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D Lodge

Publications and source records attributed to D Lodge.

At least 91 records · Page 5Linked to original sources
PubMed1989

Subchronic administration of MK-801 in the rat decreases cortical binding of [3H]D-AP5, suggesting down-regulation of the cortical N-methyl-D-aspartate receptors.

The effects of the subchronic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK-801) (0.5 mg/kg twice daily, 7 days) on N-methyl-D-aspartate, phencyclidine and sigma binding sites, behaviour and catecholamine turnover were investigated in the rat. Overt behaviours induced by MK-801 on day 7 were significantly altered relative to day 1 with subchronically treated rats not showing head weaving, goss ataxia or loss of hindlimb control: locomotion and sniffing were largely unaffected. The mean intensities of behaviour were 1.8 and 5.4 for days 7 and 1, respectively. Behavioural tolerance was accompanied by a significant reduction in the density of cortical N-methyl-D-aspartate receptors as measured by [3H]D-2-amino-5-phosphonopentanoic acid binding, while affinity was unchanged: the density of binding sites was 3.52 and 1.88 pmol/mg protein for saline- and MK-801-treated rats, respectively. The N-methyl-D-aspartate ion channel as measured by the binding of [3H]N-(1-[2-thienyl]cyclohexyl)piperidine was not affected by the schedule of MK-801. Additionally, changes were not observed to N-methyl-D-aspartate- or glycine-stimulated [3H]N-(1-[2-thienyl]cyclohexyl)piperidine binding or to sigma binding. Catecholamine turnover was unaltered in the nucleus accumbens septi after the schedule of MK-801. Our results demonstrate that the subchronic administration of MK-801 produces behavioural tolerance and down-regulation of N-methyl-D-aspartate binding sites and suggest differential regulation of the domains of the N-methyl-D-aspartate receptor-ionophore complex.

2-Amino-5-phosphonovalerate↗
PubMed1989

Non-competitive antagonism of N-methyl-d-aspartate by displacement of an endogenous glycine-like substance.

N-methyl-D-aspartate (NMDA; 40 microM) induced depolarizations of cortical wedges that were reduced by 30 - 60% in the presence of D-2-amino-5-phosphonovalerate (D-AP5; 5 microM), ketamine (5 microM), dextrorphan (5 microM), magnesium (500 microM), kynurenate (200 microM), and 1-hydroxy-3-aminopyrrolidone-2 (HA-966; 200 microM). Superfusion with glycine (1 microM - 1 mM) did not enhance the action of NMDA in control medium and in media containing D-AP5, ketamine, dextrorphan, or magnesium. In the presence of kynurenate and HA-966, however, NMDA-induced depolarizations were enhanced in a dose-dependent manner by glycine (10 microM - 3.16 mM). NMDA antagonism produced by HA-966 appeared to be more completely reversed than that produced by kynurenate. This action of glycine was mimicked by D-serine but not by GABA or L-serine, and was resistant to strychnine (10 - 50 microM). Reduction of responses to quisqualate by kynurenate was not reversed by glycine. In these cortical wedges, spontaneous synaptic activity was observed in nominally magnesium-free medium and this epileptiform activity could be blocked by the above NMDA antagonists. Glycine and D-serine reversed only the effect of kynurenate and HA-966 on such synaptic activity. These results suggest there is an endogenous glycine-like compound acting on NMDA receptor-ionophore complexes and that displacement of this compound by HA-966 or kynurenate produces antagonism of NMDA.

Journal Article↗
PubMed1989

Antitussive agents as N-methylaspartate antagonists: further studies.

The relative potencies of ketamine and the morphinan derivatives dextrorphan, dextromethorphan, and levorphanol as antagonists of the excitatory actions of N-methylaspartate on rat spinal neurones in vivo were examined, both following their microelectrophoretic administration and, with the exception of levorphanol, after intravenous injection. Applied microelectrophoretically, dextrorphan was a more potent N-methylaspartate antagonist than ketamine, levorphanol, or dextromethorphan. After systemic administration, however, dextrorphan was rather less potent than ketamine in this respect, whereas dextromethorphan remained less potent than either ketamine or dextrorphan. Noscapine, an antitussive that lacks anticonvulsant activity, failed to reduce selectively responses to N-methylaspartate as did papaverine, an isoquinoline structurally related to noscapine, and triprolidine, an antihistamine commonly found in proprietary cough medicines. The results are discussed with particular reference to the potential of the compounds tested as anticonvulsant and neuroprotective agents in vivo.

Animals↗
PubMed1989

Neocortical epileptogenesis in vitro: studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.

