Excitatory amino acid-induced convulsions in neonatal rats mediated by distinct receptor subtypes

We found that N-methyl-D-aspartate (NMDA) was a very potent, systematically active convulsant in the rat in the early period of postnatal development (7-11 days of age). Other receptor subtype-selective excitatory amino acid agonists were then examined for their convulsant effects following i.p. administration to neonatal rats. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was the most potent convulsant (ED50 0.6 mg/kg), followed by kainate (ED50 1.5 mg/kg), N-methyl-D-aspartate (NMDA) (ED50 3.1 mg/kg), then quisqualate (ED50 5.1 mg/kg). NMDA-induced convulsions were antagonized in a dose-related manner by prior administration of the NMDA antagonists cis-(+/- )-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), cis-(+/- )-4-(2H-tetrazol-5-yl)methyl-piperidine-2-carboxylic acid (LY233053), (+/- )3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-2-amino-5-phosphonovalerate (D,L-AP5) and MK801. NMDA antagonists did not protect against AMPA- or kainate-induced convulsions. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) selectively prevented the effect of AMPA at doses which had no effect on NMDA or kainate convulsions. Quisqualate-induced convulsions were antagonized by NMDA antagonists or DNQX. The greater sensitivity of neonatal rats to systemically administered excitatory amino acid agonists appears useful for evaluating the selectivity of antagonists acting at ionotropic excitatory amino acid receptors in the central nervous system. Using neonatal rats three pharmacologically distinct excitatory amino acid receptor effects were demonstrated following administration of NMDA, AMPA or kainate.     

Lowered brain stimulation reward thresholds in rats treated with a combination of caffeine and N-methyl-D-aspartate but not alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or metabotropic glutamate receptor-5 receptor antagonists

Previous studies suggested that adenosine A1 and A2A receptor agonists counteract behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists while adenosine receptor antagonists may produce opposite effects enhancing the actions of NMDA receptor antagonists. To further evaluate the effects of combined administration of adenosine receptor antagonist caffeine and various NMDA and non-NMDA glutamate receptor antagonists on brain stimulation reward (discrete-trial threshold current intensity titration procedure), rats with electrodes implanted into the ventral tegmental area were tested after pretreatment with NMDA receptor channel blocker MK-801 (0.01-0.3 mg/kg), competitive antagonist D-CPPene (0.3-5.6 mg/kg), glycine site antagonist L-701,324 (1.25-5 mg/kg), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist GYKI-53655 (1-10 mg/kg), metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (1-10 mg/kg) alone and in combination with caffeine (1-30 mg/kg). MK-801 (0.056 and 0.1 mg/kg) was the only tested glutamate antagonist that lowered self-stimulation thresholds, while D-CPPene (5.6 mg/kg) and MPEP (5.6 and 10 mg/kg) had the opposite effects. Threshold-increasing effects of D-CPPene, but not of MPEP, however, were associated with marked impairment of operant performance, reflected by longer latencies to respond and higher rates of responding during the inter-trial intervals. Operant performance was also disrupted by the highest dose of MK-801 (0.3 mg/kg). For subsequent experiments, caffeine (1-30 mg/kg) was combined with the highest doses of NMDA receptor antagonists that did not lower the brain stimulation reward thresholds and did not impair operant performance. Caffeine had no appreciable effects on self-stimulation behavior when given alone. A low dose of caffeine (3 mg/kg) significantly lowered self-stimulation thresholds only when given together with MK-801 (0.03 mg/kg) or D-CPPene (3 mg/kg). Combined with the same antagonist drugs, higher doses of caffeine (10 and 30 mg/kg) facilitated time-out responding. These results indicate that, within a limited dose range, caffeine in combination with an NMDA receptor channel blocker and a competitive antagonist significantly lowers brain stimulation reward thresholds in rats.     

