PubMed Health⌕ Search

Biomedical subjects

D Lodge

Publications and source records attributed to D Lodge.

At least 109 records · Page 6Linked to original sources
PubMed1986

Is Metaphit a phencyclidine antagonist? Studies with ketamine, phencyclidine and N-methylaspartate.

The dissociative anaesthetics, phencyclidine and ketamine, block excitation of central neurones by N-methylaspartate. Using the technique of microelectrophoresis on rat spinal neurones in vivo Metaphit, a phencyclidine receptor acylating agent, was tested to see whether it would antagonise this effect of dissociative anaesthetics. The predominant effect of Metaphit was, however, to reduce N-methylaspartate induced excitation. It is concluded that Metaphit has mixed agonist/antagonist effects at the phencyclidine receptor.

Action Potentials↗
PubMed1985

Effect of ketamine on amino acid-evoked release of acetylcholine from rat cerebral cortex in vitro.

N-Methyl-D-aspartate (NMDA), quisqualate, kainate and potassium increased, in a dose-dependent manner, the efflux of radioactivity from rat cerebral cortex minislices preincubated with [3H]choline. Ketamine (1-5 microM) and magnesium (0.1-1 mM) reduced only the release evoked by NMDA. The non-parallel shift of the NMDA dose-response curve suggests that ketamine is not acting as a competitive antagonist of NMDA.

Acetylcholine↗
PubMed1985

Differential effects of dextrorphan and levorphanol on the excitation of rat spinal neurons by amino acids.

The effects of the stereoisomers dextrorphan and levorphanol on the excitation of spinal neurons by electrophoretically administered excitatory amino acids were studied in pentobarbitone-anaesthetised rats. Both isomers reduced responses to N-methyl-DL-aspartate (NMA), dextrorphan being both more selective and more potent than levorphanol in this respect. This observation supports the proposal that the NMA-blocking activity of a variety of drugs with psychotomimetic properties is subserved by actions at phencyclidine (PCP)/sigma opiate receptors.

Acetylcholine↗
PubMed1985

Acute effects of lead at central synapses in vitro.

The acute effects of lead in the rat CNS in vitro were studied on synaptic transmission in the isolated hemisected spinal cord from newborn rats and on the transport of exogenous GABA, acetylcholine and cis-3-aminocyclohexane carboxylic acid (ACHC) from slices of cerebral cortex from adult rats. Lead had quite variable effects on monosynaptic reflexes and synaptic potentials. When it occurred, the depression of synaptic transmission by lead (typically at 18.5 mumol/liters of added lead acetate) was reversible provided exposure times were less than 15 min; furthermore, depression could be antagonised by increasing the external calcium concentration. Lead had no effect on the postsynaptic responses of motoneurons to the putative transmitters L-glutamate, GABA and glycine or to eledoisin-related peptide. The effects of lead on uptake and release of exogenous GABA and ACHC were dependent on the perfusion buffer employed: minimal effects were seen in solutions buffered with either phosphate or carbonate. When Tris HCl was used as buffer, lead inhibited the uptake of GABA and potentiated the spontaneous release of GABA with an EC50 = 50 mumol/liters as added lead acetate. In Tris HCl buffer, lead acetate (100 mumol/liters) produced a two-fold enhancement in the spontaneous release of acetylcholine under conditions where choline and acetylcholine re-uptake was blocked by hemicholinium. The availability of free lead cations in solution is highly dependent on the concentrations of other ions (particularly phosphates) and the pH. Under the appropriate conditions, lead can inhibit CNS synaptic function acutely in a manner consistent with lead competing with calcium ions in transmitter release processes as has been established for acetylcholine release at peripheral synapses.

Acetylcholine↗
PubMed1985

Selective blockade of an excitatory synapse in rat cerebral cortex by the sigma opiate cyclazocine: an intracellular, in vitro study.

In isolated slices of rat cortex, intracellularly recorded responses of pyramidal neurones to N-methylaspartate (NMA) and glutamate and responses to stimulation of the underlying white matter were compared and challenged with the sigma opiate cyclazocine. Cyclazocine blocked responses to iontophoretically applied NMA and one component of the postsynaptic response to stimulation, but left other postsynaptic events and responses to glutamate intact. These results are consistent with the view that sigma opiates act as selective NMA antagonists and block synaptic events mediated by NMA receptors.

