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Biomedical subjects

E W Harris

Publications and source records attributed to E W Harris.

31 records · Page 2Linked to original sources
PubMed1985

Effects of synaptic antagonists on perforant path paired-pulse plasticity: differentiation of pre- and postsynaptic antagonism.

The effects of different synaptic antagonists on paired-pulse plasticity of medial perforant path responses were studied in rat hippocampal slices. Baclofen reduces the response to activation of the perforant path, but does not have the same net effect on the first and second responses to paired stimulation: baclofen lessens the percent paired-pulse depression of medial perforant path responses. Furthermore, at doses that reduced the control medial perforant path response by half, paired-pulse plasticity changed from paired-pulse depression to paired-pulse potentiation. A similar effect on medial perforant path paired-pulse plasticity is produced by decreasing extracellular calcium concentration. Kynurenic acid reduces the first and second responses to paired stimulation proportionately the same, and, therefore, has no effect on the percent paired-pulse depression. These results suggest that baclofen acts presynaptically to reduce the synaptic response, whereas kynurenate acts postsynaptically. Adenosine was also found to be a potent antagonist of medial perforant path responses, with effects on paired-pulse plasticity similar to baclofen: a new synaptic antagonist, N-p-chlorobenzoyl-piperazine-2,3-dicarboxylate, was found to have effects like kynurenate, suggesting that it is also a postsynaptic receptor blocker.

Adenosine↗
PubMed1984

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors.

A series of omega-phosphono-alpha-carboxylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (+/- AP5 and +/- AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response. +/- AP5 and +/- AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpotentiated synaptic response amplitude. +/- AP4, +/- AP6 and +/- AP8 did not block amino acid excitant responses or LTP. These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.

2-Amino-5-phosphonovalerate↗
PubMed1983

Effects of acidic amino acid antagonists on paired-pulse potentiation at the lateral perforant path.

The glutamate analogue 2-amino-4-phosphonobutyric acid (APB) has been shown to selectively reduce synaptic transmission along the lateral portion of the perforant path input to the dentate gyrus. APB is studied here with respect to effects on paired-pulse potentiation (PPP) along the perforant path. Application of APB causes a reduction in lateral perforant path responses, but also an increase in the %PPP of that response. The effect does not result simply from reducing response size, because the amount of potentiation of matched first responses increases, and also because APB reduces the potentiated response proportionately less than a comparable first response. A similar effect is seen by decreasing extracellular calcium. Reducing lateral perforant path responses with kynurenic acid, which apparently acts on postsynaptic sites, does not have a similar effect on PPP. These results may indicate a presynaptic action of APB, possibly mediated via an effect on presynaptic calcium availability.

Aminobutyrates↗
PubMed1982

Structure--activity relationships of L-glutamate receptor ligands: role of the omega-acidic terminal.

Acidic amino acid analogues varying in their omega-terminal were evaluated: (1) as neuronal excitants or antagonists of excitatory synaptic transmission, and (2) as inhibitors of L-[3H]glutamate binding to synaptic membranes. omega-Phosphonates were antagonists and inhibited L-glutamate binding to the 2-amino-4-phosphonobutyrate (APB)-sensitive population of binding sites; omega-sulfonates and omega-carboxylates were excitants and inhibited L-glutamate binding to APB-sensitive and -insensitive sites. The data indicate that properties of the omega-acidic group are important for establishing the relative potencies of antagonist substances and the overall excitatory/antagonist activity of these analogues.

Aminobutyrates↗
PubMed1982

Regulation of glutamate receptors: possible role of phosphatidylserine.

The polar head group of the phospholipid phosphatidylserine is similar in structure to the glutamate analogue 2-amino-4-phosphonobutyric acid (APB), an antagonist of excitatory transmission in the brain. When tested in ligand binding assays phosphatidylserine and its polar head group components O-phosphoserine and L-alpha-glycerophosphoserine were good displacers of APB-sensitive L-glutamate binding. The polar head group components were also antagonists of synaptic field potentials in the rat dentate gyrus evoked by stimulation of a presumed glutamate-using pathway. These results suggest that phosphatidylserine may regulate the activity of synaptic L-glutamate receptors.

Animals↗
PubMed1979

Analysis of the habituation-like changes in transmission in the temporodentate pathway of the rat.

