Biomedical subjects

W Danysz

Publications and source records attributed to W Danysz.

At least 91 records · Page 5Linked to original sources

PubMed1996

Infusion of (+) -MK-801 and memantine -- contrasting effects on radial maze learning in rats with entorhinal cortex lesion.

(+)-5-Methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801) and 1-amino-3,5-dimethyladamantane (memantine), two uncompetitive antagonists of the NMDA receptor were tested in an allocentric version of the radial maze test (with four out of eight arms reinforced) both in normal rats and after quinolinic acid-induced entorhinal cortex lesions. Both agents were infused s.c. using Alzet osmotic minipumps in order to assure steady state drug levels in the serum and brain during the experiment. In non-lesioned rats, (+)-MK-801 (0.312 mg/kg per day) produced disturbances in learning of spatial information dependent on reference memory but not that involving working memory. In contrast, memantine (20 mg/kg per day) had no effect in normal rats. In rats with entorhinal cortex lesions, (+)-MK-801 enhanced the lesion-induced deficit in reference memory. In contrast, memantine reversed the lesion-induced increase in reference memory errors. The divergent effects of those two uncompetitive NMDA receptor antagonists could, at least partially, be due to the differences reported in their channel blocking kinetics and voltage dependence. The results indicate that under conditions of pathological impairment of brain structures such as entorhinal cortex lesion, memantine might produce beneficial effects on cognitive functions.

Animals↗

PubMed1996

Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine.

The NMDA receptor agonist quinolinic acid (9 mM) was infused i.c.v. via ALZET osmotic minipumps for 2 weeks. This treatment produced a persistent, short-term memory deficit in the T-maze. Autoradiography revealed a decrease in the density of choline uptake sites in the hippocampus. Parallel s.c. infusion by another minipump of the uncompetitive NMDA receptor antagonist memantine (1-amino-3,5-dimethyladamantane, 20 mg/kg per day) or (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, 0.31 mg/kg day) prevented the learning deterioration induced by quinolinic acid. The treatment with memantine resulted in steady-state serum levels of 1.2 mu M which, based on in vitro data, should assure inhibition of NMDA receptors and are similar to levels seen in the serum of demented patients treated with this agent. In naive animals this treatment had no effect on either learning or on ex vivo induction of long-term potentiation, indicating that under chronic conditions it is possible to obtain neuroprotective effects with NMDA receptor antagonists without negative effects on memory processes. This contrasts to some acute insults (e.g. ischaemia) where high doses of NMDA receptor antagonists that produce side effects are required.

Analysis of Variance↗

PubMed1996

Subchronic intraventricular infusion of quinolinic acid produces working memory impairment--a model of progressive excitotoxicity.

It has been proposed by Yamada et al. [Neurosci. Lett. 118: 128-131 (1990); J. Pharmacobiodyn. 14: 351-355 (1991)] that subchronic i.c.v. infusion of the NMDA receptor agonist quinolinic acid may serve as a model for some aspects of neurodegenerative dementia. In the present study, quinolinic acid (9 mM) was infused i.c.v. by ALZET osmotic minipumps for 2 weeks. This treatment produced a short-term working memory deficit in the T-maze (alternation) but no change in reversal learning in the same test. The working memory deficit in the T-maze was progressive i.e. seen after 14, but not 3 days of infusion and persisted for at least for 3 weeks after the termination of the infusion. Histological examination revealed a modest decrease in the number of cells in the nucleus basalis magnocellularis but not in the striatum, entorhinal cortex, or hippocampus. However, in most of the structures studied, morphological changes such as swollen somata and irregular shape were observed indicative of alterations in neuronal function. Autoradiography in the hippocampus revealed a decrease in [3H]hemicholinium and [3H]quinuclidinyl benzilate (QNB) binding to choline uptake sites and muscarinic receptors respectively. Surprisingly no change was observed in [3H]MK-801 binding to NMDA receptor channels in the hippocampus and cortex. The subchronic infusion of quinolinic acid may serve as a model of progressive deterioration of cognitive functions.

