MK-801 prevents the enhanced behavioural response to apomorphine elicited by repeated electroconvulsive treatment in mice

Repeated administration of electroconvulsive stimuli (ECS) to mice once daily for a period of 7 days results in an enhanced locomotor response induced by apomorphine (1.0 mg/kg, IP). Pretreatment (30 min) with the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.01–1.0 mg/kg IP), suppressed ECS-induced seizure activity in a dose-dependent manner. MK-801 (0.01 and 0.033 mg/kg, IP) given 30 min before each ECS dose-dependently decreased apomorphine-mediated responses. Administration of MK-801 (0.033 mg/kg IP) 30 min after each convulsion had the same effect. These results indicate that MK-801 can abolish the ECS-induced enhancement of dopamine-mediated behaviour possibly by interfering with postictal processes. Thus, NMDA receptors seem to be involved in the behavioural changes and presumably also in the neural adaptations produced by repeated ECS.     

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.     

Down-regulation of cortical β-adrenoceptors by chronic treatment with functional NMDA antagonists

Down-regulation of cortical β-adrenoceptors is observed in laboratory animals following chronic treatment with many clinically effective antidepressant therapies. [³H]Dihydroalprenolol (DHA) binding to cortical β-adrenoceptors was examined in mice treated with the functional NMDA antagonists 1-aminocyclopropane-carboxylic acid (ACPC) and MK-801. ACPC and MK-801 reduced [³H]DHA binding by 19 (P>0.05) and 21% (P<0.05), respectively, while imipramine produced a 23% (P<0.05) reduction. No corresponding changes in the K_d of [³H]DHA were observed. These findings are consistent with the observation that functional NMDA antagonists are active in animal models commonly used to evaluate antidepressants and may represent a novel approach to the treatment of depression.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

A Neuropharmacological Evaluation of Felbamate as a Novel Anticonvulsant

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) was subjected to a series of carefully selected in vivo and in vitro tests to provide additional insight into mechanism of action, margin of safety, and clinical potential. FBM was effective against intracerebroventricular (i.c.v.) N-methyl-D-aspartate (NMDA)-induced clonus and i.c.v. NMDA- and quisqualic acid (quis)-induced forelimb tonic extension in mice and ineffective against i.c.v. quis-induced clonus in mice. FBM was also effective in preventing the expression of Stage 5 kindled seizures in corneal-kindled rats. The calculated protective indices (rotorod median toxic dose divided by anticonvulsant median effective dose) ranged from 28 to 146 for those tests in which FBM displayed activity. With the in vitro tests, FBM did not significantly displace [3H]MK-801 from its binding site. In contrast, FBM was effective in blocking sustained repetitive firing in mouse spinal cord neurons grown in tissue culture (median inhibitory concentration 67 micrograms/ml). This effect on repetitive firing suggests indirectly that FBM modulates sodium channel conductance. The results, when compared to similar data for phenytoin, carbamazepine, valproate, and ethosuximide, support the concept that FBM is a relatively nontoxic agent with a unique profile of anticonvulsant action, a broad margin of safety, and a clinical potential that includes at least generalized tonic-clonic and complex partial seizures.     

Fenfluramine-induced increases in extracellular hippocampal serotonin are progressively attenuated in vivo during a four-day fenfluramine regimen in rats

The non-competitiveN-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain.dl-Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.     

The Role of N-Methyl-D-Aspartate-Type Glutamatergic Neurotransmission in the Photic Induction of Immediate-Early Gene Expression in the Suprachiasmatic Nuclei of the Syrian Hamster

