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Biomedical subjects

P Slater

Publications and source records attributed to P Slater.

At least 19 recordsLinked to original sources
PubMed1994

A polyamine binding site labelled with [3H]spermidine in developing human cerebellum.

Polyamines regulate cell division in developing brain. Neuronal membranes and the NMDA receptor have polyamine binding or functional sites. We have visualized [3H]spermidine binding in human cerebellum sections. Autoradiographs showed high specific [3H]spermidine binding in granule cell layer and low binding in molecular layer in neonate, infant and adult cerebellum which qualitatively resembled NMDA binding. Cerebellum from neonates and infants below 6 months had a further zone of dense [3H]spermidine binding in the external granule layer of migratory cells. This second zone may show a polyamine regulatory site for cerebellar development from fetal life to early infancy.

Aged↗
PubMed1993

Postnatal changes in N-methyl-D-aspartate receptor binding and stimulation by glutamate and glycine of [3H]-MK-801 binding in human temporal cortex.

1. Homogenates of human infant and adult temporal cortex were used to measure [3H]-TCP and [3H]-MK-801 binding to the N-methyl-D-aspartate (NMDA)-coupled ion channel phencyclidine site. 2. Both [3H]-TCP and [3H]-MK-801 binding increased in infant cortex by > 100% between term and 26 weeks suggesting that the numbers of NMDA receptors increase during postnatal brain development. 3. [3H]-MK-801 binding was measured under non-equilibrium conditions in temporal cortex homogenates with the addition of 100 microM of L-glutamate plus a range of concentrations (0.05 microM-100 microM) of glycine. Glutamate and glycine increased [3H]-MK-801 binding by stimulating NMDA receptors and improving [3H]-MK-801 access to ion channel binding sites; maximum stimulation in adult and infant temporal cortex was achieved with 100 microM glutamate plus 5 microM glycine; a higher concentration of glycine (50 microM) reduced [3H]-MK-801 binding to below maximum. 4. The stimulation by 100 microM glutamate plus 5 microM glycine of [3H]-MK-801 binding in infant temporal cortex was affected by postnatal age. For example, although the stimulation of [3H]-MK-801 binding in 5-6 week infant cortex (236% of basal) was similar to adult cortex (230% of basal), in samples taken from infants aged 5-6 months glycine (plus glutamate) stimulation of [3H]-MK-801 binding (392% of basal) was substantially greater than that measured in adult temporal cortex. 5. The binding of [3H]-glycine to the glycine modulatory site associated with the NMDA receptor in infant cortex also increased with postnatal age by > 100% between term and 26 weeks. 6. It is concluded that NMDA receptors in infant cortex increase to levels greater than those in adult cortex during postnatal development. The results do not exclude the possibility that the transiently increased NMDA receptor-ion channel complex in infant cortex shows enhanced responses to agonists and modulators.

Adult↗
PubMed1993

Glycine site of the excitatory amino acid N-methyl-D-aspartate receptor in neonatal and adult brain.

The N-methyl-D-aspartate (NMDA) receptor complex in brain is a glutamate receptor subtype with several recognition sites including a glycine site that is able to modulate and activate allosterically the receptor. This receptor may be important in the regulation of developmental synaptic plasticity. The release of glutamate and consequent overstimulation of NMDA receptors that follows hypoxia-ischaemia leads to brain damage. Brain tissue obtained at necropsy was studied in a total of 16 term infants aged less than 1 week to 22 weeks and in four adults aged from 66 to 84 years. Glycine sites were determined in brain sections by the binding of the selective ligand [3H]5,7-dichloro-kynurenic acid and measured by autoradiography. In infant brains the amount of binding to the glycine site was higher in temporal cortex and hippocampus than in basal ganglia and was also higher than in comparable areas of adult brain. The amount of glycine site binding in infant cortex increased with postnatal age. The data suggest that infant brain acquires a relatively high density of NMDA receptors in temporal lobe due to postnatal proliferation of glutamatergic synapses. These findings have therapeutic implications as drugs that reduce NMDA receptor function by blocking the glycine modulatory site would be pertinent to preventing brain damage after hypoxia-ischaemia.

Aged↗
PubMed1992

Age-related changes in binding to excitatory amino acid uptake sites in human cerebellum.

In vitro autoradiography and test-tube assay of the sodium-dependent binding of D-[3H]aspartate were used to localize and quantify the uptake site for the excitatory amino acid neurotransmitters glutamate and aspartate in the cerebellar cortex of human cerebellar hemispheres. Autoradiograms revealed a pronounced heterogeneity in the distribution of D-[3H]aspartate binding in cortex from adult brains, with the highest binding density corresponding to the Purkinje cell layer, high binding in molecular layer and low binding in granule cell layer. In contrast, cerebellar cortex from infants at term (40 weeks gestation) had only low binding of the ligand in both the molecular and the Purkinje cell layers. Both methods employed for measuring D-[3H]aspartate binding showed that the number of binding sites in Purkinje and molecular layers increased rapidly from term to 20 weeks postnatal age and achieved levels higher than those found in adult cerebellum. It is concluded that a substantial increase in the numbers of glutamate/aspartate uptake sites takes place in the human cerebellum during the early postnatal period. It is deduced that the excess uptake sites are eliminated as the cerebellum matures.