The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of excitatory amino acid mechanisms in gamma-hydroxybutyrate model of generalized absence seizures in rats.

gamma-Hydroxybutyric acid (GHB), a naturally occurring compound which is synthesized from gamma-aminobutyric acid (GABA), induces bilaterally synchronous spike wave discharges, associated with behavioral changes, reminiscent of petit mal or generalized absence seizures in rats. In the present study, possible involvement of excitatory amino acids (EAAs) in GHB-induced spike wave discharges was investigated. The noncompetitive antagonist of NMDA receptors, MK-801, attenuated GHB-induced spike wave discharges at all doses tested (0.025-1.0 mg/kg) but dose-dependently induced suppression of EEG bursts in GHB-treated animals. The suppression of bursts was never observed with GHB in control experiments. N-Methyl-D-aspartate (NMDA) had a similar effect on GHB-induced spike wave discharges, when it was administered prior to GHB. This effect of NMDA was partially reversed by MK-801. The competitive antagonists of NMDA receptors, (+/-)CPP and CGP 43487 and the antagonist at the strychnine-insensitive glycine site, HA-966, also suppressed GHB-induced spike wave discharges with the EEG progressing to suppression of bursts but were weaker in this regard than MK-801 or NMDA. These data raise the possibility of involvement of excitatory amino acids in the GHB model of absence seizures.     

Ethological analysis of the effects of MK-801 upon aggressive male mice: similarity to chlordiazepoxide

Previous studies have demonstrated benzodiazepine-like effects of competitive and noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. The present experiment compared the effects of the benzodiazepine chlordiazepoxide and the NMDA noncompetitive antagonist MK-801 upon the behavior of aggressive male mice in dyadic interactions using ethological analysis. OF-1 male mice housed with females were administered either chlordiazepoxide (Vehicle, 3.0, 10.0 and 30.0 mg/kg IP) or MK-801 (Vehicle, 0.1, 0.3 and 0.3 mg/kg, IP) in a randomised order thirty minutes prior to pairing with unfamiliar male opponents in an unfamiliar environment. It was found that both compounds tended to increase aggressiveness and social behavior and reduce ambivalent activity consistent with approach-avoidance conflict. The increases in aggressiveness and decreases in ambivalent activity were induced by MK-801 at doses lower than those resulting in gross motor effects. These data confirm that noncompetitive antagonists of NMDA may generate a benzodiazepine-like behavioral profile.     

The NMDA receptor antagonist MK-801 increases morphine catalepsy and lethality.

Interactions between excitatory amino acids and opioids were examined by studying the ability of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to affect morphine catalepsy and lethality. MK-801 (0.3 mg/kg) reduced the ED50 for morphine-induced catalepsy from approximately 30 mg/kg to less than 10 mg/kg, and reduced the LD50 for morphine from approximately 100 mg/kg to approximately 10 mg/kg. Lower doses of MK-801 did not affect morphine catalepsy or lethality. MK-801, in the absence of morphine, produced no catalepsy or lethality at doses up to 3.0 mg/kg; at 0.3 mg/kg MK-801 caused weaving, body rolling and ataxis, as previously described, while at 3.0 mg/kg animals appeared to lose muscle tone, becoming limp. These results demonstrate that blockade of NMDA receptors can dramatically potentiate morphine catalepsy and lethality, and suggest a potential dangerous interaction with opioids in the clinical use of NMDA receptor antagonists.     

Prevention of cocaine-induced convulsions and lethality in mice: effectiveness of targeting different sites on the NMDA receptor complex

N-methyl-D-aspartate (NMDA) receptors appear to be involved in the behavioral toxic effects of cocaine. Therefore, different classes of NMDA receptor antagonists were compared for their ability to attenuate cocaine-induced convulsions and lethality in male, Swiss Webster mice. The mice were pre-treated (i.p.) with vehicle or an antagonist from one of the following classes: NMDA/glycine site antagonist (7-chlorokynurenic acid, ACEA-1021, ACEA-1031, ACEA-1328, DCQX, R(+)-HA-966), competitive antagonist (CPP, D-AP7), channel blocker (MK-801, memantine), or allosteric modulator (ifenprodil, CP-101,606, Co 101022, haloperidol). After a 15 min pre-treatment period, the mice were administered a convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p.) dose of cocaine, equivalent to the calculated ED/LD97 values. Pre-treatment with competitive or NMDA/glycine site antagonists dose-dependently attenuated cocaine-induced convulsions and lethality (P<0.05). Pre-treatment with channel blockers or allosteric modulators of the NMDA receptor protected against cocaine-induced convulsions (P<0.05), but were ineffective or less effective than the competitive and glycine site antagonists in preventing death. The glutamate release inhibitor riluzole failed to prevent both the convulsions and lethality induced by cocaine. Significantly, post-treatment with NMDA/glycine site antagonists (ACEA-1021, ACEA-1031, ACEA-1328) after a cocaine overdose prevented death in a significant number of animals. The data suggest that NMDA receptors are involved in the pathophysiology of a cocaine overdose.     

