Systemic Administration Of MK-801 Research Articles

Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade

Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N-methyl- d-aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.25 mg/kg) twice daily for 3 weeks, developed a progressive shortening in the duration of their motor response to levodopa similar to that occurring in parkinsonian patients with wearing-off phenomenon. The acute systemic administration of MK-801 (0.1 mg/kg) to these animals completely reversed the decrease in turning duration ( P < 0.01). Intrastriatal injection of the NMDA antagonist was even more effective in prolonging the levodopa response ( P < 0.01), while intranigrally injected MK-801 produced no statistically significant change in the duration of levodopa-induced rotation. Rotational intensity was unaffected by all routes of MK-801 administration. These results suggest that drugs capable of blocking NMDA receptors, especially in striatum, may help ameliorate motor fluctuations in patients with advanced Parkinson's disease.

Role of N-methyl-D-aspartate receptor in acute spinal cord injury.

To clarify the role of N-methyl-D-aspartate (NMDA) receptors in acute spinal cord injury, changes in the intraspinal microcirculation after acute spinal cord injury in rabbits were examined. Systemic administration of MK-801, an NMDA receptor antagonist, at a dose of 5 mg/kg, significantly improved motor recovery after injury and significantly reduced edema formation at the injured site without altering spinal cord blood flow or vascular permeability at the injured site. These findings indicate that excitatory amino acids contribute to secondary spinal cord damage, especially edema formation, mediated by NMDA receptors in the early stage after injury.

Systemic administration of the NMDA receptor antagonist MK-801 potentiates circling induced by intrastriatal microinjection of dopamine

Systemic administration of the non-competitive antagonist of NMDA receptors MK-801 ((+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine) potentiates the circling response induced by direct stimulation of the striatal dopaminergic receptors through intracerebral application of dopamine. Microinjection of dopamine (1, 5, 25 or 50 μg/1.0 μl) induced a dose-dependent contralateral circling response, when injected directly into the lesioned side of unilaterally 6-hydroxydopamine-lesioned rats. Interestingly, intrastriatal application of dopamine (1, 5, 25 or 50 μg/1.0 μl) followed by a systemic administration of MK-801 (100 μg/kg i.p.) produced a potentiated contralateral circling response in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. This motor effect is reversed compared to the marked ipsilateral circling response produced by MK-801 when given alone. Moreover, the potentiated responses persist 4-fold longer compared to the circling induced by dopamine alone. The results suggest that the potentiation by NMDA receptor antagonists of motor activity induced by dopaminergic agonists in animal models of Parkinson's disease cannot be ascribed simply to increased release of dopamine. Other mechanisms including increased sensitivity of dopamine D 1 receptors or blockade or glutamatergic transmission in output structures must be considered.

Stereotaxic administration of 1-methyl-4-phenylpyridinium ion (MPP+) decreases striatal fructose 2,6-bisphosphate in rats.

The stereotaxic administration of 1-methyl-4-phenylpyridinium ion (MPP+) into the neostriatum of male rats caused a lesion that resulted in a large dose-dependent loss of striatal fructose 2,6-bisphosphate; initial values were restored 5 days after the treatment. This effect was not protected by systemic administration of MK-801 or by nitroarginine. The content of hexose 6-phosphates and ATP was also reduced by MPP+ treatment, whereas lactate was increased. Biochemical and histological results suggested that MPP+ caused a nonselective cell death, followed by a pronounced astroglial response, parallel to fructose 2,6-bisphosphate recovery. The stereotaxic administration of rotenone showed a different time effect on fructose 2,6-bisphosphate cerebral content, with a significantly faster recovery. These results indicate that cerebral fructose 2,6-bisphosphate may be a sensitive metabolite related to brain damage caused by potent neurotoxins such as MPP+. On the other hand, they show that MPP+ acts in the brain through a quick, strong cytotoxic mechanism, which probably involves mechanisms other than mitochondrial chain blockage.