Animals↗
PubMed1985

Ketamine acts as a non-competitive N-methyl-D-aspartate antagonist on frog spinal cord in vitro.

The effects of the dissociative anaesthetic, ketamine, the divalent cation, magnesium and the organic antagonist, 2-amino-5-phosphonovalerate (APV), were examined on responses of motoneurones to excitatory amino acids in the hemisected spinal cord of the frog in vitro. The amino acids, N-methyl-D-aspartate (NMDA), kainate and quisqualate, produced dose-dependent depolarizations. Ketamine, magnesium and APV depressed responses to NMDA but had no effect on those to quisqualate and kainate. Magnesium and APV produced Schild plot slopes that were not different from unity, whereas ketamine had a slope significantly less than unity, indicative of a non-competitive action. Experiments in which combinations of drugs were tested indicated that these substances act by three distinct mechanisms to cause antagonism of the actions of NMDA.

2-Amino-5-phosphonovalerate↗
PubMed1984

Benz(f)isoquinolines as excitatory amino acid antagonists: an indication of their mechanism of action?

Using the technique of microelectrophoresis on cat and rat spinal neurones, the bridged benz(f)isoquinoline, LY154045, like ketamine and dextrorphan, was found to be a selective antagonist of N-methylaspartate, an amino acid used for characterizing excitatory amino acid synaptic receptors. The unbridged analogue, LY154005, was inactive as an amino acid antagonist. This result correlates well with the ability of LY154045, but not LY154005, to displace phencyclidine from CNS tissue and to mimic phencyclidine in behavioural tests. The potential role of N-methylaspartate antagonism in the aetiology of some of the behavioural effects of LY154045, phencyclidine and related drugs is considered.

Acetylcholine↗
PubMed1984

The effect of the dioxolanes on amino acid induced excitation in the mammalian spinal cord.

The effects of the dissociative anaesthetic, etoxadrol, and the stereoisomers of dioxadrol, dexoxadrol and levoxadrol, were examined on the excitation of spinal neurones by electrophoretically administered amino acids in pentobarbitone- or urethane-anaesthetized rats, or pentobarbitone-anaesthetized cats. Both etoxadrol and the (+)isomer of dioxadrol, dexoxadrol, administered locally or systemically, exhibited a selective antagonism of N-methyl-D,L-aspartate relative to quisqualate and kainate. This selective antagonism was not observed with the (-)isomer of dioxadrol, levoxadrol. Since such a stereoselective antagonism of the excitation of spinal neurones by N-methyl-D,L-aspartate is also displayed by the dissociative anaesthetics phencyclidine and ketamine, it is suggested that a reduced efficiency at excitatory synapses utilising N-methyl-D,L-aspartate receptors contributes to that part of the pharmacological spectrum common to both arylcyclohexylamines and dioxolanes.

Animals↗
PubMed1984

Effects of ketamine and three other anaesthetics on spinal reflexes and inhibitions in the cat.

The effects of ketamine, alphaxalone/alphadolone, methohexitone and di-isopropylphenol have been compared on synaptic excitations and inhibitions in the spinal cord of decerebrate or pentobarbitone-anaesthetized cats. Ketamine selectively and reversibly decreased polysynaptic reflexes over a wide dose range. With the other three anaesthetic drugs decreases in reflex activity were accompanied by increases in the prolonged inhibition of reflexes, and in the amplitude and time course of dorsal root potentials. It was concluded that ketamine decreases synaptic transmission at terminals of excitatory interneurones, whereas the other three anaesthetics enhance synaptic inhibitions mediated by gamma-aminobutyric acid. Such specific effects of anaesthetics on particular synaptic processes do not support a unitary hypotheses of anaesthesia.

Action Potentials↗
PubMed1984

Comparison of sigma- and kappa-opiate receptor ligands as excitatory amino acid antagonists.

Using the technique of microelectrophoresis in pentobarbitone-anaesthetized cats and rats, the effects of benzomorphans, with known actions at sigma- and kappa- opioid receptors, were tested on responses of spinal neurones to amino acids and acetylcholine. The racemic mixture and both enantiomers of the sigma opiate receptor agonist, N-allylnormetazocine (SKF 10, 047), and the dissociative anaesthetic, ketamine, reduced or abolished excitation evoked by N-methyl-aspartate (NMA) with only small and variable effects on responses to quisqualate or kainate. (+)-SKF 10, 047 was 1.2 +/- 0.7 times more potent than the (-)-enantiomer in antagonizing NMA. On Renshaw cells, (+)-SKF 10, 047 enhanced responses to acetylcholine whereas the (-) enantiomer produced only a small reduction. The kappa- opiate receptor agonist, ethylketocyclazocine, had no selective effects on responses to amino acids or to acetylcholine. We conclude that actions at sigma- but not kappa-, opiate receptors are responsible for the NMA antagonism observed with benzomorphans.