Protection from kainic acid neuropathological syndrome by NMDA receptor antagonists: effect of MK-801 and CGP 39551 on neurotransmitter and glial markers.

Systemic administration of kainic acid results in the development of a characteristic convulsive syndrome, accompanied by neuropathological alterations and loss of transmitter markers in some forebrain regions. Since some of these effects appear to involve the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors, the protection given by a non-competitive (MK-801) and a competitive (CGP 39551) NMDA receptor antagonist against the loss of glutamatergic and gamma-amino butyric acid (GABAergic) neurochemical markers was compared. Appropriate doses of both compounds (1 mg/kg MK-801 and 25 mg/kg CGP 39551) completely reversed the decrease of high affinity uptake of glutamate and activity of glutamate decarboxylase in the olfactory cortex, amygdala, hippocampus and lateral septum. In addition, they also essentially counteracted the increase of a glial marker, the enzyme glutamine synthetase, consequent to neuronal degeneration. The results confirmed that involvement of NMDA receptors is essential for the full expression of neuropathological effects of kainic acid. They also support the use of a competitive antagonist of the NMDA receptor, such as CGP 39551, to afford substantial protection against the excitotoxic damage, whilst giving fewer side effects and motor disturbances than MK-801.     

Effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, in mice]

The effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, were studied in mice. The combination of enoxacin at 30 or 100 mg/kg, p.o. and fenbufen at 100 mg/kg, p.o. induced convulsions; and the mice died as a result of the convulsions. Pretreatment with either phenobarbital, phenytoin, valproic acid intraperitoneally, or morphine intravenously did not influence the convulsions. A high dose of diazepam or clonazepam prolonged the survival time, but could not prevent the mice from dying. After the occurrence of convulsions induced by enoxacin with fenbufen, administration of the excitatory amino acid antagonist MK-801 at 1 mg/kg, i.v. extended the survival time, even though all the mice died as a result of the convulsions. Simultaneous intravenous injections of MK-801 and diazepam suppressed the convulsions. This suppression was stronger than that produced by MK-801 or diazepam, injected separately. However, no mouse survived at the end. From these results, participation of both GABA-ergic and excitatory amino acidergic systems in the convulsions induced by enoxacin and fenbufen was discussed.     

MK-801 antagonizes the lethal action of centrally and peripherally administered cypermethrin in mice and rats.

The present study investigated the effect of MK-801, an N-methyl-D-aspartate antagonist, on the convulsant lethal action of cypermethrin administered centrally or peripherally. Cypermethrin produced severe convulsions and death in a dose-dependent manner. MK-801 (0.5, 1 and 2 mg kg-1, intraperitoneally) significantly increased the onset time of convulsions and decreased the mortality in the peripherally treated cypermethrin group. MK-801 (1.0 and 2.0 mg kg-1) attenuated the convulsant action of cypermethrin (50 micrograms, intracerebroventricularly) significantly. Survival rate was also increased significantly. However, MK-801 (0.5 mg kg-1) did not produce any significant protective effect against centrally administered cypermethrin. These results suggest excitatory amino acids to be a target for pyrethroid-induced neurotoxicity.     

Kainic Acid-Induced Seizures and Brain Damage in the Rat: Different Effects of NMDA- and AMPA Receptor Antagonists

Abstract: We have studied the effect of two glutamate receptor antagonists on seizures and hippocampal neurone loss in the rat after systemic kainic acid administration. Intraperitoneal injection of the novel AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid) receptor antagonist NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione) (30 mg/kgx3 and 15 mg/kgx3) administered 30 and 15 min. before and simultaneously with injection of kainic acid (5 mg/kg) intraperitoneally, dramatically enhanced the toxicity of kainic acid leading to death of all animals. When the NBQX dose was reduced to 8 mg/kg x 3, all animals survived and neurone damage in the hippocampus did not differ from control animals. When NBQX (30 mg/kg x 3) was administered 30 - or 60 min after injection of kainic acid (8 mg/kg) intraperitoneally, no changes were observed concerning survival rates, seizure generation and neurone loss. Postkainic acid treatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg and 1.0 mg/kg), 30 and 60 min. after intraperitoneally injection of kainic acid 8 mg/kg, abolished seizures in all animals and the neurone damage in the hippocampus was completely prevented. The results emphasize the importance of the NMDA-receptor activation for seizure generation and subsequent brain damage after intraperitoneally kainic acid. The paradoxical, unexpected effects of NBQX contrast to the protective effect of this compound after cerebral ischaemia and hypoglycaemia, conditions which are also characterized by glutamate-mediated damage. One possible explanation of the lowered seizure threshold to kainic acid after NBQX could be that NBQX is blocking AMPA receptors on interneurones more efficiently than on pyramidal cells.     

