not been extensively investigated. Nevertheless, there is direct and circumstantial evidence to indicate that some circuits involved with feeding behavior include glutamatergic elements. To test the hypothesis that endogenous glutamate participates in the control of food intake, we performed experiments to determine whether MK-801, a non-competitive N-methyl- d-aspartate (NMDA) ion channel antagonist, is capable of altering intake of liquid and solid foods in hungry or satiated rats. Following a 16 h fast, intake of 15% sucrose was significantly enhanced by systemic treatment with MK-801. Water intake was not altered by the NMDA antagonist. Rats did not ingest more rat chow after MK-801, unless they had been fasted. When a more palatable food (cookies) was offered, MK-801 did increase intake. Thus MK-801 enhanced food intake only when feeding was initiated by food-deprivation or increased palatability. In conclusion, our results support the hypothesis that endogenous glutamate plays a role in the control of food intake. Blockade of NMDA receptor function by MK-801 may diminish or delay satiety signals, rather than initiate feeding behavior per se.

YM90K, a selective-amino-3-hydroxy5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, prevents induction of heat shock protein HSP -70 and hsp -70 mRNA in rat retrosplenial cortex by phencyclidine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist such as an abused drug phencyclidine (PCP) causes the induction of heat shock protein HSP-70, a sensitive marker of neuronal injury, in the retrosplenial cortex of rat brain. The present study was undertaken to examine the role of a -amino-3- hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in the expression of heat shock protein HSP-70 and hsp-70 mRNA in the retrosplenial cortex by PCP. Administration of PCP (50 mg/kg, i.p.) caused the induction of heat shock protein HSP-70 in the retrosplenial cortex of rat brain, whereas no HSP-70 immunoreactivity was detected in the vehicle-treated group. Pretreatment with a potent and selective AMPA receptor antagonist YM90K (1, 3 or 10 mg/kg, i.p; 15 min) inhibited in a dose dependent manner, the induction of heat shock protein HSP-70 by PCP (50 mg/kg). Furthermore, administration of PCP (50 mg/kg, i.p) caused marked expression of hsp-70 mRNA in the retrosplenial cortex of rat brain, whereas the expression of hsp-70 mRNA was NOT found in the vehicle-treated group. Pretreatment with YM90K (1, 3 or 10 mg/kg, i p; 15 min) also inhibited the expression of hsp-70 mRNA by PCP (50 mg/kg), in a dose-dependent manner. These results suggest that AMPA receptor may play a role in the expression of heat shock protein HSP-70 and heat shock gene hsp-70 mRNA in the retrosplenial cortex of rat brain by non-competitive NMDA receptor antagonists such as PCP.

Dissociation of Effects of Glutamate Receptor Antagonists on Excitotoxic and Hypoxic Neuronal Cell Death in a Novel Rat Cortical Culture System

A novel in vitro cell culture model has been developed to investigate the mechanisms of delayed neuronal cell death following exposure to excitatory amino acids and hypoxia. Medium change damages cortical cells possibly leading to preselection of the neuronal population. This model allowed compounds to be administered in the absence of a medium change. In this system, the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801, attenuated the neurotoxic effects of overnight exposure to glutamate and NMDA completely, and partially protected neurones exposed to α-amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA). The non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, did not attenuate the effects of glutamate or NMDA but blocked the excitotoxic effects of AMPA completely. These results suggest partial involvement of NMDA receptor activation in AMPA-induced toxicity. By contrast, hypoxia-induced neuronal degeneration in this model was attenuated by either NMDA or non-NMDA antagonism, which confirms previous reports that the mechanisms of hypoxic and excitotoxic neurodegeneration in these in vitro models are not identical. A number of other compounds, which have been reported previously as neuroprotective in vitro and in vivo, including the calcium channel antagonists, SB 201823, flunarizine, and nifedipine, and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester, L-NAME, demonstrated no significant neuroprotective effects in this in vitro system. In common with other in vitro models that include a change of medium, these data suggest that this system does not have predictive validity for the identification of novel neuroprotective agents in vivo.

Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors

The present study examined the effects of colonic inflammation on reflex responses to colorectal distension (CRD) in awake rats. Visceromotor responses (VMR) to CRD were recorded in rats that received either no treatment or intracolonic saline or zymosan. Three hours following zymosan treatment (25 mg/ml; 1 ml) VMR response magnitudes were significantly increased at all intensities of CRD tested (10–80 mmHg). The enhanced responses to CRD were attenuated in a dose-dependent fashion by intrathecal administration of the non-competitive N -methyl- d -aspartate (NMDA) receptor channel blocker MK-801 to 60% of control and by the non-NMDA receptor antagonist DNQX to less than 20% of control. The metabotropic receptor antagonist AP-3 was without effect. Signs of multi-focal colonic inflammation were clearly present 3 h after zymosan treatment, characterized by an ingress of inflammatory cells and damaged crypts in and around these foci. Taken together these findings suggest that tissue inflammation increases the sensitivity of the colon to mechanical stimuli, leading to enhanced responses to CRD. This enhancement involves the activation of spinal NMDA as well as non-NMDA receptors, but not metabotropic receptors.

Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors

The present study examined the effects of colonic inflammation on reflex responses to colorectal distension (CRD) in awake rats. Visceromotor responses (VMR) to CRD were recorded in rats that received either no treatment or intracolonic saline or zymosan. Three hours following zymosan treatment (25 mg/ml; 1 ml) VMR response magnitudes were significantly increased at all intensities of CRD tested (10–80 mmHg). The enhanced responses to CRD were attenuated in a dose-dependent fashion by intrathecal administration of the non-competitive N-methyl- d-aspartate (NMDA) receptor channel blocker MK-801 to 60% of control and by the non-NMDA receptor antagonist DNQX to less than 20% of control. The metabotropic receptor antagonist AP-3 was without effect. Signs of multi-focal colonic inflammation were clearly present 3 h after zymosan treatment, characterized by an ingress of inflammatory cells and damaged crypts in and around these foci. Taken together these findings suggest that tissue inflammation increases the sensitivity of the colon to mechanical stimuli, leading to enhanced responses to CRD. This enhancement involves the activation of spinal NMDA as well as non-NMDA receptors, but not metabotropic receptors.

MK-801 PARTIALLY PROTECTS AGAINST THE ACUTE MPP + DEPLETING EFFECT ON DOPAMINE LEVELS IN RAT STRIATAL SLICES

We tested the ability of the non-competitive N-methyl- d-aspartate (NMDA) antagonist, dizocilpine (MK-801), to promote protection against the acute effect of 1-methyl-4-phenylpyridinium ion (MPP +) in rat striatal slices. Pretreatment with MK-801 at concentrations higher than 15 μM partially prevented the dopamine (DA)-depleting effect induced by further incubation with 25 μM MPP + for 60 min in Mg 2+-free conditions. Incubation of slices with 15 μM MK-801 without MPP + only affected the levels of 3-methoxytyramine (3-MT). The ratio of 3-MT to 3,4-dihydroxyphenylacetic acid (DOPAC), a proposed index of DA reuptake inhibition, increased +68% of control levels, clearly suggesting an inhibitory effect of MK-801 on the high affinity DA transport system. To test this possibility, we performed a dose-response study of MK-801 on the high-affinity DA transport system in rat striatal synaptosomes. MK-801 induced a dose-dependent inhibition of DA uptake, with an ic 50 of 57.0 μM. We present evidence that the protective effect rendered by MK-801 against the acute DA-depleting effect induced by MPP + is not associated to NMDA receptor function, but rather to an inhibition of the high affinity DA uptake system. Copyright © 1996 Elsevier Science Ltd.

P.1.039 - Fluvoxamine versus desipramine in elderly patients with major depression: A double-blind comparison

Lumbar subarachnoid injection of dynorphin A causes an ischemia-induced neuronal degeneration and persistent hindlimb paralysis. The protective effects of a variety of competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists indicate that activation of the NMDA receptor complex is essential for dynorphin A-induced spinal cord injury. 1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity, partial agonist at strychnine-insensitive glycine receptors associated with the NMDA receptor complex. Pretreatment of rats with ACPC (100 and 200 mg/kg, i.p., 30 min prior to dynorphin A) significantly eliminated the persistent hindlimb motor deficits and neuropathological changes produced by 20 nmol of this peptide. The neuroprotective effects of ACPC (100 mg/kg, i.p.) were abolished by parenteral administration of glycine (800 mg/kg, 30 min prior to ACPC), consistent with other in vivo and in vitro studies indicating that the pharmacological actions of ACPC are effected through strychnine-insensitive glycine receptors. When given instead as six daily injections (200 mg/kg, i.p.) followed by an injection-free day, ACPC also significantly improved neurological recovery following dynorphin-A injection. These results support earlier indications that: (1) activation of the NMDA receptor complex plays a critical role in mediating dynorphin A-induced rat spinal cord injury; (2) ACPC provides an effective means of antagonizing excitotoxic phenomena; and (3) chronic administration of ACPC can elicit a persistent change in the NMDA receptor complex.