Acetylcholine↗
PubMed1984

Depolarization of feline primary afferent fibres by acidic amino acids.

When administered micro-electrophoretically into the spinal grey matter of cats anaesthetized with pentobarbitone, acidic amino acids known to be neuronal excitants lower the threshold of electrically stimulated muscle and cutaneous primary afferent fibres and terminations. This depolarizing effect was not observed with fibres stimulated in the white matter. Depolarization by micro-electrophoretic potassium and excitant amino acids appeared not be be associated with an alteration in terminal membrane conductance since there was no change in synaptically evoked primary afferent depolarization. Excitant amino acid depolarization was not blocked by the gamma-aminobutyric acid antagonist bicuculline methochloride, but was reduced by selective excitant amino acid antagonists. The results are discussed in relation to the probable absence of specific excitant amino acid receptors on afferent terminals, the depolarizing effect of the amino acids on myelinated fibres and non-myelinated terminals being more likely a consequence of changes in the extracellular medium associated with the depolarization and firing of neurones.

Action Potentials↗
PubMed1983

Stereoselective effects of two phencyclidine derivatives on N-methylaspartate excitation of spinal neurones in the cat and rat.

In pentobarbitone-anaesthetised cats and rats effects of stereoisomers of two methylated congeners of phencyclidine, GK4 and GK5, and (+)- and (-)-PCMP, were examined on the excitation of spinal neurones by electrophoretically administered excitatory amino acids and acetylcholine. GK5 and (+)-PCMP were more potent and selective antagonists of N-methylaspartate (NMA) than were GK4 and (-)-PCMP. None of these phencyclidine derivatives showed stereoselectivity in their effects on excitation of neurones by kainate, quisqualate and acetylcholine. The differences in potency between each pair of isomers as NMA antagonists correlates well with the differences reported in results from phencyclidine binding assays and behavioural tests.

Action Potentials↗
PubMed1983

The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate.

The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone-anaesthetized cats and rats. Both ketamine and phencyclidine selectively blocked excitation by N-methyl-aspartate (NMA) with little effect on excitation by quisqualate and kainate. Ketamine reduced responses to L-aspartate somewhat more than those of L-glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other. On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root-evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation. Intravenous ketamine, 2.5-20 mg/kg, and phencyclidine, 0.2-0.5 mg/kg, also selectively blocked excitation of neurones by NMA. Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or gamma-aminobutyricacid (GABA). The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.

Acetylcholine↗
PubMed1982

The depolarization of feline ventral horn group Ia spinal afferent terminations by GABA.

The unmyelinated terminal regions of extensor muscle Ia afferent fibres were stimulated electrically near lumbar motoneurones in anaesthetised cats using 300 microseconds pulses of less than 1 microA passed through the central NaCl barrel of seven barrel micropipettes. Such terminations were identified by anodal blocking factors of less than four and the latency of the antidromic impulse recorded in the appropriate peripheral muscle nerve. Although the effects of microelectrophoretically administered GABA were occasionally complex, the most consistent finding was a reduction in termination threshold followed by an increase. Both this reduction in threshold by GABA, and that produced by tetanic stimulation of low threshold flexor afferents (PAD) were diminished by microelectrophoretic bicuculline methochloride. This GABA antagonist alone elevated the threshold of some terminations but did not reduce the depolarizing action of either potassium or L-glutamate. Furthermore, since reductions in threshold by GABA, but not by either potassium or L-glutamate, were associated with a decrease in PAD, GABA appears to increase terminal membrane conductance. Since neither GABA nor bicuculline methochloride influenced the threshold or afferent depolarization of non-terminal regions of Ia fibres, there results are consistent with the function of GABA as a depolarizing transmitter at gabergic axoaxonic synapses upon the terminals of Ia afferent fibres synapsing with motoneurones.

Afferent Pathways↗