Effects of NMDA receptor antagonists in squirrel monkeys trained to discriminate the competitive NMDA receptor antagonist NPC 12626 from saline

Because excitatory amino acids have been implicated in several physiological phenomena, antagonists of excitatory amino acid function may have significant therapeutic potential as anticonvulsant, neuroprotectants and anxiolytics. Drug discrimination procedures in animals have proven useful to compare and contrast the behavioral effects of site-selective NMDA antagonists. In the only previous study using a competitive NMDA antagonist as a training drug, rat wwere trained to discriminate NPC 12626 (2-amino-4,5(1,2-cyclohexyl)-7-phosphonoheptanoic acid) from nondrug. The major goal of the present study was to establish and characterize a nonhuman primate model of NPC 12626 discrimination. Adult male squirrel monkeys were trained to discriminate NPC 12626 from saline under a two-lever fixed ratio-30 schedule of food reinforcement. The monkeys required between 80 and 120 training sessions to acquire this discrimination after the training dose had been raised from 3 to 20 mg/kg i.m. The competitive NMDA antagonists CGP 37849 (D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) and CPPene (D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid) substituted completely for NPC 12626, while the potent noncompetitive NMDA antagonist, dizocilpine (MK-801), did not. These results reflect a profile of discriminative stimulus effects which support that observed in rats and establish a primate model for use in further study of the behavioral effects of the competitive NMDA antagonists.     

The competitive N-methyl-D-aspartate (NMDA) antagonist CGS 19755 attenuates the rate-decreasing effects of NMDA in rhesus monkeys without producing ketamine-like discriminative stimulus effects

The purported competitive excitatory amino acid antagonist CGS 19755 was compared to the non-competitive antagonists ketamine and MK-801 in three rhesus monkeys discriminating between 1.78 mg/kg of ketamine and saline while responding under a fixed-ratio 100 schedule of food presentation. MK-801 substituted completely for the ketamine discriminative stimulus and was 32 times more potent than ketamine as a discriminative stimulus. CGS 19755 was studied using single and cumulative dosing procedures up to a dose of 10.0 mg/kg; for all conditions, CGS 19755 produced responding exclusively on the saline lever and had only modest rate-decreasing effects. N-Methyl-D-aspartate administered alone also did not produce ketamine-appropriate responding but did decrease response rates in a dose-related manner. N-Methyl-D-aspartate eliminated responding in all monkeys at doses of 5.6-10.0 mg/kg. MK-801 and ketamine antagonized the rate-decreasing effects of N-methyl-D-aspartate, however, ketamine was most effective as an antagonist at doses that decreased response rates when administered alone. CGS 19755 also attenuated the rate-decreasing effects of N-methyl-D-aspartate and shifted the N-methyl-D-aspartate dose-effect curve more than 5-fold to the right. The magnitude of antagonism of N-methyl-D-aspartate appeared to be somewhat greater with CGS 19755 than with MK-801 or ketamine. Thus, a competitive (CGS 19755) and some non-competitive (MK-801 and ketamine) excitatory amino acid antagonists can attenuate the rate-decreasing effects of N-methyl-D-aspartate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antagonism of the toxicity of cocaine by MK-801: Differential effects in spontaneously hypertensive and Wistar-Kyoto rats

