Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats

NMDA receptor antagonists have been reported to affect learned behaviors conditioned with abused drugs, with the outcome dependent, in part, on the class of NMDA receptor antagonist used. The present study tested the ability of various site-selective NMDA receptor antagonists to modify cocaine-conditioned motor activity. Two procedures were used for independently assessing drug effects on spontaneous activity and expression of cocaine-conditioned behavior. In the conditioning experiments, rats were administered i.p. injections of cocaine (30 mg/kg) or saline paired with distinctive environments. Spontaneous horizontal activity was dose-dependently enhanced by dizocilpine (0.03-0.3 mg/kg) and memantine (1-30 mg/kg), but not by D-CPPene (3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494; 1-10 mg/kg), ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2, 3-quinoxalinedione; 3-56 mg/kg), or eliprodil (3-30 mg/kg). Higher doses of memantine, D-CPPene (1-10 mg/kg), eliprodil (3-30 mg/kg), or ACEA-1021 reduced vertical activity. Following five cocaine-environment pairings, rats displayed significant increases in motor activity when exposed to the cocaine-paired environment. The following antagonists were administered prior to the conditioning test: dizocilpine (MK-801; 0.03-0.1 mg/kg), memantine (1-10 mg/kg), D-CPPene (0.3-3 mg/kg), ACEA-1021 (3-10 mg/kg), and eliprodil (1-10 mg/kg). Of these, memantine, ACEA-1021 and, to the lesser degree, eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity. These results show that cocaine-conditioned behaviors can be selectively modulated by some, but not all, NMDA receptor antagonists.     

Cortical epileptic afterdischarges in immature rats are differently influenced by NMDA receptor antagonists

Linopirdine was developed as a cognitive enhancing molecule and demonstrated to specifically block the potassium current generated by the brain specific KCNQ2-KCNQ3 proteins (M-channel). In this study we investigated the relevance of [(3)H]linopirdine binding in rat brain extracts to the interaction with the M-channel proteins. Our results confirm the presence of a high affinity site for [(3)H]linopirdine in rat brain tissues (KD = 10 nM) but we also identified a high affinity binding site for [(3)H]linopirdine in rat liver tissues (KD = 9 nM). Competition experiments showed that [(3)H]linopirdine is displaced by unlabelled linopirdine with comparable affinities from its binding sites on rat brain and rat liver membranes. [(3)H]linopirdine was completely displaced by a set of cytochrome P450 (CYP450) ligands suggesting that [(3)H]linopirdine binding to rat brain and liver membranes is linked to CYP450 interaction. The testing of CYP450 ligands on the M-channel activity, using a Rb(+) efflux assay on cells expressing the KCNQ2-KCNQ3 proteins, demonstrated that [(3)H]linopirdine binding results cannot be correlated to M-channel inhibition. The results obtained in this study demonstrate that [(3)H]linopirdine binding to rat brain and rat liver membranes is representative for CYP450 interaction and not relevant for the binding to the M-channel proteins.     

The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent,orally-active anticonvulsants in rodents

Summary Anticonvulsant properties of CGP 37849 and CGP 39551, two novel phosphono-amino acids which are competitive NMDA receptor antagonists, were examined in rodents. At optimal pretreatment times CGP 37849 suppressed electroshock-induced seizures in mice and rats with ED₅₀ ^s ranging from 8 to 22 mg/kg after oral administration, and 0.4 to 2.4 mg/kg after i. v. and i. p. injection. Relative to CGP 37849, CGP 39551 was more potent after p. o. (ED₅₀ 3.7–8.1 mg/kg), and less potent after i.v. or i.p. treatment (ED₅₀ 2.7–8.7 mg/kg). Following oral treatment, the duration of action of CGP 37849 was about 8 h, while CGP 39551 still showed good activity after 24 h (ED₅₀ 8.7 mg/kg, mouse; 21 mg/kg, rat). Both compounds were anticonvulsant at doses below those at which overt behavioural side effects were apparent. CGP 39551 delayed the development of kindling in rats at doses of 10 mg/kg p. o. and above, and showed weak anticonvulsant activity against pentylenetetrazolevoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anticonvulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man. Send offprint requests to M. Schmutz at the above address     

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.     

Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice

The effects of NMDA antagonists on passive avoidance learning, shock sensitivity and locomotor activity were examined. Pre-training administration of the antagonists 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) in mice and rats resulted in impaired performance in a retention test 24 h later. No such impairment resulted from immediate post-training administration of either compound in either species. In addition neither compound, given only before the retention test, reduced the retention latencies of mice. In rats CPP was similarly ineffective whereas MK-801 reduced retention latencies, but only at a dose which significantly elevated locomotor activity at the time of the retention test. As assessed by vocalization threshold in mice and by the proportion of animals vocalizing in response to the passive avoidance training shock, neither compound produced analgesia. The vocalization threshold was, in fact, slightly reduced by both compounds. MK-801, but not CPP, stimulated locomotor activity in mice. These results indicate that in the passive avoidance task activation of NMDA receptors is involved in memory formation, but is not critical for the maintenance of memory or its retrieval.     

The effect of NMDA receptor antagonists on the neuroleptics-induced catalepsy in mice

The effect of non-competitive (MK-801:/+/-5-methy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate) and competitive (CGP 37849: DL-/E/-2-amino-4-methyl-5-phosphono-3-pentenoic acid) NMDA receptor antagonists on the catalepsy induced by neuroleptics in mice was studied. MK-801 and CGP 37849 antagonized the catalepsy induced by haloperidol, spiperone and fluphenazine. (+)-Cycloserine, a partial glycine agonist, reversed the anticataleptic effect of CGP 37849, but not that of MK-801. The above results indicate that the anticataleptic activity of both these NMDA receptor antagonists is induced by an indirect activation of the dopamine system. The results provide further evidence that competitive NMDA receptor antagonists may be a new class of antiparkinsonian drugs.     

选择性N-甲基-D-天门冬氨酸受体NR2B亚型阻滞剂的研究进展

选择性N-甲基-D-天门冬氨酸受体NR2B亚型阻滞剂近年来受到了越来越多的关注。目前，已报道的NR2B亚型阻滞剂的结构类型绝大多数仍为艾芬地尔发展而来的哌啶衍生物，另外还有酰胺、脒、氨基喹啉等结构类型；NR2B亚型阻滞剂在神经元保护、镇痛、抗药物依赖、抗帕金森病等方面表现了潜力。现根据不同结构类型综述NR2B亚型阻滞剂的结构及药理活性，并探讨其毒副作用较低的可能原因和临床应用潜力。     

NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats

Antagonists at the N-methyl- -aspartate (NMDA) sub-type of glutamate receptor are purported to have detrimental effects on cognitive processes. In order to examine the site selectivity of these effects, phencycline (PCP), dizocilpine, and memantine (PCP-site antagonists), SDZEAA 494 and NPC17742 (competitive NMDA antagonists), ACEA 1021 (glycine-site antagonist), and eliprodil (NR2B-selective polyamine-site selective antagonist) were tested in rats performing a delayed nonmatch-to-sample task. Dizocilpine, PCP and memantine significantly decreased accuracy and discriminability, particularly during brief delay trials. In contrast, the competitive NMDA antagonists, SDZ EAA 494 and NPC 17742, did not affect accuracy or discriminability at any delay. Similarly, ACEA 1021, and eliprodil did not alter behavioral indices in a manner suggesting compromise in information processing at any delay even at doses that decreased the total number of trials completed. These data support previous findings that the effects of NMDA antagonists on accuracy are site-selective, with PCP-site antagonists producing the greatest disruption. Further, while not conclusive, the results are consistent with the hypothesis that NMDA receptor-mediated neurotransmission may be important at early stages of information processing, although further research is necessary to confirm these latter observations.     

Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats

Rationale Antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists.Objective The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle.Methods Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03–0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1–10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075–0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1–3 mg/kg, s.c.) and MRZ 2/621 (0.3–10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3–10 mg/kg, i.p.).Results In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED₅₀=0.67 mg/kg) and MRZ 2/621 (ED₅₀=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose–response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding.Conclusions NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.     