Alzheimer Disease↗

PubMed1996

Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats.

Chronic treatment of adult male F-344 rats (9-12 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for > 8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses recorded in the fascia dentata in vivo. In contrast, there was no effect of memantine on baseline synaptic responses or population spikes. Likewise, short-term exploratory modulation of these hippocampal evoked responses was not different between memantine-treated and control rats. Both groups of rats were able to learn the spatial version of the Morris water task equally well, but the memantine-treated group showed a strong tendency to show more selective spatial search patterns in the training quadrant of the water pool during a final probe trial. As such, these studies provide the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provide preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients.

Animals↗

PubMed1996

Concanavalin A enhances quisqualate-induced calcium influx in cerebellar granule cells in culture.

In primary cultures of cerebellar granule cells kainate produced marked influx of 45Ca2+, partially sensitive to the N-methyl-D-aspartate (NMDA) antagonist, 3-(+/-)-2-carboxypiperazin-4-yl)- propyl-1-phosphonic acid (CPP), indicating involvement of an NMDA receptor-sensitive component that may be secondary to kainate-induced glutamate release. Sodium removal partially inhibited kainate's effect. Quisqualate also produced influx of 45Ca2+, but with lower efficacy and higher potency than kainate. This action of quisqualate was unaffected by CPP and by sodium removal. Preincubation of cells with the plant lectin concanavalin A (Con A), but not with its succinyl derivative, enhanced quisqualate-induced calcium influx, and to a lesser extent kainate's effect. Inclusion of quisqualate in preincubation medium antagonized Con A potentiation of quisqualate response. Also Con A was ineffective when included in the incubation medium only, without preincubation. Preincubation of rat brain cortical membranes with Con A but not with succinyl Con A increased the binding of the AMPA receptor agonist, [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA). The results suggest that Con A enhancement of quisqualate response possibly involves the modification of an AMPA recognition site and requires preincubation in the absence of an agonist (here quisqualate).

Animals↗

PubMed1995

MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis.

The activation of glutamate receptors by endogenuous glutamate has been implicated in the processes that underlie cell loss associated with ischemia and trauma and in the development of some neurodegenerative diseases. The antagonism of NMDA-sensitive glutamate receptors may therefore have therapeutic applications. The present study compared the side effects and neuroprotective potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5-dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly into the nucleus basalis magnocellularis of rats. Each drug significantly attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50 for the side effects observed, including ataxia, myorelaxation and stereotypy, and the ED50 for neuroprotective ability, was highest for memantine and the lowest for (+)-MK-801. The results suggest that a potential neuroprotective action of NMDA receptor antagonists, memantine and amantadine in particular, can be seen at low doses lacking side effects.

Amantadine↗

PubMed1995

Chronic treatment with the uncompetitive NMDA receptor antagonist memantine influences the polyamine and glycine binding sites of the NMDA receptor complex in aged rats.

Receptor binding studies on rat cortical membranes were used to characterize the NMDA receptor in aged rats (22 months) treated for 20 months with a memantine containing diet delivering 30 mg/kg/day in comparison to aged and young/adult rats treated with control-diet. Spatial memory impairing effects of (+)-MK-801 (0.16 mg/kg) in the radial maze was not altered within the course of memantine-treatment (up to 16 months). However, chronic memantine-treatment significantly increased the number of [3H]MK-801 binding sites and the affinity of [3H]glycine. A non-significant trend to such changes was also seen in aged-control rats. Glycine-dependent [3H]MK-801 binding (functional binding under non-equilibrium conditions at a fixed L-glutamate concentration) revealed that a decreased ability of glycine to stimulate channel opening in aged rats was partially attenuated by the long-term memantine treatment. Furthermore, an increased ability of spermidine to enhance [3H]MK-801 binding in aged-control rats was even more pronounced in the aged memantine-treated group. Together these findings may indicate that changes in functional receptor-channel properties during the process of aging occur prior to a detectable loss of binding sites and that memantine enhances an endogenous compensatory mechanism triggered by glutamatergic hypofunction which is suggested to take place in aging.