The NMDA receptor antagonist MK-801 differentially modulates μ and κ opioid actions in spinal cord in vitro

We have examined the interactions between NMDA receptors and opioid effects in isolated neonatal rat spinal cord. Electrical stimulation of a lumbar dorsal root evoked a nociceptive-related slow ventral root potential (sVRP) recorded at the corresponding ipsilateral ventral root. The κ opiate receptor agonist U69,593 (2.5 nM-1 μM) depressed sVRP area by a maximum of 80%; EC50 was approximately 33 nM. Both the non-specific antagonist naloxone and the κ-specific antagonist nor-binaltorphimine (nor-BNI) antagonized the effects of U69,593. Morphine, a μ agonist, (1 nM-1 μM) depressed sVRP area with an approximate EC50 of 90 nM. The effects of both μ and κ opioid agonists were selective for the very slow metabotropically mediated components of the sVRP, compared to the relatively fast NMDA receptor-mediated components. The non-competitive N-methyl- d-aspartate (NMDA) antagonist MK-801 (20 nM) had no effect on sVRP area when applied alone but co-applied with morphine significantly potentiated the depressant effects of morphine. In contrast, MK-801 either had no effect on or slightly antagonized the depressant effects of U69,593. Naloxone following morphine produced a significant increase in sVRP area above pre-morphine control values; the increase lasted 30 min or more. Neither naloxone nor nor-BNI was associated with an increase in sVRP area when given alone or following U69,593. MK-801 co-applied with morphine blocked the rebound increase in sVRP area following naloxone. These results suggest that (1) both μ and κ receptor agonists exert similar selective depressant effects on spinal nociceptive neurotransmission; (2) μ but not κ agonists exert prolonged excitatory effects that oppose the depression; and (3) NMDA receptors play a role in determining opioid analgesic potency and naloxone-precipitated hyperresponsiveness. The results may be related to initial steps in the development of acute tolerance to μ opioids, and suggest that tolerance to κ opioids may have a different mechanism.

Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered excitatory amino acid receptor antagonists

A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemiccally administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl- d-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury.

Prevention of trauma-induced neurodegeneration in infant rat brain.

Recent evidence implicates the endogenous excitatory neurotransmitters, glutamate (Glu) and aspartate, in the pathophysiology of traumatic injury in the adult CNS, but it is not known whether similar excitotoxic mechanisms mediate traumatic injury in the immature CNS. Therefore, we developed a model of brain contusion injury in infant rats and used this model to study the nature and evolution of the acute cytopathologic changes and to evaluate the ability of Glu receptor antagonists to protect the immature brain against such changes. Seven-day-old rat pups were subjected to contusion injury and were killed 0, 0.5, 1, 2, 4, and 6 h later for histologic evaluation of the brain. Physical tearing of the dura and minor disruption of underlying brain tissue was noted at 0 h. At 30 min a discrete zone of neuronal necrosis began to appear at the border of the trauma site; this zone progressively expanded over a period of 4 h. The cytopathologic changes closely resembled the type of changes Glu is known to cause; these changes consisted of swollen dendrites, degenerating neurons with pyknotic nuclei and markedly swollen cytoplasm, and dark cells with vacuolated cytoplasm. The noncompetitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine maleate, when administered 30 min before or 1 h after trauma, significantly attenuated the lesion. The competitive NMDA antagonist, 3-((-2)-carboxypiperazine-4-yl)-propyl-1-phosphonate, was also neuroprotective. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline did not significantly suppress the lesion when given as three treatments (30 mg/kg each) 30 min before plus 15 and 75 min after the insult. These findings suggest that traumatic injury in the infant rat brain is mediated by endogenous excitotoxins (Glu and aspartate) acting at NMDA receptors and can be substantially mitigated by timely treatment with NMDA receptor antagonists.

Effect of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on food-anticipatory activity rhythm in the rat

When feeding was restricted to a single meal scheduled at a fixed time (1300–1700 h) in the day, rats exhibited increased prefeeding locomotor activity 1–3 h before the feeding time, which increased over 6 days. The activity increase was seen for about 5 h (1100–1600 h) on the seventh day when no food was provided (fasting day), as the rat anticipated mealtime. Thus, mealtime-associated activity rhythm on the fasting day was considered to be another good index of food-anticipatory activity. In this study, we investigated the effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, which has been reported to cause impairment of spatial learning, on food-anticipatory activity.in rats. Daily injection of MK-801 (0.2 mg/kg) at 1700 h for 6 successive days impaired the development of increased prefeeding activity. The appearance of mealtime-associated activity was impaired by daily injection of MK-801 (0.2 mg/kg) at 1700 h (immediately after food restriction, FR) or at 1900 h (2 h after FR) but not at 0900 (16 h after FR). In addition, mealtime-associated activity was impaired by MK-801 injected at 1700 h in a dose-dependent manner (0.1–1 mg/kg). The present results demonstrate that NMDA receptor mechanisms were involved in learning processes of food anticipation and suggest that an impairment of food-anticipatory activity may be considered an animal model of a deficit of “temporal learning.”