Affinity and specificity of <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats

Abstract Rationale. Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl-D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. Objectives. The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. Methods. Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. Results. As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. Conclusions. These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients). Electronic Publication     

The competitive NMDA antagonists CGP 43487 and APV potentiate dopaminergic function

The administration to rats of different doses of the non competitive NMDA receptor blocker MK-801 (0.03–1 mg/kg IP) induced stimulation or reduction of locomotor activity, depending on the dose, whereas the competitive NMDA antagonists CGP 43487 (0.188–6 mg/kg IP) and APV (2.5–20 g/rat ICV) inhibited locomotion at the highest doses. Unlike MK-801 and APV treatment, the administration of CGP 43487 did not induce impairment of rota-rod test performance. Both competitive and non-competitive NMDA antagonists, at doses devoid of any behavioral effect per se, potentiated the responses elicited by apomorphine (0.25 mg/kg SC). In particular, the occurrence of episodes of licking was weakly affected by MK-801 administration, but significantly increased by CGP 43487 and APV treatment; the presence of gnawing was augmented by all the pretreatments; sniffing, locomotion, grooming and rearing occurrence were not affected by the administration of NMDA antagonists. The results suggest that the competitive antagonists which facilitated dopaminergic function without causing motor impairment could be useful supplements in the treatment of Parkinson's disease.     

Therapeutic potential of NMDA receptor antagonists in the treatment of alcohol and substance use disorders

Despite the fact that the use of alcohol, nicotine and other drugs is the major external factor contributing to mortality in industrialised countries, there are few medications available to treat alcohol and substance use disorders. In recent years, major advances have been made in the understanding of the neurobiological basis for these disorders and these advances should lead to the development of new pharmacotherapeutics. A substantial amount of the research suggests that N-methyl-D-aspartate (NMDA) receptor neurotransmission contributes to mediating the behavioural effects of alcohol and other drugs of abuse. This research supports the therapeutic potential of NMDA receptor antagonists in alcohol and substance use disorders. In this paper the authors present their opinion on the goals and stages of pharmacological treatment of these complex psychiatric disorders. Available preclinical research using designs that model aspects of alcohol and substance use disorders is summarised, with an emphasis on research published in the last two years. In animal models, NMDA antagonists inhibit physical dependence and the reinforcing effects of a variety of abused substances. The ability of NMDA antagonists to inhibit tolerance to drug effects and contribute possible antidepressant and anxiolytic effects are also important from the perspective of drug development. This review summarises the relevant clinical laboratory and treatment data. Finally, it presents the status of the current development of NMDA receptor antagonists and discusses candidates with the greatest potential for clinical development.     

Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice

 Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine. Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17 mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency of dizocilpine>TCP>(–)-MK-801>SKF 10,047>dextrorphan>PCP. There was a positive correlation between the potencies of the compounds that substituted for dizocilpine and their previously reported affinities for the [³H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex, including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil, failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABA_A receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers, the competitive NMDA antagonists, CGS 19755, NPC 17742, (±)CPP and LY 233536 dose-dependently substituted for dizocilpine. The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in the behavioral and subjective profiles of competitive and non-competitive NMDA blockers. Received: 29 October 1996 / Final version: 9 April 1997     

A matching law analysis of the effects of dopamine receptor antagonists

Herrnstein's matching equation was used to analyze drug effects on performance in random interval reinforcement schedules. Pimozide caused effects compatible with both motor and motivational impairments, in a 5-component multiple schedule, a 3-schedule 3-day cycle (ALT-3), and a 2-schedule 2-day cycle (ALT-2). However, at low doses, both sulpiride and SCH-23390, tested in the ALT-3 and ALT-2 procedures, caused effects compatible with selective motivational impairments. In experiments using the non-multiple schedules, motivational effects increased during the course of the experimental session, under all three drugs. The interpretation of motor and motivational deficits in the ALT-2 procedure was validated by experiments in which the response-force and deprivation level were systematically varied. The results support the view that dopamine may be involved in the maintenance of rewarded behaviour, but do not differentially implicate the D1 or the D2 receptor subtype.     