Slices of rat neocortex have been used to study the role of N-methyl-D-aspartate (NMDA) receptors in the induction of epileptiform activity. The NMDA antagonist potency of a range of compounds with putative anticonvulsant activity has been compared with their ability to reduce epileptiform activity in this tissue. Epileptiform activity was induced by the omission of magnesium from the bathing medium. Competitive and noncompetitive phencyclidine-like NMDA antagonists reduced such spontaneous and stimulus-evoked epileptiform bursts and after potentials. Similar epileptiform activity induced by the addition of proconvulsant drugs, e.g. gamma-aminobutyric acidA antagonists, potassium channel blockers or carbachol was reduced by ketamine and/or D-2-amino-5-phosphonovaleric acid. In magnesium-free medium, the frequency of spontaneous bursts and the number of afterpotentials per burst were reduced in parallel. There was a good correlation (r greater than 0.9) between their potencies against NMDA depolarizations and against epileptiform bursts (MK-801 [(+)-5-methyl-10,11- dihydro-5H-dibenzvo[a,d]cyclohepten-5,10-imine] greater than thienylcyclohexylpiperidine phencyclidine greater than 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid greater than cyclazocine greater than D-2-amino-5-phosphonovaleric acid greater than dextrorphan greater than SKF10,047 (N-allylnormetazocine) greater than ketamine greater than dextromethorphan = or greater than pentazocine). Sigma and dextromethorphan receptor ligands (e.g. ditolyguanidine, carbetapentane and phenytoin), whereas inactive as NMDA antagonists, reduced epileptiform activity by decreasing the number of afterpotentials per burst with less effect on the burst frequency. The quisqualate/kainate antagonist, FG9041 (6,7-dinitro-quinoxaline-2,3-dione), only reduced spontaneous bursts at doses which also reduced NMDA. Our results imply a central role for NMDA receptors in epileptogenesis in neocortical slices.

Animals↗
PubMed1988

N-methyl-D-aspartate receptor-mediated increase in intracellular calcium is reduced by ketamine and phencyclidine.

L-Glutamate, N-methyl-D-aspartate, quisqualate and potassium chloride enhanced Ca2+ accumulation by rat cortical slices as determined using 45Ca2+ uptake and Ca2+ mobilisation in cortical synaptosomes as determined using quin-2 fluorescence. Quinolinate and kainate were ineffective. Responses to L-glutamate and N-methyl-D-aspartate were blocked by non-competitive (ketamine, phencyclidine, Mg2+) and competitive (2-amino-5-phosphonovalerate) antagonists. These data suggest that activation of excitatory amino acid receptors in the cortex results in enhanced Ca2+ mobilisation which can be blocked by selective antagonists. Such effects may be related to neurotoxic properties of the excitatory amino acids and the neuroprotection afforded by excitatory amino acid antagonists.

Animals↗
PubMed1988

Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists.

The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the "non-NMDA" glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1988

Differences in results from in vivo and in vitro studies on the use-dependency of N-methylaspartate antagonism by MK-801 and other phencyclidine receptor ligands.

We have used microelectrophoretic and intravenous administration of drugs to rat spinal cord neurones in vivo and bath application to rat cortical wedges in vitro to evaluate MK-801 and other phencyclidine (PCP) receptor ligands as N-methylaspartate (NMA) antagonists, paying particular regard to the possible use-dependent nature of their action. MK-801, 0.1-0.5 mg/kg, was a selective and long-lasting NMA antagonist. We were unable to demonstrate significant use-dependent onset of antagonism of NMA by any of the drugs in vivo. Recovery, however, for MK-801 was use-dependent. In vitro there was a gradation with MK-801 being very use-dependent, followed by (PCP), cyclazocine and ketamine, the last showing little or no use-dependence. Results of experiments modulating the in vitro environment suggest that a significant difference between the in vitro and in vivo systems was temperature. Raising the temperature of the wedge chamber from 23 to 33 degrees C reduced the use-dependence of MK-801, and lowering the temperature to 13 degrees C increased the use-dependence of PCP. The mechanism of action of PCP receptor ligands is discussed in the light of these results.

Animals↗
PubMed1988

Phencyclidine receptors and N-methyl-D-aspartate antagonism: electrophysiologic data correlates with known behaviours.

Using cortical wedges and isolated frog spinal cords, the potency of a series of psychoactive phencyclidine (PCP) and sigma receptor ligands as antagonists of N-methyl-D-aspartate (NMDA) has been compared with their potency in neurochemical and behavioural studies. Phencyclidine receptor, but not sigma or kappa, ligands were selective antagonists of NMDA on both preparations. Combination studies suggested that dissociative anaesthetics and sigma benzomorphans act at the same site. The relative potencies of the drugs as NMDA antagonists correlated well with their potency in PCP receptor binding studies in vitro and in PCP discrimination studies in vivo.