A dose-response analysis of the behavioral effects of (+)MK-801 in guinea pig: Comparison with CPP

The noncompetitive N- methyl- d- aspartate (NMDA) antagonist, dizocilpine maleate (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a, d] -cyclohepten-5, 10-imine maleate [(+)MK-801], has attracted considerable interest because of its potential use as an anticonvulsant and neuroprotectant. However, its cognitive side effects in humans have limited its use in human pharmacotherapy. Although the behavioral effects of (+)MK-801 have been documented in mouse, rat, pigeon, and rhesus monkey, there are no available data on its effects in guinea pig. The objective of this study was to conduct a dose-response analysis of the effects of (+)MK-801 on stereotyped behavior, ataxia, locomotor activity, and righting reflex latency in guinea pig. In the dose range used (0.0625–0.5 mg/kg, IP), we found no significant differences between (+)MK-801 and vehicle in terms of stereotyped behavior and locomotor activity; however, at higher doses, (+)MK-801 caused significant ataxia and impairment of the righting reflex. By comparison, the competitive NMDA receptor antagonist, 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 5 mg/kg, IP), produced neither stereotyped behavior nor impairment of the righting reflex; at higher doses (10 mg/kg, IP), it produced only ataxia and an increase in locomotor activity.

Behavioral evidence for modulation by sigma ligands of (+)MK-801-induced hyperlocomotion in monoamine-depleted mice

The selective non-competitive N-methyl- d-aspartate (NMDA) antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5, 10-imine maleate ((+)MK-801) led to a dose-dependent increase in locomotor activity in mice pretreated with a combination of reserpine and α-methyl-para-tyrosine (α-MT). A selective and potent sigma receptor “antagonist” NE-100 (N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride), which did not per se affect spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. Sulpiride, a dopamine D 2 receptor antagonist, and clozapine, a dopamine D 4 receptor antagonist, which decreased spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. The sigma receptor “agonists” (+)N-allynormetazocine [(+)SKF10,047], (+)pentazocine and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)3-PPP], which did not per se affect spontaneous locomotor activity, did dose-dependently enhance the hyperlocomotion induced by (+)MK-801. The enhancement of (+)MK-801-induced the hyperlocomotion by (+)SKF10,047, (+)pentazocine and (+)3-PPP was completely blocked by NE-100. The enhancement of (+)MK-801-induced hyperlocomotion by (+)pentazocine was not affected by treatment with sulpiride and clozapine. As sigma ligands can markedly attenuate NMDA antagonist-induced behavior, the major physiological role of sigma receptors in vivo might be to modulate functions of the NMDA receptor ion channel complex.

EEG seizure activity and behavioral neurotoxicity produced by (+)-MK801, but not the glycine site antagonist L-687,414, in the rat

The objective of the present study was to compare the in vivo effects of the anticonvulsant/ neuroprotective glycine-site partial agonists L-687,414 (3 R-amino-1-hydroxy-4 R-methylpyrrolidin-2-one) and (+)-HA966 (3-Amino-1-hydroxypyrrolidin-2-one) and the non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-MK801 on spontaneous cortical EEG activity and behavior in the unanesthetized rat. Comprehensive dose-response assessments demonstrated that acute i.v. injections of (+)-MK801 induced a behavioral neurotoxic syndrome comprised of head-weaving, ataxia, hyperlocomotion and myoclonic/clonic behaviors and associated with disruptions in normal EEG rhythms including paroxysmal EEG spike/wave complexes. Injections of (+)-HA966 produced behavioral sedation associated with high-amplitude, slow-wave synchronized EEG patterns; signs of ictal EEG activity were minimal (33% incidence) and only seen at the highest dose tested (100 mg/kg). Both (+)-MK801 and (+)-HA966 severely delayed the latency to slow-wave sleep (SWS). In contrast, the EEG dynamics and overt behavior associated with L687,414 were essentially indistinguishable from controls. There was no disruption in the latency to SWS and mild ataxia was evident only upon awakening. The calculated protective indices (EEG seizure ED 50/anticonvulsant ED 50) for (+)-MK801 and L-687,414 were 1.2 and > 4.5, respectively. The results of this study confirm that valuable pharmacological actions mediated via glycine site modulation of the NMDA receptor are possible without the clinical manifestation of unwanted neurotoxic side-effects. Published by Elsevier Science Ltd 1996.