Inhibition of clonic seizure-like excitatory effects induced by intrathecal morphine using two NMDA receptor antagonists: MK-801 and ACEA-1011

Microinjection of high doses of morphine into the spinal lumbar intrathecal (i.t.) space of mice produces dose-dependent clonic seizure-like excitatory effects. Naloxone, an opioid antagonist (10 mg/kg, i.p.), injected 5 min prior to i.t. morphine, did not reverse the seizure-like motor effects, suggesting that these effects of morphine are not mediated through opioid receptors. Systemic administration of MK-801, a non-competitive NMDA receptor antagonist (0.01–0.10 mg/kg, i.p.), or ACEA-1011, a novel NMDA receptor/glycine site antagonist (0.5–20.0 mg/kg, i.p.), attenuated the clonic seizure-like excitatory effects induced by i.t. morphine in a dose-dependent manner. Sensorimotor performance of the mice was evaluated using the rotarod test. Although both compounds (MK-801 and ACEA-1011) impaired the sensorimotor performance of mice in a dose-dependent fashion, there was no impairment of motor performance at doses employed to block the excitatory effects induced by i.t. morphine. These data suggest that NMDA receptors play a pivotal role in the clonic seizure-like behaviors induced by i.t. morphine.

Noncompetitive and Competitive NMDA Antagonists Exert Anticonvulsant Effects by Actions on Different Sites within the Neuronal Network for Audiogenic Seizures

Excitant amino acids are implicated in audiogenic seizure (AGS) susceptibility in the genetically epilepsy-prone rat (GEPR). In the present study systemic administration of NMDA receptor antagonists significantly decreased AGS severity in the GEPR. Systemic administration of the competitive NMDA antagonists 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) and 2-amino-7-phosphonoheptanoic acid and the noncompetitive antagonist dizocilpine (MK-801) were effectively anticonvulsant in the GEPR. The inferior colliculus is the most critical nucleus for AGS initiation in the GEPR and an excitant amino acid is implicated as an important excitatory transmitter in inferior colliculus neurons. Systemically administered CPP significantly reduced inferior colliculus neuronal firing in the normal behaving rat and the GEPR concurrently with blockade of AGS and this effect occurred at nearly all sound intensities tested. Systemic administration of MK-801, while effective in blocking AGS, produced no consistent change in inferior colliculus neuronal firing, which is consistent with its very low potency in blocking AGS with bilateral microinjection into the inferior colliculus. These findings suggest that an important action of competitive, but not noncompetitive, NMDA antagonists is on brain stem auditory nuclei, especially the inferior colliculus, that are critical to AGS. MK-801 appears to exert its anticonvulsant effects in AGS network sites beyond the inferior colliculus. These findings and recent inferior colliculus slice studies suggest that NMDA receptors in inferior colliculus may have quantitatively different properties from those in other brain regions. These differences in NMDA receptor function in inferior colliculus may reflect NMDA receptor heterogeneity observed in binding studies. The differential effects of competitive and noncompetitive NMDA antagonists on inferior colliculus neuronal firing may be one of the first examples of the functional significance in vivo of NMDA receptor heterogeneity.

Blockade of NMDA receptor-channels by MK-801 alters breathing in adult rats

The role of N- methyl- d-aspartate (NMDA) receptor-channel activation in the production of respiratory pattern was studied by administration of the NMDA receptor-channel blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801, 1–3 mg/kg, i.v.) to anesthetized adult rats. This dose of MK-801 blocked the excitatory effects of NMDA (applied iontophoretically) ob brainstem respiratory neurons. The predominant respiratory response to systemic MK-801 administration was an increase in inspiratory duration and a decrease in amplitude of diaphragm electromyogram and phrenic nerve discharge. Effects on inspiratory timing and amplitude were most pronounced when the rats were vagotomized. Significant changes in arterial blood gases and pH after systemic MK-801 administration in spontaneously breathing rats (vagi intact or cut) indicated that ventilation was depressed by NMDA receptor-channel antagonism. Respiratory timing changes in response to systemic MK-801 administration differed between two rat strains studied. Breathing patterns resembling apneusis, i.e., with irregular inspiratory durations prolonged 2- to 30-fold, occurred in 60% of the vagotomized, spontaneously breathing Sprague-Dawley rats and none of the Wistar rats. Thus, the breathing pattern in Sprague-Dawley rats is more sensitive to interference with NMDA-mediated mechanisms. We propose that respiratory pattern generation and transmission of rhythmic respiratory drive are mediated by synergistic activation of NMDA and non-NMDA receptors at brainstem and spinal cord sites.

MK-801 prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in primates.

