Comparison of the anticonvulsant activity of organic mono- and di-cations and their potential to inhibit NMDA and AMPA glutamate receptors

Effects of mono- and dicationic derivatives of adamantine and phenylcyclohexyl were studied on: (i) open channels of NMDA and AMPA glutamate receptors in the experiments on the isolated rat brain neurones, and (ii) convulsions induced by intraventricular injections of NMDA or kainate in mice. Monocations inhibited the NMDA receptors in vitro and prevented convulsions induced by NMDA in vivo, but failed to affect both the AMPA receptors and kainite-induced convulsions. Dications (IEM-1754 and IEM-1925) revealed both anti-NMDA and anti-AMPA potency in vitro, were highly effective against kainite-induced convulsions and excelled monocations in preventing the NMDA-induced ones. Evidently some steps connected with the AMPA receptor activity are involved in the genesis of the NMDA-induced convulsions. Anticonvulsant potency of IEM-1754 and IEM-1925 is comparable with those of known NMDA receptor inhibitors: memantine and MK-801. The IEM-1754 and IEM-1925 show no side effects. An incomplete correspondence between the activity in vitro and in vivo found studying some derivatives, may be due to peculiarities of their pharmacokinetics.     

Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801

"Reverse tolerance" was produced in rats and mice by repeated exposure to either cocaine or amphetamine. The locomotorstimulant effect was studied in mice; stereotypy and convulsions in rats. MK-801, the NMDA antagonist, blocked the development of "reverse tolerance" to all three effects. In contrast, haloperidol selectively blocked "reverse tolerance" to cocaine-induced stereotypy but not to convulsions. The data suggest that the glutamate system participates in the mechanism of "reverse tolerance" to the dopaminergic effects of cocaine and amphetamine, as well as to the convulsant effect of cocaine.     

Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats

The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.     

Rats With Different Thresholds to Clonic Convulsions Induced by DMCM Differ in the Binding of [3H]-MK-801 and [3H]-Ouabain in the Membranes of Brain Regions

Considering the putative participation of N-methyl-D-aspartate (NMDA) receptors and the Na(+), K(+)-ATPase enzymes in the susceptibility to convulsions induced by the benzodiazepine inverse agonist methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), the present study sought to determine if rats with high (HTR) and low (LTR) thresholds to clonic convulsions induced by DMCM differed in the following aspects: the binding of NMDA receptors by [(3)H]-MK-801, Na(+), K(+)-ATPase activity (K(+)-stimulated p-nitrophenylphosphatase) and high-affinity [(3)H]-ouabain binding to membranes from discrete brain regions. Compared to the HTR subgroup, the LTR subgroup presented a lower binding of [(3)H]-MK-801 in the hippocampus, frontal cortex and striatum. The subgroups did not differ in K(+)-p-nitrophenylphosphatase activity, but the LTR subgroup had a lower density of isozymes with a high-affinity to ouabain in the brainstem and in the frontal cortex and a lower affinity to ouabain in the hippocampus than the HTR subgroup. These results suggest that NMDA receptors and ouabain-sensitive Na(+), K(+)-ATPase isozymes may underlie the susceptibility to DMCM-induced convulsions.     

Evidence against the presence of NMDA receptors at a central glutamatergic synapse in leeches

The N-methyl-D-aspartate (NMDA) receptor, able to detect the coincidence of pre- and postsynaptic events, is considered to be the molecular analogue of associative learning. Associative learning is well known in leeches, particularly for reflexive shortening. The neuronal circuits underlying shortening have been documented and include neurons that release glutamate. Is this type of learning in leeches also mediated by NMDA receptors? The synapse between the P sensory neuron and the motoneuron-like AP cell was examined and: (1) NMDA failed to elicit a response in the AP cell, (2) the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid affected synaptic transmission only at high, non-specific levels, and (3) the antagonist for the glycine-binding site 7-chloro-kynurenic acid at 20 μM did not inhibit transmission. Therefore, there are evidently no NMDA receptors at the P to AP synapse, suggesting other mechanisms of associative learning in leeches. Electronic Publication     

NMDA Receptors Mediate Consolidation of Contextual Memory in the Hippocampus after Context Preexposure

Male Wistar rats received bilateral infusions of vehicle (VEH) or aminophosphonopentanoic acid (AP5), an N-metil-D-aspartate (NMDA) receptor antagonist, into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intrahippocampal infusion of AP5 blocked 24 h IA retention. In the second experiment, animals were preexposed to the IA training context 24 h prior to training and received an infusion of either VEH or AP5 immediately after the preexposure trial and a second infusion of VEH or AP5 immediately after IA training. AP5 did not affect retention in animals preexposed to the IA box and given VEH after preexposure, but blocked retention when given after both preexposure and training. AP5 impaired retention in rats preexposed to an environment distinct from the IA box. These results suggest that NMDA receptors in the dorsal hippocampus mediate the formation of a contextual representation of the task environment.     