This study investigated the role of N-methyl-D-aspartate (NMDA)-type glutamatergic neurotransmission in mediating the photic induction of immediate-early gene expression in the Suprachiasmatic nucleus (SCN) of the Syrian hamster. Activation of c-fos, c-jun and egr-1 was assessed by immunocytochemical detection of their protein products. To characterize the circadian basis to the inductive effects of light, hamsters were allowed to free-run in constant dim red light and received a 1 h light pulse at different circadian phases relative to activity onset (defined as CT 12). In control animals which did not receive light pulses, c-fos and egr-1 expression was absent or restricted to a small area of the dorsolateral region of the SCN, and expression of c-jun could not be detected in the SCN. In hamsters killed after presentation of a light pulse at either CT 14 or CT 20, there was a marked increase in c-fos and egr-1 immunoreactivities throughout the ventrolateral division of the SCN. In contrast, light pulses given at CT4 or CT 8 failed to activate immediate-early gene expression. Light pulses did not induce c-jun immunoreactivity at any circadian phase tested. Staining for c-fos was maximal 1 h after the start of the light pulse and had started to decline by 2 h. At this later time, c-jun expression was still undetectable. To compare the distribution of retinal afferents with that of c-fos induction, hamsters held on a light schedule of 16 h light: 8 h dark received an intraocular injection of cholera toxin-horseradish peroxidase conjugate 3 days before exposure to a 1 h light pulse given 2 h after lights off. Comparison of adjacent sections processed for c-fos immunoreactivity or for cholera toxin-horseradish peroxidase revealed that light-induced c-fos expression was precisely restricted to retinal terminal fields in the SCN. Light pulses also induced c-fos expression in the retinoreceptive ventral lateral geniculate nucleus and intergeniculate leaflet but not in the retinal fields of the dorsal lateral geniculate nucleus, indicating that the expression of cfos in response to light is spatially specific. The aim of the subsequent experiments was to investigate the role of NMDA-type glutamatergic neurotransmission in mediating the effects of light on c-fos expression in the SCN. To determine whether NMDA had the potential to activate c-fos expression in the SCN, hamsters were infused with 2.5 nmol NMDA or vehicle via an intracerebroventricular (icv) cannula positioned adjacent to the nuclei. In contrast to the effects of light, icv NMDA activated c-fos expression at both CT8 and CT 14. The distribution of immunoreactivity was more widespread than that observed after light, extending throughout the SCN and adjacent hypothalamus. To test whether NMDA receptors had a physiological role in the photic response, hamsters were treated systemically with the non-competitive NMDA antagonist MK801 (dose range 0.6 to 6.0 mg/kg body wt, ip) or vehicle prior to exposure to a 1 h light pulse given at CT 14 or CT 20. Expression of c-fos was still detectable in the dorsolateral SCN but MK801 blocked expression in the ventral portion of the retinoreceptive zone of the SCN. MK801 (10 or 100 nmol) delivered centrally (icv) also prevented light-induced c-fos expression in the ventral region of the SCN bordering the optic chiasm, though staining again persisted in the dorsolateral region. The induction of c-fos by icv NMDA, and the partial blockade of light-induced c-fos expression by the antagonist MK801, are consistent with the hypothesis that glutamate mediates the effects of light on SCN activity. However, the persistent photic induction of c-fos expression in a subfield of retinal afferents following treatment with MK801 suggests that other, non-NMDA-type mechanisms may contribute to photic entrainment.     

Partial protection of hippocampal neurons by MK-801 during perforant path stimulation in the immature brain

We investigated whether the non-competitive NMDA receptor antagonist, MK-801, could protect neurons in the immature brain from the excitotoxic affects of perforant path stimulation. A high dose of MK-801 reduced the number of injured hilar interneurons in the stimulated hippocampus from 30.0±5.2 in unmedicated rats to 12.2±9.6 in MK-801 treated animals (P<0.05). MK-801 injection also protected the animals from the scattered dentate granule cell injury observed in non-medicated animals 1 day after stimulation. Other effects of drug injection included exacerbated damage in limbic cortices, retrosplenial cortical damage, and reduced inhibition in a highly epileptogenic region of the dentate gyrus. Our results show that a subpopulation of hilar interneurons is vulnerable to NMDA-induced damage in the immature hippocampus but that non-competitive blockade of the NMDA receptor may be a dangerous therapeutic strategy.© 1997 Elsevier Science B.V. All rights reserved.     

小儿急性中毒143例分析

本研究拟通过观察谷氨酰胺合成酶（GS）、谷氨酰胺酶（PAG）、琥珀酸脱氢酶（SDH）和Na^＋-K^＋-ATPase活性的改变,探讨地卓西平（MK-801）和牛磺酸对锰致大鼠兴奋性毒性的影响。将大鼠按体重随机分成4组,第1组为对照组,皮下注射0．9％的氯化钠;第2组为单纯染锰组,皮下注射0．9％的氯化钠;第3、4组为预处理干预组,分别皮下注射0．3μmnol／kg的MK-801和1mmol／kg的牛磺酸,皮下注射2h后,第1组腹腔注射0．9％的氯化钠,第2-4组腹腔注射200μmol／kg的氯化锰,染锰25d,MK-801和牛磺酸隔日注射一次,共预处理13次。最后一次染毒后24h处死大鼠,切取大脑皮质和纹状体。测定大脑皮质SDH、Na^＋-K^＋-ATPase的活性;测定脑纹状体GS、PAG的活性。结果显示单纯染锰组与对照组比较,纹状体GS、脑皮质SDH和Na^＋-K^＋-ATPase的活性明显降低（P〈0．01）,纹状体PAG的活性升高。MK-801预处理干预组与单纯染锰组比较,纹状体GS和脑皮质Na^＋-K^＋-ATPase的活性明显升高,脑皮质SDH的活性升高,纹状体PAG的活性降低;牛磺酸预处理干预组纹状体CS和脑皮质SDH的活性明显升高,脑皮质的Na^＋．K^＋-ATPase活性升高。提示MK-801和牛磺酸对锰所致兴奋性毒性均有不同程变的拮抗作用。