In cynomologus monkeys, systemic administration of MK-801, a noncompetitive antagonist for the N-methyl-D-aspartate receptor, prevented the development of the parkinsonian syndrome induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MK-801 also attenuated dopamine depletion in the caudate and putamen and protected dopaminergic neurons in the substantia nigra from the degeneration induced by the neurotoxin. Nevertheless, 7 days after MPTP administration in the caudate and putamen of monkeys also receiving MK-801, the levels of toxic 1-methyl-4-phenylpyridinium were even higher than those measured in monkeys receiving MPTP alone. This indicates that the protective action of MK-801 is not related to MPTP metabolism and strongly suggests that, in primates, the excitatory amino acids could play a crucial role in the mechanism of the selective neuronal death induced by MPTP.

Inhibitory effects of NMDA receptor antagonists on hypoxia-induced seizures in dietary Mg 2+-deficient mice

The effects of the non-competitive N-methyl-D-aspartate (NMDA) antagonists, (+)-MK-801 hydrogen maleate (MK-801) and phencyclidine hydrochloride (PCP), were tested against hypoxia-induccd tonic convulsions and hippocampal epileptiform discharges. Systemic administration of MK-801 and PCP suppressed the hypoxia-induecd tonic convulsions in dietary Mg 2+-deficient mice in a dose-dependent manner. The ED 50 values (and their 95% confidence limits) of MK-801 and PCP were 0.19 (0.14–0.26) and 1.14 (0.32–4.11) μmol/kg, respectively. These values were lower than those of the conventional anticonvulsants tested. Induction of epileptiform discharges following hypoxia was also prevented by the presence of MK-801 and PCP at concentrations of 5–30 μM. The hypoxia-induced epileptiform discharges, however, were reduced, but not blocked completely, by the application of MK-801 and PCP. These results strongly suggest that activation of NMDA receptors in the hippocampus plays a pivotal role in the induction of hypoxia-induced tonic convulsions in dietary Mg 2+-deficient mice.

Effects of MK-801 upon local cerebral glucose utilisation in conscious rats following unilateral lesion of caudal entorhinal cortex

Local cerebral glucose utilisation was examined in 62 discrete regions of conscious rats following unilateral ibotenic acid lesion of the caudal entorhinal cortex, and subsequent pharmacological challenge with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate (MK-801), a non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist. Fourteen days after unilateral lesion of the entorhinal cortex, there were no significant alterations in local cerebral glucose use except within the lesioned entorhinal cortex (reduced by 31% compared to sham-operated control animals). In sham-operated animals, systemic administration of MK-801 (0.5 mg/kg, i.v.) induced anatomically organised alterations in glucose use with increases in olfactory areas, subicular complex and some limbic areas (posterior cingulate cortex, mammillary body and anteroventral thalamic nucleus), and decreases in the inferior colliculus and neocortex (auditory, sensory-motor, somatosensory and frontal cortices). In animals with unilateral entorhinal cortex lesions, the metabolic response to MK-801 differed significantly from the response to the drug in sham-lesioned animals in a number of regions, viz. hippocampus, molecular layer (ipsilateral to lesion), entorhinal cortex (ipsilateral), dentate gyrus (ipsilateral), presubiculum (bilateral), parasubiculum (bilateral) and nucleus accumbens (bilateral). The ability of MK-801 to reduce glucose use in the neocortex was not altered by entorhinal cortex lesion. These data suggest that the functional consequences of non-competitive NMDA receptor blockade are dependent in some areas upon the integrity of the perforant pathway from the entorhinal cortex to the hippocampus.

Injection of excitatory amino acid antagonists into the medial pallidal segment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated primate reverses motor symptoms of parkinsonism

Intracerebral injections of the broad spectrum exitatory amino acid antagonist kynurenic acid (50ug) alleviated the symptoms of akinesia, tremor and rigidity in a severely parkinsonian monkey. Unilateral injection of kynurenic acid within the medial pallidal segment produced rotational behaviour away from the side of the injection, and the limbs on the contralateral side showed relief of the MPTP-induced parkinsonian symptoms. The subsequent bilateral injection of the excitatory amino acid antogonist allowed the monkey to move freely, unhindered by tremor or rigidity. In addition unilateral injections of the NMDA antagonist MK-801 (5, 25 and 50ug) within the medial pallidum also produced dose-related rotational behaviour, with alleviation of parkinsonian symptoms in the contralateral limbs. Systemic administration of MK-801 (1ng/kg - 1ug/kg i.m.) was without effect.