Aging↗

PubMed1995

Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats.

Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and alpha-methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.

Animals↗

PubMed1995

Different binding affinities of NMDA receptor channel blockers in various brain regions--indication of NMDA receptor heterogeneity.

The N-methyl-D-aspartate (NMDA) receptor-channel complex exists in multiple forms which probably have different physiological and pharmacological properties. To further evaluate this concept of different NMDA receptor subtypes, receptor binding and autoradiographic techniques were used to study the phencyclidine (PCP) binding site of the NMDA receptor ion-channel complex. [3H]MK-801 was employed to characterize binding properties of (+)-MK-801, (-)-MK-801, phencyclidine (PCP), (+/-)-ketamine, amantadine (1-amino-adamantane) and memantine (3,5-dimethyl-1-amino-adamantane) in different brain regions. Saturation experiments on homogenized membranes revealed the existence of single classes of binding sites in cortex and cerebellum but with significant different affinities between these regions (KD/Cortex = 4.59 nM, Bmax/Cortex = 0.836 pmol/mg protein; KD/Cereb. = 25.99 nM, Bmax/Cereb. = 0.573 pmol/mg protein) suggesting that the lower affinity in cerebellum indicates another population of NMDA receptor channels. In contrast, in striatum there was clear evidence for two binding sites (KD/high = 1.43 nM, Bmax/high = 0.272 pmol/mg protein; KD/low = 12.15 nM, Bmax/low = 1.76 pmol/mg protein). Displacement studies (autoradiography and binding) revealed a lower affinity for unlabeled (+)-MK-801 in striatum which was clearly not the case for memantine. In cerebellar membranes there was a significant decrease in the affinity for both MK-801 enantiomers and PCP but not for the 1-amino-adamantanes. In contrast, all compounds showed lowered affinity in the dentate gyrus. These findings support NMDA receptor heterogeneity which may be of particular relevance for the development of subtype-selective drugs.

Animals↗

PubMed1995

Therapeutic brain concentration of the NMDA receptor antagonist amantadine.

Amantadine (1-amino-adamantane) is clinically used for the management of Parkinson's disease and drug-induced extrapyramidal symptoms. It has previously been shown that amantadine is a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with rapid blocking and unblocking channel kinetics (Ki-value at the PCP binding site = 10 microM). The aim of the present studies was to estimate concentrations of amantadine in the central nervous system under therapeutic conditions. In homogenates of postmortem human brain tissue the amantadine concentration appeared to be homogeneously distributed over a wide range of brain areas. Amantadine concentration increased with duration of treatment and decreased wit drug-free time. When the duration of treatment was > or = 10 days and drug-free time < or = 3 days, mean amantadine concentrations in postmortem brain tissue ranged from 48.2 to 386 microM. In contrast to brain tissue, amantadine concentration in cerebrospinal fluid (CSF) and serum was in the low micromolar range ( < 17 microM). CSF and serum total values were highly correlated to each other and were always lower in CSF. The mean CSF/serum ratio for total amantadine was 0.76. To further estimate the extracellular concentration, amantadine was determined in microdialysates in the rat striatum. At behaviorally active doses, amantadine concentration in striatal microdialysates ranged between 6 and 21 microM. These results indicate that extracellular concentrations of amantadine (CSF and serum values in patients, striatal microdialysates in the rat) are in the range of its Ki-value at the PCP binding site. Amantadine concentrations in brain tissue are much higher, probably due to intralysosomal accumulation.

Aged↗

PubMed1995

Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo.