The impact of a competitive and a non-competitive NMDA receptor antagonist on dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra

The study compares effects of the competitive and non-competitive NMDA receptor antagonists, CGP 40116 and MK-801 respectively, on the metabolism of dopamine and on the density of D-1 and D-2 dopaminergic receptors in the rat ventral tegmental area and substantia nigra. The effects of CGP 40116 were tested in a range of doses which either were devoid of or had locomotor- or stereotypy-stimulating effects. It was found that (1) CGP 40116 given in a dose of 5 mg/kg enhanced the locomotor activity of rats and evoked a stereotypy-like activity; doses of 1.25 and 2.5 mg/kg were devoid of such effects; (2) CGP 40116 (5 mg/kg) enhanced the concentrations of dopamine, DOPAC and HVA in the ventral tegmental area, whereas the lowest dose, 1.25 mg/kg was without effect; a dose of 2.5 mg/kg increased the concentration of dopamine only; the only effect of CGP 40116 (5 mg/kg) observed in substantia nigra, was an increase in dopamine concentration; its doses of 1.25 and 2.5 mg/kg were ineffective. (3) MK-801 (0.2 and 0.4 mg/kg) enhanced the concentrations of dopamine, DOPAC and HVA in both structures. A dose of 0.1 mg/kg increased the dopamine concentration only. The effects of MK-801 in substantia nigra were quantitatively weaker than those observed in ventral tegmental area. (4) Both CGP 40116 (5 mg/kg) and MK-801 (0.4 mg/kg) evolved alterations in the density of dopaminergic receptors. D-2 receptors, were up-regulated by MK-801 in ventral tegmental area and subregions of substantia nigra, i.e. pars compacta and pars reticulata, whereas CGP 40116 evoked similar effects in ventral tegmental area only. D-1 receptors in pars compacta and pars reticulata of substantia nigra were down-regulated after administration of either drug.It is concluded that competitive NMDA receptor antagonists in doses which evoke hyperlocomotion and stereotypy-like activity, may have a substantial impact on the dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra, similar to that described for MK-801, a non-competitive NMDA receptor antagonist. The obtained results may suggest that CGP 40116 and, possibly, other competitive NMDA antagonists may have dopaminomimetic properties, and that their clinical potentials may be limited by the risk of evoking dopamine-dependent psychotomimetic and abusing effects, similar to those described for MK-801.     

NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats

Rationale N-Methyl-d-aspartate (NMDA) receptors have an important role in different forms of behavioral and neural plasticity. Evidence suggests that these receptors may also be involved in plasticity arising from long-term treatment with different drugs of abuse, including tolerance, sensitization, and physical dependence. There is abundant evidence demonstrating that NMDA receptors are involved in tolerance to opiate-induced antinociception; however, the role of these receptors in sensitization to the locomotor effects of opiates is more controversial. Objective The ability of NMDA receptor antagonists to modify the development of sensitization to the locomotor stimulant effect of three different opiates was examined. In selected studies, the ability of the antagonists to modify tolerance to the antinociceptive effects of the opiates was also examined. Materials and methods Adult male Sprague–Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine. It was predicted that low, selective doses of the antagonists would inhibit the development of opiate tolerance and sensitization. Results Consistent with our predictions, the noncompetitive NMDA receptor antagonists MK-801 and memantine and the competitive NMDA receptor antagonist LY235959 inhibited the development of sensitization to the locomotor stimulant effect of morphine. Additionally, MK-801 inhibited the development of tolerance and sensitization to methadone and buprenorphine in a similar manner. Conclusions The results, together with previous research, suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization.     

The adenosine receptor antagonist theophylline induces a monoamine-dependent increase of the anticataleptic effects of NMDA receptor antagonists

Previous work revealed that adenosine antagonists as theophylline reversed neuroleptic-induced catalepsy and potentiated anticataleptic effects of dopamine agonists reflecting specific adenosine-dopamine receptor interactions in the central nervous system. We tested whether similar functional interactions exist between adenosine receptors and glutamate receptors of the N-methyl-D-asparte (NMDA) subtype. The present study demonstrates that the anticataleptic effects of the competitive NMDA receptor antagonist CGP37849 and the non-competitive NMDA receptor antagonist dizocilpine can be potentiated by coadministration of a threshold dose of the adenosine receptor antagonist theophylline (2.5 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.)-pretreated rats. This potentiation was elicited only with higher doses of CGP37849 (4 and 8 mg/kg, i.p.) or dizocilpine (0.16 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.), but not in reserpine (5 mg/kg, i.p.) plus -methyl-ptyrosine (100 mg/kg, i.p.)-pretreated animals. Therefore, these synergistic interactions seem to be brought about by indirect monoamine-dependent mechanisms rather than direct functional interrelationships between NMDA and adenosine A_2a receptors.     