Systemic administration of mk-801 protects against N-methyl- d-aspartate-and quisqualate-mediated neurotoxicity in perinatal rats

MK-801, a non-competitive antagonist of N-methyl- d-aspartate-type glutamate receptors, was tested for its ability to antagonize excitotoxic actions of N-methyl- d-aspartate or quisqualic acid injected into the brains of seven-day-old rats. Stereotaxic injection of N-methyl- d-aspartate (25nmol/0.5μl) or quisqualic acid (100 nmol/1.0μ1) into the corpus striatum under ether anesthesia consistently produced severe unilateral neuronal necrosis in the basal ganglia, dorsal hippocampus and overlying neocortex. The distribution of the damage corresponded to the topography of glutamate receptors in the vulnerable regions demonstrated by previous autoradiographic studies. N-Methyl- d-aspartate produced severe, confluent neuronal destruction while quisqualic acid typically caused more selective neuronal necrosis. Intraperitoneal administration of MK-801 (0.1–l.0 mg/kg) 30 min before. N-methyl- d-aspartate injection had a prominent dose-dependent neuroprotective effects as assessed morphometrically by comparison of bilateral striatal, hippocampal and cerebral hemisphere cross-sectional areas five days later. A 1 mg/kg dose of MK-801 given as pre-treatment completely protected the infant brain. The same dose of MK-801 was also completely protective when administered 30 or 40 min after N-methyl- d-aspartate and afforded partial protection when given 2 h later. MK-801 pre-treatment also prevented the electrically confirmed behavioral seizures induced by N-methyl- d-aspartate. The drug significantly reduced striatal but not hippocampal or neocortical injury when given as two doses (1 mg/kg) 30 min prior to and immediately following quisqualic acid injection. The data indicate that systemic administration of MK-801 can prevent N-methyl- d-aspartate-induced neuronal injury in perinatal rat brain even when administered after the initial insult. MK-801 also partially antagonized quisqualic acid-mediated neurotoxicity, suggesting that quisqualic acid-induced toxicity is, in part, mediated through N-methyl- d-aspartate receptor activation. The sensitivity of the developing b0rain to the toxicity of N-methyl- d-aspartate provides a sensitive and reproducible in vivo model for exploring these issues and for screening prospective neuroprotective drugs that act at the N-methyl- d-aspartate receptor-channel complex.

Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil

The neuroprotective effects of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, were evaluated in models of cerebral ischemia using Mongolian gerbils. Bilateral occlusion of the carotid arteries for a period of 5 min resulted in a consistent pattern of degeneration of hippocampal CA1 and CA2 pyramidal neurons, which was quantified using an image analyzer. Systemic administration of MK-801 (0.01-10 mg/kg, i.p.) 1 hr prior to the occlusion caused a dose-dependent protection of the CA1 and CA2 neurons. The ED50 value for neuroprotection by MK-801 was calculated to be 0.3 mg/kg, and at doses greater than or equal to 3 mg/kg the majority of animals were completely protected against the ischemic insult. Systemic administration of MK-801 (1 or 10 mg/kg, i.p.) 1 hr prior to unilateral occlusion of the right carotid artery resulted in significant protection against hippocampal neurodegeneration following 10 min of occlusion, and increased the survival rate after 30 min of occlusion. The potent neuroprotective effects of MK-801 in these cerebral ischemia models add further weight to the evidence that NMDA receptors are involved in the mechanism of ischemia-induced neuronal degeneration.

Systemic administration of MK-801 prevents [formula omitted] neuronal degeneration in rat brain

MK-801 is a novel, potent and selective non-competitive antagonist of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors. Pretreatment of rats with MK-801 (1 10 mg kg, i.p.) prevented neuronal degeneration in the hippocampus and striatum caused by direct intracranial injections of NMDA (20 120 nmol), but did not protect against the loss of neurones induced by kainate (2.5 nmol) injected into the striatum. Thus, MK-801 is a selective antagonist of neuronal degeneration caused by excessive stimulation of NMDA receptors in vivo.