Pore dilation occurs in TRPA1 but not in TRPM8 channels

Pain-related sensitization and synaptic plasticity in the central nucleus of the amygdala (CeA) depend on the endogenous activation of NMDA receptors and phosphorylation of the NR1 subunit through a PKA-dependent mechanism. Functional NMDA receptors are heteromeric assemblies of NR1 with NR2A-D or NR3A, B subunits. NMDA receptors composed of NR1 and NR2B subunits have been implicated in neuroplasticity and are present in the CeA. Here we used a selective NR2B antagonist (Ro-256981) to determine the contribution of NR2B-containing NMDA receptors to pain-related sensitization of CeA neurons. Extracellular single-unit recordings were made from CeA neurons in anesthetized adult male rats before and during the development of an acute arthritis. Arthritis was induced in one knee joint by intraarticular injections of kaolin and carrageenan. Brief (15 s) mechanical stimuli of innocuous (100–500 g/30 mm²) and noxious (1000–2000 g/30 mm²) intensity were applied to the knee and other parts of the body. In agreement with our previous studies, all CeA neurons developed increased background and evoked activity after arthritis induction. Ro-256981 (1, 10 and 100 μM; 15 min each) was administered into the CeA by microdialysis 5–6 h postinduction of arthritis. Ro-256981 concentration-dependently decreased evoked responses, but not background activity. This pattern of effect is different from that of an NMDA receptor antagonist (AP5) in our previous studies. AP5 (100 μM – 5 mM) inhibited background activity and evoked responses. The differential effects of AP5 and Ro-256981 may suggest that NMDA receptors containing the NR2B subunit are important but not sole contributors to pain-related changes of CeA neurons.     

Role of NMDA and AMPA glutamate receptors in the mechanism of korazol-induced convulsions in mice

The potency of mono- and dikationic derivatives of adamantane and phenylcyclohexyl to prevent seizures induced in mice by intraperitoneal administration of 80 mg/kg pentylenetetrazol (corazol), was studied. Monocationic derivatives of phenylcyclohexyl, being the selective channel blockers of NMDA glutamate receptors, as well memantine and MK-801 in micromolar concentrations, prevented both clonic and tonic components of corazol-induced convulsions. Their dicatonic derivatives which are channel blockers of NMDA and AMPA types of glutamate receptors, failed to prevent clonic seizures but at submicromolar concentrations prevented the tonic extensions provoked by corazol. Evidently, convulsive action of corazol originating from suppression of GABA-ergic inhibition is realized through activation of glutamergic synaptic transmission, and NMDA receptors are mainly involved in genesis of clonic seizures whereas activation of AMPA receptors is important for the tonic component of the corazol-induced syndrome.     

NMDA受体通道参与大鼠脊髓背角C纤维诱发电位LTP的表达

以往研究表明,激动NMDA受体是引起海马长时程增强(LTP)的必备条件,而LTP的表达主要与AMPA受体的磷酸化及其受体组装到突触后膜有关.但是,近年来有研究表明NMDA受体通道也参与了LTP的表达.为探讨NMDA受体通道是否参与了脊髓背角C纤维诱发电位LTP的表达,诱导LTP后,分别静脉或脊髓局部给予NMDA受体拮抗剂MK801或APV,观察其作用.发现静脉注射非竞争性NMDA受体MK801(0.1mg/kg)对脊髓LTP无影响,注射0.5mg/kg显著抑制LTP,但是当剂量增高到1.0mg/kg时,抑制作用并未进一步增大.脊髓局部给予MK801也能抑制脊髓背角LTP.为验证上述结果,使用了竞争性NMDA受体拮抗剂APⅤ.结果显示,脊髓局部给予50μmol/LAPⅤ对LTP无影响,100μmol/L对LTP有显著的抑制作用,当浓度升至200μmol/L时,抑制作用并未见进一步增强.因此认为,NMDA受体通道部分地参与了脊髓背角C纤维诱发电位LTP的表达.     