The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics (Koff, r = 0.904). Although, onset kinetics as assessed by Kon were not correlated to potency (r = 0.023), tau on estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency (r = -0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [3H](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED50 rotarod and traction reflex over ED50 in MES-induced convulsions; TI = 2-4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 (TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices (TI < or = 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED50 in the MES test was negatively-correlated to therapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.

Amantadine↗

PubMed1995

Microdialysis studies with amantadine and memantine on pharmacokinetics and effects on dopamine turnover.

Amantadine and memantine are in clinical use for the treatment of neurodegenerative diseases such as M. Parkinson and dementia syndrome. In order to contribute to the understanding of the interaction of these uncompetitive NMDA-antagonists with the dopaminergic system in the striatum, the pharmacokinetics and the effects of amantadine and memantine on the dopaminergic system were examined in a microdialysis study in anaesthetized rats. Both substances achieved extracellular fluid concentrations in the striatum known to block NMDA receptors, supporting the assumption that NMDA receptor antagonism is their primary mechanism of action. Both, memantine, and to a lesser degree, amantadine induce a modest dopamine overflow not paralleled by HVA or DOPAC. The small increase in dopamine overflow cannot add substantially to the drugs' action and may be generated indirectly via their NMDA-antagonistic properties.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat.

The present study investigated the specific ways by which cytotoxicity due to glutamate receptor stimulation could be attenuated by the administration of agonists and antagonists of the ionotropic and metabotropic glutamate receptors within the nucleus basalis magnocellularis (NBM) of rats as measured by cortical choline acetyltransferase activity. The results of these studies suggest that (1) the cytotoxicity of ibotenate to NBM cholinergic cells is not dependent upon stimulation of metabotropic glutamate receptors, but results from activation of N-methyl-D-aspartate (NMDA) receptors, (2) the cytotoxicity of quisqualate to cholinergic cells within the NBM is not dependent upon stimulation of NMDA or metabotropic receptors, and (3) the cytotoxicity of NMDA was prevented by administration (i.p.) of the un-competitive NMDA antagonist memantine (30 mg/kg), resulting in plasma levels of 2.5 micrograms/ml, a concentration known to block efficiently NMDA receptors in vitro. Finally, performance of a food-motivated, delayed-alternation task on a T-maze was impaired by injections of NMDA into the NBM, but was prevented by co-administration of NMDA with memantine.

Acetylcholine↗

PubMed1994

Glycine site antagonists abolish dopamine D2 but not D1 receptor mediated catalepsy in rats.

Catalepsy--a state of postural immobility (akinesia) with muscular rigidity (rigor)--and reduced locomotion in animals are behavioral deficits showing similarities with symptoms of Parkinson's disease (PD). The effects of the glycine site antagonists 7-chlorokynurenate and (R)-HA-966 on haloperidol-(D 2 antagonist) and SCH 23390- (D 1 antagonist) induced catalepsy and reduced locomotion are investigated in rats. Both antagonists dose-dependently counteract dopamine D 2 receptor mediated catalepsy but they have no influence on locomotion. Neither 7-chlorokynurenate nor (R)-HA-966 has any effect on dopamine D 1 receptor mediated catalepsy. This finding is surprising, since NMDA receptor antagonists counteract both, dopamine D 1 and D 2 receptor mediated catalepsy. D 1 and D 2 receptors are located on different populations of neurons. Thus, the present findings suggest that these different neuronal populations have different sensitivity for ligands binding at the glycine binding site of the NMDA receptor.

Animals↗

PubMed1994

Memantine, amantadine, and L-deprenyl potentiate the action of L-dopa in monoamine-depleted rats.

Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.

Amantadine↗

PubMed1994

Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?--case of amantadine and memantine.