Aged↗
PubMed1992

Age-related changes in binding to excitatory amino acid uptake site in temporal cortex of human brain.

The binding of D-[3H]aspartate to the specific uptake site for the excitatory amino acids glutamate and aspartate was measured in homogenates of temporal lobe cortex taken at postmortem from 76 human infant and adult brains. Binding levels were very low in brains of preterm and term infants but increased rapidly during the first 20 postnatal weeks to reach levels which exceeded those in adult brains. Linear regression analysis which compared the amount of D-[3H]aspartate binding with the age of the infant, showed a positive correlation up to 25 postnatal weeks. Saturation analysis showed that the maximum number of D-[3H]aspartate binding sites (Bmax) in temporal cortex from infants aged 20 postnatal weeks was 3 times greater than the number of sites in adult brain. The findings show that the number of excitatory amino acid uptake sites, which may be associated in part with presynaptic terminals, increase in number rapidly after birth. Furthermore, the data may indicate that a slow regression of excitatory amino acid terminals occurs during the later stages of brain development.

Aging↗
PubMed1992

Regionally selective deficits in uptake sites for glutamate and gamma-aminobutyric acid in the basal ganglia in schizophrenia.

In a post-mortem study of schizophrenic and control subjects, the sodium-dependent binding of D-[3H]aspartate and [3H]nipecotic acid were used to investigate uptake sites of glutamate and gamma-aminobutyric acid (GABA), respectively, in subcortical brain regions. Binding to the glutamate uptake site was substantially reduced in both the putamen and lateral pallidum of the schizophrenic subjects. Binding to the GABA uptake site was substantially reduced in the putamen; smaller reductions were apparent in the caudate nucleus and lateral pallidum. The results suggest that glutamatergic and GABAergic mechanisms in the basal ganglia are abnormal in schizophrenia. These abnormalities could be relevant to the development of psychosis but could also relate to the spectrum of mild motor disturbances often described in the disease.

Aspartic Acid↗
PubMed1991

Binding to the glycine site of the NMDA receptor complex in brains of patients with Alzheimer's disease.

Ligand binding and in vitro receptor autoradiography were used to measure [3H]glycine binding to the modulatory site associated with the glutamate N-methyl-D-aspartate (NMDA) receptor in 4 areas of control and Alzheimer's disease brains. Binding of [3H]glycine to membranes prepared from temporal cortex was significantly reduced in Alzheimer's disease brains. Saturation analysis showed reductions in both the affinity of binding and the maximum number (Bmax) of binding sites. Autoradiograms of [3H]glycine binding in temporal cortex sections did not show a statistically significant reduction in binding in Alzheimer's disease. The findings suggest that in Alzheimer's disease the glycine modulatory site of the NMDA receptor complex is affected to a small extent by the loss of glutamatergic terminals which has previously been demonstrated.

Aged↗
PubMed1991

Analysis of laminar distribution of kappa opiate receptor in human cortex: comparison between schizophrenia and normal.

Quantitative receptor autoradiography using the ligand [3H]U 69593 and tritium sensitive film was used to visualize the kappa subtype of opiate receptor in sections from 4 normal human postmortem brains. Data obtained from cortical scans, which measured receptor densities across the left and right parahippocampal gyri, were subject to Fourier analysis. This revealed that the kappa receptor distribution was described by a curve having significant first and second component harmonics. This analysis method can be used to describe a binding pattern mathematically, thus enabling a comparison to be made between normal and diseased brains. The same analysis was applied to [3H]U 69593 autoradiograms prepared from sections of 4 schizophrenic postmortem brains. The kappa receptor distribution in the schizophrenic group not only failed to produce the same pattern as the controls, but also showed no consistent pattern within the group. The method described can be used to investigate alterations in receptor distribution which occur in neuropsychiatric diseases involving neuronal dysplasia or atrophy.

Adult↗
PubMed1991

Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Effects of disease process and neuroleptic medication.