Habituation-like decrements in extracellular measures of synaptic activation (population EPSP) and cell discharge (population spike) were analyzed in the dentate gyrus of the rat following repetitive low-frequency stimulation of the medial and lateral entorhinal cortex. Stimulation of either subdivision of the entorhinal projection system resulted in comparable habituation-like response decrements with similar stimulation regimens. However, habituating stimulation of one subdivision did not result in decreased responsiveness to stimulation of the other. Repetitive low-frequency stimulation or even a single pulse delivered to either subdivision did, however, result in a potentiation of granule cell discharge in response to stimulation of the other subdivision (a form of heterosynaptic potentiation). This heterosynaptic potentiation of granule cell discharge was not accompanied by any increase in the extracellular EPSP. Comparisons of the relationship between the population EPSP and population spike before and during habituating stimulation revealed changes in cell discharge in response to the habituating stimulus which could not be accounted for by changes in synaptic activation alone. The results suggest that repetitive activation of the temporodentate pathway alters granule cell output as a result of two processes, a habituation-like decrement in synaptic activation, and a potentiation of granule cell discharge as a consequence of prior activation.

Afferent Pathways↗
PubMedDate not supplied

Classification of compounds for prevention of NMDLA-induced seizures/mortality, or maximal electroshock and pentylenetetrazol seizures in mice and antagonism of MK801 binding in vitro.

Intravenous injection of N-methyl-D,L-aspartic acid (NMDLA) into mice produces characteristic convulsions followed by death. The present study was designed to determine the degree of blockade of these seizures/mortality by compounds acting at various subsites on the N-methyl-D-aspartic acid (NMDA) receptor complex (competitive and noncompetitive antagonists, as well as inhibitors of the strychnine-insensitive glycine subsite, and Zn++ subsite agonists), and also calcium channel blockers, clinically used anticonvulsants, plus selected compounds with activities or structures similar to specific agents chosen. Activity among compounds was correlated to in vitro potency regarding inhibition of binding of MK801 to the ionic channel subsite associated with the NMDA receptor. Furthermore, all compounds were examined for antiseizure properties with respect to tonic hindlimb extension elicited by maximal electroshock (MES) and clonus induced by pentylenetetrazol (PTZ). Drugs were subsequently classified according to their spectra of efficacy in these tests. The following characteristics emerged: 1) agents active at all 3 NMDA mechanisms (convulsions/mortality/MK801 binding) plus MES and PTZ, were MK801 and CPP [3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid]; 2) active at all the NMDA mechanisms and MES were ketamine and dextromethorphan; 3) active against NMDLA-induced convulsions/mortality, MES and PTZ, but not MK801 binding, were doxepin, desipramine and diazepam; 4) active against NMDLA-induced convulsions/mortality and MES were des-Me-doxepin, flunarizine and remacemide; 5) active against NMDLA-induced convulsions/mortality and PTZ was nisoldipine; 6) active against only NMDLA-induced convulsions/mortality were chlorpheniramine and iproniazid; 7) active in the MES and PTZ tests were phenobarbital, pentobarbital and valproate; 8) active in the MES test alone were phenytoin and carbamazepine; 9) active against PTZ only was ethosuximide; 10) active only in the in vitro MK801 binding assay were HA966, 7-Cl-kynurenate and AP7 (2-amino-7-phosphonoheptanoic acid); and 11) no demonstrable actions had AP4 (2-amino-4-phosphonobutyric acid) and mianserin. In conclusion, inhibition of NMDLA-induced convulsions/mortality in vivo is not necessarily correlated to a noncompetitive displacement of MK801 binding to NMDA receptor sites in vitro, nor is inhibition of NMDA-elicited convulsions/mortality correlated with a specific ability of a compound to inhibit either MES or PTZ seizures.

Animals↗
PubMedDate not supplied

Comparison of liquid chromatographic and bioassay procedures for determining depletion of intramuscularly injected tylosin.

Crossbred pigs weighing 80-110 kg were injected intramuscularly in the ham with 8.8 mg/kg tylosin. Animals were slaughtered in groups of 3 at intervals of 4 h, and 1, 2, 4, and 8 days after injection, and samples of blood, injected muscle, uninjected muscle, liver, and kidney were analyzed by liquid chromatography (LC) and by bioassay using Sarcina lutea as the test organism. The LC method was far more sensitive with a detection limit of less than 0.1 ppm, while the detection limit by bioassay was about 0.5 ppm in tissue. Results by bioassay and LC sometimes differed considerably for tissue samples. Residues in all tissues were below the tolerance limit of 0.2 ppm at 24 h, except in the injected muscle in one animal. Residues were not detected in any tissue of any animal at 48 h after treatment.

Animals↗