Anticonvulsant effects of phencynonate hydrochloride and other anticholinergic drugs in soman poisoning: neurochemical mechanisms

Previous studies have paid little attention to the anticonvulsant effect of anticholinergic drugs that act on both muscarinic (M) and nicotinic (N) receptors during soman-induced seizures. Therefore, with the establishment of a soman-induced seizures model in rats, this study evaluated the efficacy in preventing soman-induced convulsions of two antagonists of both the M and N receptors, phencynonate hydrochloride (PCH) and penehyclidine hydrochloride (8018), which were synthesized by our institute, and of other anticholinergic drugs, and investigated the mechanisms of their antiseizures responses. Male rats, previously prepared with electrodes to record electroencephalographic (EEG) activity, were pretreated with the oxime HI-6 (125 mg kg-1, i.p.) 30 min before they were administered soman (180 microg kg-1, s.c.). All animals developed seizures subsequent to this treatment. Different drugs were given at different times (5, 20 and 40 min after seizures onset) and their anticonvulsant effects were monitored and compared using the two variables, i.e. the dose that could totally control the ongoing seizures, as well as the speed of seizures control. The anticonvulsant effects of atropine, scopolamine and 8018 decreased with the progression of the seizures, and they eventually lost their anticonvulsant activity when the seizures had progressed for 40 min. In contrast, PCH showed good anticonvulsant effectiveness at 5 and 20 min, and especially at 40 min after seizures onset. Of the anticholinergic drugs tested, atropine, scopolamine, and 8018 showed no obvious protection against pentylenetetrazol (PTZ)-induced convulsions or N-methyl-D-aspartate (NMDA)-induced lethality in mice. However, PCH antagonized the PTZ-induced convulsions in a dose-dependant manner with an ED50 of 10.8 mg kg-1, i.p. (range of 7.1-15.2 mg kg-1) and partly blocked the lethal effects of NMDA in mice. PCH also dose-dependently inhibited NMDA-induced injury in rat primary hippocampal neuronal cultures, suggesting a possible neuroprotective action in vivo. In conclusion, our study suggests that the mechanisms of PCH action against soman-induced seizures might differ from those of the M receptor antagonists atropine and scopolamine, and that of the antagonist of both the M and N receptors, 8018. The pharmacological profile of PCH might include anticholinergic and anti-NMDA properties. Compared with the currently recommended anticonvulsant drug diazepam, with known NMDA receptor antagonists such as MK-801 and with conventional anticholinergics such as scopolamine and atropine, the potent anticonvulsant effects of PCH during the entire initial 40 min period of soman poisoning, and its fewer adverse effects, all suggest that PCH might serve as a new type of anticonvulsant for the treatment of seizures induced by soman.     

Effect of caerulein on decreased latency of passive avoidance response in rats treated with NMDA receptor antagonists

The effect of subcutaneous injection of caerulein on memory impairment induced by intracerebroventricular administration of NMDA receptor antagonists was examined in the passive avoidance response of the rat. When rats were treated with AP5, AP7, CPP or MK-801, the retention latencies decreased markedly. However, in rats that received caerulein immediately after the training trials, the latency increased to some extent. Pretreatment with caerulein and subsequent injection of the competitive NMDA receptor antagonists AP5, AP7 and CPP caused a more apparent increase in the latency. The noncompetitive NMDA receptor antagonist MK-801 was not affected by pretreatment with caerulein. The difference might be, at least in part, due to the sites of action of these NMDA receptor antagonists.     

GluN1 hypomorph mice exhibit wide-ranging behavioral alterations

The psychotomimetic effects of N-methyl-d-aspartate receptor (NMDA) antagonists such as ketamine and phencyclidine suggest a role for reduced NMDA receptor-mediated neurotransmission in schizophrenia. GluN1 'hypomorph' (GluN1(hypo) ) mice exhibit reduced NMDA receptor expression and have been suggested as a mouse model of schizophrenia. However, NMDA receptors are ubiquitous and are implicated in many physiological and pathological processes. The GluN1(hypo) mice have a global reduction of NMDA receptors and the consequences of such a global manipulation are likely to be wide-ranging. We therefore assessed GluN1(hypo) mice on a battery of behavioral tests, including tests of naturalistic behaviors, anxiety and cognition. GluN1(hypo) mice exhibited impairments on all tests of cognition that we employed, as well as reduced engagement in naturalistic behaviors, including nesting and burrowing. Behavioral deficits were present in both spatial and non-spatial domains, and included deficits on both short- and long-term memory tasks. Results from anxiety tests did not give a clear overall picture. This may be the result of confounds such as the profound hyperactivity seen in GluN1(hypo) mice, although hyperactivity cannot account for all of the results obtained. When viewed against this background of far-reaching behavioral abnormalities, the specificity of any one behavioral deficit is inevitably called into question. Indeed, the present data from GluN1(hypo) mice are indicative of a global impairment rather than any specific disease. The deficits seen go beyond what one would expect from a mouse model of schizophrenia, thus questioning their utility as a selective model of this disease.     