The specific binding of [3H]TCP and [3H](+)3-PPP, radioligands which respectively label PCP-NMDA and sigma binding sites was measured in tissue homogenates prepared from dissected areas of control and schizophrenic postmortem brains. [3H]TCP binding was bilaterally increased in orbital frontal cortex (Brodmann area 11) of schizophrenic brains. This finding may be due to an increased glutamatergic innervation of orbital frontal cortex since it parallels our findings of increased [3H]kainate and [3H]D-aspartate binding in this area. In contrast, [3H](+)3-PPP binding was reduced in each of the four brain regions examined. The reductions were greatest in brains from the schizophrenic subjects receiving neuroleptics at the time of death. Neuroleptics remaining in the brains of these subjects may compete in vitro with [3H](+)3-PPP for binding to the sigma site.

Antipsychotic Agents↗
PubMed1991

A synthesis of acylphosphonic acids and of 1-aminoalkylphosphonic acids: the action of pyruvate dehydrogenase and lactate dehydrogenase on acetylphosphonic acid.

Acylphosphonic acids, R-CO-PO(OH)2, have been synthesized by the steps [formula: see text] of which the last is new and provides a mild method for de-esterifying acylphosphonic acids. Their reductive amination gives a simple way of making 1-aminoalkylphosphonic acids. Acetylphosphonic acid inhibited NAD+ reduction by pyruvate with the pyruvate dehydrogenases from Escherichia coli and Bacillus stearothermophilus. The inhibition was competitive with pyruvate, with Ki of 6 microM for the E. coli enzyme (pyruvate Km 0.5 mM) and one of 0.4 mM of the B. stearothermophilus enzyme (pyruvate Km 0.1 mM). Acetylphosphonate and its monomethyl ester are substates for pig heart lactate dehydrogenase, with Km values of 15 mM and 10 mM respectively (pyruvate Km 0.05 mM) and specificity constants one thousandth that for pyruvate.

Acetaldehyde↗
PubMed1990

Identification and distribution of 5-HT3 recognition sites within the human brainstem.

The present studies demonstrate the presence of specific [3H]GR65630 binding sites within the human brainstem using the techniques of in vitro receptor autoradiography and ligand binding to homogenates. Autoradiography revealed the greatest accumulation of specific binding in the area postrema and subpostrema (AP/ASP). A lower level of specific binding was identified in the nucleus tractus solitarius (excluding area subpostrema). No specific binding was evident in the remainder of the hindbrain at this level. Discrete dissection followed by ligand binding to homogenates revealed that the specific binding of [3H]GR65630 (defined by the presence of 30 microM metoclopramide) was differentially distributed with highest levels in the AP/ASP (112.1 fmol/mg protein) and lower levels in the dorsal vagal complex (nucleus tractus solitarius--excluding the area subpostrema--dorsal motor nucleus of the vagus and hypoglossal nucleus) (DVC) and olivary nucleus (ON) (22.9 and 3.9 fmol/mg, respectively). No specific binding was detectable in the reticular formation (RF) located ventral to the dorsal vagal complex. The specific [3H]GR65630 binding site was pharmacologically similar to the 5-HT3 receptor since the potent and selective 5-HT3 receptor antagonists ICS 205-930 and zacopride (100 nM) and the agonist 5-HT (10 microM) inhibited binding to the same extent as metoclopramide in each of the individual areas (90, 60 and 20% in the AP/ASP, DVC and ON, respectively). The 5-HT1-like and 5-HT2 receptor antagonist methysergide (10 microM) failed to compete for the binding site. 5-HT3 receptor recognition sites within the AP/ASP and the DVC may be functionally involved in the ability of 5-HT3 receptor antagonists to control emesis.

Adult↗
PubMed1989

Reduced GABA uptake sites in the temporal lobe in schizophrenia.

The binding of [3H]nipecotic acid, a ligand for labelling GABA uptake sites in brain, was measured in left and right frontal cortex, polar temporal cortex, hippocampus and amygdala from control and schizophrenic postmortem brains. In schizophrenic brains, single concentration [3H]nipecotic acid binding was reduced bilaterally in amygdala and hippocampus and on the left side only in polar temporal cortex. These data suggest that GABA neurones are involved in the cerebral atrophy of schizophrenia and, in agreement with other studies, that this process is most pronounced in left temporal cortex.

Amygdala↗
PubMed1989

Reduced D-[3H]aspartate binding in Down's syndrome brains.

The binding of D-[3H]aspartate to glutamate uptake sites was measured in post-mortem brains from subjects with Down's syndrome (DS) and age-matched controls. DS brains had substantially reduced D-[3H]aspartate binding in the frontal and temporal cortex, hippocampus and caudate nucleus. There was no correlation between the numbers of Alzheimer-like plaques and tangles or clinically-assessed dementia and D-[3H]aspartate binding in DS brains. The binding of [3H]N-(1-[2-thienyl]cyclohexyl)piperidine ([3H]TCP) to postsynaptic N-methyl-D-aspartate sites was normal in DS brains. This study suggests that the reduction in glutamate uptake sites in DS is more substantial and widespread than in Alzheimer's disease.

Aged↗