Amantadine (25, 50, 100 mg/kg), memantine (5, 10, 20 mg/kg) and MK-801 (0.05, 0.1, 0.2 mg/kg), all having NMDA channel blocking properties, were compared in three tests used for screening of antiparkinsonian agents in rats, namely: haloperidol-induced catalepsy, locomotor activity in monoamine depleted rats and rotation in rats with a unilateral substantia nigra lesion. Additionally, plasma levels of amantadine and memantine were assessed to gain an insight into the concentration ranges achieved at behaviorally active doses. Amantadine and (+)-MK-801 produced dose-dependent inhibition of haloperidol-induced catalepsy while memantine was less efficacious producing clear-cut anticataleptic action at a dose of 10 mg/kg only but failing at 20 mg/kg due to myorelaxant activity. All agents attenuated sedation in monoamine depleted rats with amantadine being the least and MK-801 being the most effective. The same rank order of efficacy was seen in inducing ipsilateral rotations in rats after a substantia nigra lesion. On the basis of the present study and published data, it can be assumed that the doses of amantadine, memantine and MK-801 showing antiparkinsonian-like activity in animals result in plasma levels leading to NMDA antagonism. However, in the haloperidol-induced catalepsy test the efficacy of amantadine was higher than memantine, while the opposite was true for rotation and reserpine-induced sedation indicating pharmacodynamic differences between both agents.

Amantadine↗

PubMed1994

Glutamate antagonists have different effects on spontaneous locomotor activity in rats.

Locomotor activity, ataxia, and stereotypy were assessed in the open field after administration of NMDA and AMPA antagonists acting by different mechanisms. The interaction with glutamatergic receptors was confirmed in the binding assay. (+)MK-801 and phencyclidine (PCP) produced similar changes in horizontal activity, i.e., a strong increase from the beginning of the test. Ketamine, and to a lesser extent, memantine, enhanced horizontal activity at the later observation periods only. Amantadine and NBQX produced a slight inhibition, while GYKI-52466, d-cycloserine, (+R)-HA-966, CGP-37849, and dextromethorphan were ineffective. Vertical activity (rearings) were inhibited by most agents except GYKI-52466 and gly-B partial agonists. At higher doses ataxia was seen after: MK-801, PCP, ketamine, memantine, amantadine, CGP-37849, dextromethorphan, and GYKI-52466. Hence, the inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.

Amphetamine↗

PubMed1993

Effect of glutamate receptor antagonists on N-methyl-D-aspartate- and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced convulsant effects in mice and rats.

Selected antagonists of N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, acting through different recognition sites were studied in three in vivo experimental procedures: systemic administration of NMDA or AMPA to mice and 7-day-old rats or i.c.v. injection in adult rats. Antagonists were given i.p. before the agonists. Of the substances tested (+)-5-methyl-10,11- dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, an uncompetitive NMDA receptor antagonist) and DL-(E)-2-amino-4-methyl-5- phosphono-3-pentanoic acid (CGP-37849, a competitive NMDA receptor antagonist) were the most potent and selective NMDA receptor antagonists, having ED50s below 1 mg/kg in all three tests. 1-Amino-3,5-dimethyladamantane (memantine, an uncompetitive NMDA receptor antagonist) was less potent and, additionally, inhibited AMPA-induced seizures in adult rats. Aminocyclopropane carboxylic acid--a partial agonist at the glycine site coupled to NMDA receptors (GlyB)--was a weak antagonist (ED50 > 150 mg/kg) in mice. Other partial GlyB receptor agonists, aminocyclobutane carboxylic acid, (+,R)-3-amino-1-hydroxy-2-pyrrolidine ((+,R)-HA-966) and d-cycloserine, and antagonists, 5,7-dinitroquinoxaline-2,3-dione (MNQX) and 5,7-dichlorokynurenic acid, were ineffective in mice after systemic administration. The last two agents however were active in adult rats when given i.c.v. Thus affinity, intrinsic activity (GlyB receptor partial agonists) and/or penetration into the brain (GlyB receptor antagonists) seem to be important factors in determining the effectiveness of these agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