Anesthetics, Dissociative↗
PubMed1988

Validation of a neocortical slice preparation for the study of epileptiform activity.

A simple slice chamber was designed to achieve easy manipulations of temperature, ionic composition and drug concentrations. Spontaneous and evoked extracellular potentials could be recorded with glass microelectrodes from 500 micron thick slices of rat frontal neocortex. In the absence of magnesium ions in the superfusing medium or in the presence of convulsant agents, epileptiform activity was seen. The amplitude of this activity was greatest in layer II/III, each burst consisting of a long-lasting negative potential on the decay phase of which were superimposed many afterpotentials. There were multiple foci from which spontaneous epileptiform bursts spread to other ipsi- and contralateral parts of the cortex via both the grey and white matter. Although such bursts were observed between 23 and 37 degrees C, optimal recording of discrete epileptiform activity was achieved at 29 +/- 1 degrees C. Decreasing extracellular calcium or increasing extracellular concentrations of potassium enhanced burst discharges. Proconvulsant agents initiated both interictal and ictal epileptiform events. This, together with the reduction of epileptiform activity by standard anticonvulsant drugs such as carbamazepine and phenobarbitone suggested that this in vitro model may be useful for studying the pharmacology of epileptogenesis and for developing new therapeutic strategies for epilepsy.

Animals↗
PubMed1988

The neuroprotective action of ketamine and MK-801 after transient cerebral ischemia in rats.

The neuroprotective activity of two systemically administered N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine and MK-801, were investigated in a long-term recovery model of near-complete forebrain ischemia in the rat. Doses of each drug were chosen on the basis of the known degree and time course of NMDA antagonism seen in vivo after their systemic administration. Ketamine, administered at a dose of 20 mg.kg-1 iv, either immediately before or shortly after the 10-min ischemic period, failed to lessen neuronal damage in the selectively vulnerable hippocampal CA1 region. Increasing doses of ketamine administered over an increasing length of time in the postischemic period, however, did provide significant protection. MK-801 0.25 or 0.5 mg.kg-1 iv administered before ischemia also resulted in significant protection. The results support the proposal that NMDA receptor-mediated events may contribute to neuronal damage in selectively vulnerable regions of the central nervous system after ischemia.

Animals↗
PubMed1988

Quinoxalinediones selectively block quisqualate and kainate receptors and synaptic events in rat neocortex and hippocampus and frog spinal cord in vitro.

1. Two quinozalinediones, FG9041 and FG9065, which had previously been shown to displace binding to the quisqualate receptor, were tested on rat neocortex and frog spinal cord in vitro against depolarizations induced by quisqualate, kainate and N-methyl-D-aspartate (NMDA). In both preparations effects of quisqualate were reduced the most and those of NMDA the least. 2. The near unitary slopes of the Schild plots were consistent with a competitive type of interaction. pA2 values for FG9041 were estimated to be 6.6, 6.1 and 5.1 in frog cord and 5.9, 5.3 and and about 4 in the rat neocortex for quisqualate, kainate and NMDA antagonism, respectively. FG9065 gave equivalent pA2 values of 6.2, 5.6 and 4.5. 3. At concentrations, which were without effect on depolarizations induced by NMDA, FG9041 and FG9065 reduced or blocked synaptically-evoked field potentials in hippocampal and neocortical slices superfused with normal magnesium-containing medium. Since these synaptic components are also insensitive to NMDA antagonists, these results are consistent with their mediation by postsynaptic receptors of the quisqualate (or kainate) type. 4. By contrast, quinoxalinediones had only limited effects on spontaneous epileptiform activity seen in both neocortical and hippocampal preparations when superfused with magnesium-free medium. These burst discharges were, however, abolished by NMDA antagonists. 5. In the frog spinal cord the early component of the dorsal root to ventral root reflexes was selectively reduced by FG9041 whereas NMDA antagonists reduced the longer latency components. 6. Our results suggest that the quinoxalinediones are likely to be useful pharmacological probes for elucidating the role of non-NMDA receptors in the vertebrate central nervous system.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1988

A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists.