A putative role for endogenous excitatory amino acid systems in the mediation of the cardiovascular and toxic responses to acute administration of cocaine, was examined in spontaneously hypertensive and normal Wistar-Kyoto rats. Conscious, restrained, male hypertensive and normal rats (12 weeks of age) received either the non-competitive excitatory amino acid receptor antagonist, MK-801 (0.01–10 mg/kg, i.v.) or vehicle, 30 min prior to initiation of infusion of cocaine hydrochloride (1.25 mg/kg min, i.v.). Administration of MK-801 produced increases in mean blood pressure and heart rate in both hypertensive and normal rats. Resting rectal temperature was reduced by MK-801 only at the largest dose tested (10 mg/kg). Infusion of cocaine caused convulsions and death at doses of 27.8 ± 2.3 and 48.2 ± 5.7 mg/kg, respectively in the normals, and 21.2 ± 2.5 (P < 0.05) and 31.1± 3.4 (P < 0.05) in the hypertensive rats. Pretreatment with MK-801 abolished the enhanced sensitivity of the hypertensive rats to the toxicity of cocaine. The doses of cocaine required to cause death were significantly increased, in the hypertensive rats at doses 0.05 mg/kg, an effect which was not evident, at any dose, in the normals. The maximally effective dose of MK-801 (0.5 mg/kg) increased the dose of cocaine required to cause lethality by 272% (P < 0.05) in the hypertensive rats; the increase produced by MK-801 in the normals (163%) was not significant. Cocaine-induced convulsions were abolished in both hypertensive and control rats with doses of MK-801 >0.1 mg/kg. Progressively developing hypotensive and bradycardiac effects were noted during infusion of cocaine in hypertensive and control rats, pretreated with MK-801. The drug MK-801 was an effective antagonist of cocaine-induced convulsions in both hypertensive and normal rats but protected against cocaine-induced lethality only in the hypertensive rats.     

Effects of competitive and non-competitive NMDA receptor antagonists on dopamine output in the shell and core subdivisions of the nucleus accumbens

The effects of acute intravenous administration of the non-competitive NMDA receptor antagonists, phencyclidine (PCP), dizocilpine (MK-801; (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,b)cyclohepten-5,10-imine), and the competitive NMDA receptor antagonist CGP 39551 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) on extracellular dopamine concentrations were analyzed in the shell and core subdivisions of the nucleus accumbens (NAC), associated with limbic and motor functions, respectively. Extracellular dopamine concentrations were assessed utilizing differential normal pulse voltammetry in chloral hydrate anesthetized, pargyline pretreated rats. Intravenous administration of PCP (0.5 mg/kg) or MK-801 (0.1 mg/kg) both significantly elevated extracellular dopamine levels in the NAC shell but not in the core. However, administration of relatively low doses of the competitive NMDA receptor antagonist CGP 39551 (2.5 mg/kg) failed to affect dopamine output in either region. However, when a higher dose (10 mg/kg) was administered a significant elevation in dopamine output was obtained in the shell compared to the core. Our data demonstrate that non-competitive NMDA receptor antagonists evoke an accumbal dopamine output that is selective to limbic cortical related NAC regions. This profile is shared also by competitive NMDA receptor antagonists when given in high, but not low doses. Our results are compatible with the reported elicitation of PCP-like behavioral effects by competitive NMDA receptor antagonists when administered in relatively high doses. Moreover, these findings suggest that differences in the regional accumbal dopamine output between competitive and non-competitive NMDA receptor antagonists may be essentially attributable to the relative degree of NMDA receptor antagonism achieved by the drugs. This experimental model may afford a biochemical means to assess the psychotomimetic liability of NMDA receptor antagonists, a side effect that may reduce their usefulness as neuroprotective agents.     

Are glycineB sites involved in the development of morphine tolerance?

Numerous data have indicated that competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists attenuate the development of tolerance to the analgesic effect of morphine. This study extends these findings on the effects of glycine(B) site antagonist, L-701.324. Tolerance to the analgesic effect of morphine was measured in hot-plate test in Wistar rats. For 9 days, animals were first injected with vehicle or glycine(B) receptor antagonist, L-701.324 (2.5 and 5 mg/kg, po). The non-competitive NMDA receptor antagonist, MK-801 (0.05 or 0.1 mg/kg, ip) was used as a reference compound. The injection of L-701.324, MK-801 or saline was followed, 20 min later, by the injection of morphine (10 mg/kg, sc). Hot-plate latencies were determined 20 min after the second injection on odd-numbered days. The results indicated that chronic administration of glycine(B) site antagonist, L-701.324 decreased the analgesic effect of morphine and they may suggest that this substance at both used doses increased the development of morphine tolerance, whereas non-competitive NMDA antagonist, MK-801 at the dose of 0.1 mg/kg potentiated the analgesic effect of morphine and attenuated the development of morphine tolerance.     