Behavioral effects of NMDA receptor agonists and antagonists in combination with nitric oxide-related compounds

Responding of rats was maintained under a 120-response fixed ratio (FR) schedule of food delivery, and animals received individual and combined injections of N-methyl-D-aspartic acid (NMDA), phencyclidine hydrochloride, (+)-MK-801 hydrogen maleate (MK-801), (+/-)-2-amino-5-phosphonopentanoic acid (AP5), 7-chlorokynurenic acid (7CK), ifenprodil tartrate, N(G)-nitro-L-arginine methyl ester hydorchloride (L-NAME), 7-nitroindazole, aminoguanidine hemisulfate, L-arginine, molsidomine, sodium nitroprusside, and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8). Behavioral suppression after NMDA was completely and dose-dependently reversed by MK-801, phencyclidine, AP5, and aminoguanidine; partially and dose-dependently attenuated by molsidomine, ifenprodil, and 7CK; and not attenuated at all by L-NAME, 7-nitroindazole, or TMB-8. These findings suggested that behavioral suppression after NMDA was associated with nitric oxide from the inducible synthase. In a second series of experiments, comparable behavioral suppression by 0.1 mg/kg MK-801, but not 3 mg/kg phencyclidine, was attenuated by nitroprusside, molsidomine, and L-arginine, suggesting that suppressions from MK-801 and phencyclidine were mediated by different final common pathways, and that behavioral suppression from MK-801, but not phencyclidine, may be associated with Ca(2+)-dependent nitric oxide.     

Protection of methylmercury effects on the in vivo dopamine release by NMDA receptor antagonists and nitric oxide synthase inhibitors

The possible protective effects of NMDA receptor antagonists dizocilpine (MK-801) and D(-)-2-amino-5-phosphonopentanoic acid (AP5), and nitric oxide synthase (NOS) inhibitors L-nitro-arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on the methylmercury (MeHg)-induced dopamine (DA) release from rat striatum were investigated using in vivo microdialysis. Intrastriatal infusion of 400 microM or 4 mM MeHg increased the extracellular DA levels to 1941+/-199 and 7971+/-534% with respect to basal levels. Infusion of 400 microM or 4 mM MeHg in 400 microM MK-801 pretreated animals, increased striatal DA levels to 677+/-126 and 2926+/-254%, with respect to basal levels, these increases being 65 and 63% smaller than those induced by MeHg in non-pretreated animals. Infusion of 400 microM or 4 mM MeHg in 400 microM AP5 pretreated animals, increased striatal DA levels to 950+/-234 and 2251+/-254% with respect to basal levels, these increases being 51 and 72% smaller than those induced by MeHg in non-pretreated animals. Infusion of 400 microM MeHg in 100 microM L-NAME or 7-NI pretreated animals, increased the extracellular DA levels to 1159+/-90 and 981+/-292%, with respect to basal levels, these increases being 40 and 50% smaller than those induced by MeHg in non-pretreated animals. In summary, MeHg acts, at last in part, through an overstimulation of NMDA receptors with possible NO production to induce DA release, and administration of NMDA receptor antagonists and NOS inhibitors protects against MeHg-induced DA release from rat striatum.     

The non-NMDA glutamate receptor antagonist GYKI 52466 counteracts locomotor stimulation and anticataleptic activity induced by the NMDA antagonist dizocilpine

Summary The effects of the non-NMDA glutamate receptor antagonist GYKI 52466 (2.4 and 4.8 mg/kg, i.p.) on spontaneous locomotor activity and haloperidol-induced catalepsy (0.5 mg/kg, i.p.) were assessed in naive rats and in rats pretreated with the NMDA antagonist dizocilpine (0.08 mg/kg, i.p.). GYKI 52466 given alone did not alter locomotor activity and haloperidol-induced catalepsy, but significantly antagonized the dizocilpine-induced locomotor stimulation and counteracted the anti-cataleptic effects of dizocilpine on haloperidol-induced catalepsy. Thus blockade of non-NMDA glutamate receptors antagonized the behavioural stimulant effects of a NMDA receptor blockade. Correspondence to: W. Hauber at the above address