Effect of glutamate on spontaneous secretion of acetylcholine in the nerve-muscle synapse in rats]

In rats, glutamate was shown to exert no effect on the mean frequency, character of interstimuli distribution, amplitude and temporal parameters of the miniature EPPs. Glutamate suppressed nonquantal release. The glutamate effect depended on its concentration and was abolished by blockade of NMDA receptors, NO-synthase inhibitoin, and NO molecules binding by haemoglobin in extracellular medium. Glutamate seems to modulate the nonquantal acetylcholine secretion by initiation of the NO synthesis in muscle fibres via activation of the NMDA receptors.     

Poster Sessions CP07: Ions,Channels, Pumps and Transporters. Functional relationship between Na/K‐pump and glutamate receptors in cerebellum granule cells

Stationary level of reactive oxygen species (ROS) in cerebellum granule cells of 12‐day‐old‐rats was measured using three fluorescent dyes characteristic of different location within the neuronal cell: BODIPY 581/591 (for LOO.radicals), DCF‐DA (for H202) and DHR123 (OH‐radicals in mitochondria). When the neurons were activated by N‐methyl‐d ‐aspartate (NMDA) a dose‐ and time‐dependent rise of the fluorescent signal was registered with each of the three dyes; the former dye provided the smallest and the latter the largest response. 3‐HPG, a ligand for metabotropic receptors decreases ROS fluorescence and suppressed the NMDA‐induced effect. NMDA and kainic acid presented simultaneously cumulatively increased ROS levels. Ouabain, specific inhibitors of Na/K‐pump induced a considerable increase in ROS fluorescence, which was decreased by 2.5–5 mm KCl, 50 mkM Vanadate or 10 mkM D‐AP5, an inhibitor of NMDA‐activated ionic channels. The K0.5 for activation of ROS generation by Ouabain was more than 250 mkM, which is much higher than that for inhibition of Na/K‐ATPase or its rubidium pumping activity. The data show that the Na/K‐pump protein regulates ROS production by NMDA‐receptors and that the E1(Na) conformation of the Na/K‐pump being less sensitive to ouabain may be responsible for the effects. The data illustrate functional interaction between ionotropic and metabotropic receptors and Na/K‐ATPase. Acknowledgements: Supported by DAAD, Grant 325‐sm, Germany.     

Neuronal expression of mutations affecting primarily glia in the mouse: studies in the dysmyelinated and convulsive mutant quaking

1. Various aspects of the noradrenergic system in the brain of the dysmyelinating convulsive mutant mice quaking have been examined. 2. Determination of the endogenous contents of noradrenaline and its metabolite 3-methoxy 4-hydroxyphenyl-ethyleneglycol (MOPEG), as well as measurement of the electrically-evoked release of (3H)-noradrenaline shows an increased noradrenergic activity in the brain of the mutants, when compared to non convulsive controls of the same strain. 3. Ontogenic development of alpha adrenergic receptors indicate that an increased density of alpha-2 sites precedes the appearance of the first convulsions by approximately one week. 4. Anatomical determination of the number of noradrenergic neuronal cell bodies in the locus coeruleus shows a hyperplasia of this nucleus in the mutants. 5. Electrolytic coagulation of the locus coeruleus inhibits the convulsions of the quaking mice. 6. These results suggest that an alteration of the embryonic differentiation of the locus coeruleus, which gives rise to the majority of brain noradrenergic neurons, provokes a hyperactivity of this neuronal system, thereby triggering the convulsions of the quaking mutant mice. 7. The possible involvement of other neurotransmitter systems in the convulsions of these mutants, together with the nature of the relationship between neuronal abnormalities and dysmyelination phenomenon, are discussed.     

mGlu5 receptor deletion does not confer seizure protection to mice

Metabotropic glutamate mGlu5 receptors have been implicated in the regulation of seizures and have been suggested as a target against which discovery of novel anticonvulsants may be possible. However, the experimental literature is not consistent in reporting anticonvulsant efficacy of mGlu5 receptor antagonists. Additional assessment of this target was approached in the present study by comparing convulsions in wild-type (WT) and mGlu5 receptor null (knockout or KO) mice. Chemically induced seizures induced by a variety of mechanisms including pentylenetetrazole, N-methyl-d-aspartic acid (NMDA), cocaine, kainic acid, aminophylline, 4-aminopyridine, strychnine, and nicotine did not differentially increase clonic, clonic/tonic, or lethality in WT vs. mGlu5 receptor KO mice. The mGlu5 receptor antagonist 3-[(2-Methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) did not significantly prevent seizures induced by NMDA; in contrast, the uncompetitive NMDA receptor antagonist, dizocilpine, significantly prevented NMDA-induced seizures and lethality in both WT and KO mice. The present findings do not support the idea that mGlu5 receptors play as important a role in seizure control as previously speculated.     