In vivo labelling of the NMDA receptor channel complex by [3H]MK-801

An in vivo radioligand binding assay for the N-methyl-D-aspartate (NMDA) receptor channel complex in the mouse brain has been developed using the non-competitive NMDA receptor antagonist [3H]MK-801. In vivo binding of [3H]MK-801 was displaced by MK-801 (ED50 = 0.17 mg/kg i.p.), (-)-MK-801 (1.0 mg/kg), thienylcyclohexylpiperidine (1.8 mg/kg), etoxadrol (5.1 mg/kg) and (+)-SKF 10,047 (34.5 mg/kg). The potency of these drugs in this in vivo binding assay was highly correlated (r = 0.97) with their functional effects as antagonists of N-methyl-DL-aspartate-induced tonic convulsions.     

Effects of N-methyl-D-aspartate antagonists on the cough reflex

The effects of antagonists of N-methyl-D-aspartate (NMDA) on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i. cist.) injection of MK-801, a non-competitive antagonist of NMDA, significantly decreased the number of coughs in a dose-dependent manner. The competitive antagonists of NMDA, 2-DL-amino-5-phosphonovalerate and 2-DL-amino-7-phosphonoheptanoate, also decreased the number of coughs after i. cist. injection. The antitussive potencies of both the competitive and non-competitive antagonists were similar to that of dextromethorphan. Intraperitoneal injection of MK-801 also decreased the number of coughs in a dose-dependent manner. These data suggest that excitatory amino acid neurotransmitters and NMDA receptors may be involved in the regulation of the cough reflex.     

On the interactions between antimuscarinic atropine and NMDA receptor antagonists in anticholinesterase-treated mice

Both organophosphate (OP) and carbamate pesticides may produce seizures and death commonly attributed to the inhibition of acetylcholinesterase (AChE) and subsequent excess of acetylcholine (ACh). The anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) receptor antagonists in animals encouraged us to investigate their effects on the toxic and convulsant properties of OP and carbamate pesticides. Adult Swiss mice were systemically injected with the OP pesticide, chlorfenvinphos (CVP), or the carbamate pesticide, methomyl (MET). Both CVP and MET induced dose-dependent seizure activity and death in mice. Pretreatment with the muscarinic antagonist, atropine (ATR), at a dose of 1.8 mg/kg did not prevent seizures but decreased the lethal effects of CVP and MET. Pretreatment with the NMDA antagonists, dizocilpine (MK-801) at a dose of 1 mg/kg or 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at a dose of 10 mg/kg, influenced neither MET-induced seizures nor CVP- or MET-induced death. However, both MK-801 and CPP blocked CVP-induced seizures. Concurrent administration of ATR and the NMDA antagonists prevented seizures produced by CVP, but not those produced by MET. Nevertheless, both MK801 and CPP coadministered with ATR markedly enhanced its antilethal effects in CVP- and MET-intoxicated mice. The antidotes had no influence upon brain AChE activities in mice treated with saline or CVP or MET. It seems that combined treatment with ATR and NMDA receptor antagonists might be of clinical relevance.     

beta-Adrenoceptor blockade enhances the anticonvulsant effect of glutamate receptor antagonists against maximal electroshock.

In this study, we evaluated whether beta-adrenoceptor antagonists may modify the protective efficacy of dizocilpine (MK-801), a NMDA receptor antagonist, and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a non-NMDA (AMPA/kainate) receptor antagonist, against maximal electroshock-induced seizures in mice. Propranolol, acebutolol, metoprolol and atenolol were used in doses that did not alter the electroconvulsive threshold. Propranolol potentiated the anticonvulsant activity of MK-801 and GYKI 52466, significantly lowering their ED(50) values from 0.38 and 15.0 to 0.15 (P<0.001) and 8.4 mg/kg (P<0.001), respectively. Similarly, metoprolol lowered the ED(50) of MK-801 and GYKI 52466 from 0.38 and 15.0 to 0.17 (P<0.05) and 11.2 mg/kg (P<0.05). Acebutolol enhanced the protective action of GYKI 52466, lowering its ED(50) value from 15.0 to 12.2 mg/kg (P<0.05), but not that of MK-801. Atenolol, not penetrating the blood-brain barrier, did not affect the anticonvulsive efficacy of MK-801 and GYKI 52466. In conclusion, beta-adrenoceptor antagonists may act synergistically with excitatory amino acid receptor antagonists to inhibit generalised tonic-clonic seizures.