1. Phosphonate analogues of glutamate have been tested and compared as N-methyl-D-aspartate (NMDA) antagonists in electrophysiological and binding experiments. The compounds tested were three established NMDA antagonists: D-2-amino-5-phosphonopentanoate (D-AP5), DL-2-amino-7-phosphonoheptanoate (DL-AP7), 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), and two novel putative NMDA antagonists: 3-(2-carboxypiperidin-4-yl)propyl-1-phosphonate (CPPP) and 3-(2-carboxy-piperidin-4-yl)methyl-1-phosphonate (CPMP). 2. When administered electrophoretically to rat spinal neurones in vivo, these compounds were found to be selective NMDA antagonists with little effect on excitations evoked by quisqualate and kainate. CPMP and CPPP were approximately equipotent with CPP and about 5 times more potent than D-AP5. 3. Following systemic administration, 2-5 mg kg-1 i.v. of CPP, CPMP and CPPP reduced NMDA-evoked excitations by 70-100% whereas 50-100 mg kg-1 of D-AP5 and DL-AP7 produced a similar effect. The onset of the effects required 20-30 min and lasted more than six hours. 4. On bath application to cortical wedges, the IC50 values (microM) for antagonism of 40 microM NMDA were: CPP, 0.64 +/- 0.06 (mean +/- s.e.mean; n greater than 4); CPMP, 1.65 +/- 0.13; CPPP 0.89 +/- 0.09; D-AP5, 3.7 +/- 0.32; DL-AP7, 11.1 +/- 2.1; and DL-AP4 and DL-AP6 were inactive at 100 microM. 5. In binding studies with [3H]-CPP, the Ki values (nM) were: CPP, 446 + 150 (mean + s.e.mean; n > 3); CPMP, 183 + 74 and CPPP, 179 +/- 13 whereas against NMDA (lO microM)-stimulated [3H]- TCP (thienylcyclohexylpiperidine) binding the ICjo values (microM) for CPMP and CPPP respectively were 5.6 + 2.7 and 4.5 + 2.2. 6. Systemic administration of CPPP and CPMP, at doses sufficient to antagonize NMDA, also reduced cardiovascular responses to 5-hydroxytryptamine (Bezold-Jarisch reflex). This illustrates a role for NMDA receptors in central cardiovascular control. 7. The results indicate the systemic doses of piperidine and piperazine analogues of D-AP5 which may be used for assessing the role ofNMDA receptors in central synaptic function.

2-Amino-5-phosphonovalerate↗
PubMed1987

Epileptiform activity induced by alkalosis in rat neocortical slices: block by antagonists of N-methyl-D-aspartate.

The effects of changing extracellular pH on epileptiform activity induced by the removal of magnesium ions from the perfusing medium were studied. The proportion of bicarbonate in the artificial cerebrospinal fluid and of CO2 in the gas mixture were altered to mimic metabolic and respiratory acid-base disturbances. Changes in pH of 0.2 unit from control produced marked effects. Epileptiform activity was enhanced by alkalosis and diminished by acidosis. In normal magnesium-containing medium metabolic alkalosis (pH greater than 7.8) induced spontaneous epileptiform activity that was blocked by selective N-methyl-D-aspartate antagonists. The relevance of these findings to acid/base changes in clinical epilepsy is discussed.

2-Amino-5-phosphonovalerate↗
PubMed1987

Evidence for involvement of N-methylaspartate receptors in 'wind-up' of class 2 neurones in the dorsal horn of the rat.

We have examined the effects of ketamine and kynurenate on the initial response and frequency dependent potentiation of response (wind-up) of class 2 neurones of the rat dorsal horn induced by repeated electrical stimulation of their receptive fields. Iontophoretic kynurenate reduced both the initial response and the wind-up. Iontophoretic or intravenous ketamine had no consistent effect on the initial response but consistently reduced wind-up. N-Methylaspartate receptors therefore appear to contribute to the wind-up, but not the initial response, of class 2 neurones in the rat.

Animals↗
PubMed1987

Biphasic effect of quinolinate on frog spinal, but not rat cortical, neurones: N-methyl-D-aspartate-like depolarisation and a novel type of hyperpolarisation.

Using grease seal techniques on rat cerebral cortical slices and on frog hemisected spinal cords, bath applied N-methyl-D-aspartate (NMDA; 10-160 microM) and quinolinate (0.25-8 mM) induced dose-dependent depolarisations. These depolarising responses, but not those to quisqualate or kainate, were reduced by 2-amino-5-phosphono-valerate (2-AP5; 10-100 microM), magnesium (0.1-10 mM) and ketamine (10-100 microM). A novel dose-dependent hyperpolarising response to quinolinate (0.1-2 mM) but not to NMDA was observed only on frog motoneurones, and this was not reduced by classical amino acid receptor antagonists.

2-Amino-5-phosphonovalerate↗
PubMed1987

Non-pharmacological effects of the use of microelectrophoresis and pressure ejection of drugs in combination.

Pressure ejection of physiological saline from multibarrel micropipette assemblies has been shown to selectively reduce responses of rat spinal cord neurones to electrophoretic ejection of kainate, N-methyl-aspartate and 4-methyl-homoibotenate, but not of quisqualate or L-glutamate. Reduction of response to an excitatory amino acid therefore appears to be correlated with the absence of an active transport system for that amino acid.

Amino Acids↗