Modulators of N-methyl-D-aspartate protect against diazepam- or phenobarbital-resistant cocaine convulsions.

The anticonvulsants diazepam (1-10 mg/kg) and phenobarbital (30-100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor complex, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.     

Mechanism of Action of Nitrogen Pressure in Controlling Striatal Dopamine Level of Freely Moving Rats is Changed by Recurrent Exposures to Nitrogen Narcosis

In rats, a single exposure to 3 MPa nitrogen induces change in motor processes, a sedative action and a decrease in dopamine release in the striatum. These changes due to a narcotic effect of nitrogen have been attributed to a decrease in glutamatergic control and the facilitation of GABAergic neurotransmission involving NMDA and GABA_A receptors, respectively. After repeated exposure to nitrogen narcosis, a second exposure to 3 MPa increased dopamine levels suggesting a change in the control of the dopaminergic pathway. We investigated the role of the nigral NMDA and GABA_A receptors in changes in the striatal dopamine levels. Dopamine-sensitive electrodes were implanted into the striatum under general anesthesia, together with a guide-cannula for drug injections into the SNc. Dopamine level was monitored by in vivo voltammetry. The effects of NMDA/GABA_A receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) on dopamine levels were investigated. Rats were exposed to 3 MPa nitrogen before and after five daily exposures to 1 MPa. After these exposures to nitrogen narcosis, gabazine, NMDA and AP7 had no effect on the nitrogen-induced increase in dopamine levels. By contrast, muscimol strongly enhanced the increase in dopamine level induced by nitrogen. Our findings suggest that repeated nitrogen exposure disrupted NMDA receptor function and decreased GABAergic input by modifying GABA_A receptor sensitivity. These findings demonstrated a change in the mechanism of action of nitrogen at pressure.     

Role for NMDA receptors in visceral nociceptive transmission in the anterior cingulate cortex of viscerally hypersensitive rats

We have identified colorectal distension (CRD)-responsive neurons in the anterior cingulate cortex (ACC) and demonstrated that persistence of a heightened visceral afferent nociceptive input to the ACC induces ACC sensitization. In the present study, we confirmed that rostral ACC neurons of sensitized rats [induced by chicken egg albumin (EA)] exhibit enhanced spike responses to CRD. Simultaneous in vivo recording and reverse microdialysis of single ACC neurons showed that a low dose of glutamate (50 microM) did not change basal ACC neuronal firing in normal rats but increased ACC neuronal firing in EA rats from 18 +/- 2 to 32 +/- 3.8 impulses/10 s. A high dose of glutamate (500 microM) produced 1.95-fold and a 4.27-fold increases of ACC neuronal firing in sham-treated rats and in EA rats, respectively, suggesting enhanced glutamatergic transmission in the ACC neurons of EA rats. Reverse microdialysis of the 3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainite receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) reduced basal and abolished CRD-induced ACC neuronal firing in normal rats. In contrast, microdialysis of N-methyl-d-aspartate (NMDA) receptor antagonist AP5 had no effect on ACC neuronal firing in normal rats. However, AP5 produced 86% inhibition of ACC neuronal firing evoked by 50 mmHg CRD in the EA rats. In conclusion, ACC nociceptive transmissions are mediated by glutamate AMPA receptors in the control rats. ACC responses to CRD are enhanced in viscerally hypersensitive rats. The enhancement of excitatory glutamatergic transmission in the ACC appears to mediate this response. Furthermore, NMDA receptors mediate ACC synaptic responses after the induction of visceral hypersensitivity.     

Excitatory amino acid receptors and synaptic excitation in the mammalian central nervous system.

At least two different types of excitatory amino acid receptors have been identified in the mammalian and amphibian central nervous systems. One type ('NMDA receptors') appears to be important in amino acid-mediated synaptic excitation, NMDA being the most potent and specific exogenous agonist for this type of receptor. Many antagonists have selective blocking actions at these NMDA receptors, and such substances are also selective antagonists of synaptic excitation in the vertebrate spinal cord. It is proposed that these receptors are transmitter receptors activated by an excitatory amino acid. In addition, extrasynaptic receptors, activated by domoate, kainate, quisqualate and L-glutamate, but not by NMDA, and only weakly by L-aspartate, have been identified on dorsal root fibres of the immature rat.