N-methyl-D-aspartate binding sites in neonatal and adult brain.
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Aged↗
Biomedical subjects
P Slater
Publications and source records attributed to P Slater.
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↗
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↗
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↗
Social signalling and schizophrenia: the significance of neurochemical and morphological abnormalities of the basolateral circuit.
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8-Hydroxy-2-(di-n-propylamino)tetralin↗
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.
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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↗
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↗
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↗
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↗
Consensus meeting agrees distribution of 5-HT3 receptors in mammalian hindbrain.
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Animals↗
Hyperinnervation of orbital frontal cortex in schizophrenia.
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Frontal Lobe↗
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↗
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.
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High affinity serotonin binding sites in human brain: a comparison of cerebral cortex and basal ganglia.
The high-affinity binding of 3H-serotonin and 3H-DPAT was studied in membrane preparations and tissue sections of cerebral cortex and basal ganglia of human brain. In tissue sections, 3H-serotonin bound to sites present at high density in the cerebral cortex, hippocampus and basal ganglia. 3H-DPAT bound predominantly to the outer layers of the cerebral cortex and the hippocampus, no significant binding was observed in the basal ganglia. In cortical membranes 3H-serotonin bound to a heterogeneous population of sites, one of which was similar to a binding site labelled by 3H-DPAT (the putative 5HT-1A receptor). 3H-serotonin binding to membranes prepared from the putamen displayed low affinity for DPAT, mesulergine and spiperone, RU24969 was considerably less potent than serotonin itself. This 3H-serotonin binding site does not have the properties of those sites described in rodent brain (5HT-1A, 5HT-1B, and 5HT-1C), and may represent a novel serotoninergic binding site.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia.
Glutamatergic mechanisms have been investigated in postmortem brain samples from schizophrenics and controls. D-[3H]Aspartate binding to glutamate uptake sites was used as a marker for glutamatergic neurones, and [3H]kainate binding for a subclass of postsynaptic glutamate receptors. There were highly significant increases in the binding of both ligands to membranes from orbital frontal cortex on both the left and right sides of schizophrenic brains. The changes are unlikely to be due to antemortem neuroleptic drug treatment, because no similar changes were recorded in other areas. A predicted left-sided reduction in D-[3H]aspartate binding was refuted at 5% probability, but not at 10%. Previously reported high concentrations of dopamine in left amygdala were strongly associated with low concentrations of D-[3H]aspartate binding in left polar temporal cortex in the schizophrenics. The findings are compatible with an overabundant glutamatergic innervation of orbital frontal cortex in schizophrenia. The results also suggest that schizophrenia may involve left-sided abnormalities in the relationship between temporal glutamatergic and dopaminergic projections to amygdala.
Aspartic Acid↗
Autoradiographic visualization of kappa opioid receptors with labelled dynorphins in guinea pig brain.
The distribution of kappa opioid receptors in guinea pig brain was measured by in vitro receptor autoradiography using [3H]dynorphin A1-9, [3H]dynorphin A1-8 and [3H]bremazocine as ligands. The sites labelled by the two dynorphins had identical, heterogeneous distributions in brain sections. High levels of kappa receptors were seen in striatum, claustrum, nucleus accumbens and laminae V and VI of the cerebral cortex. The substantia nigra and superior colliculus also had high dynorphin binding levels. The [3H]dynorphin autoradiographs were closely similar to those obtained using [3H]bremazocine in the presence of mu and delta receptor displacers. It is concluded that tritiated dynorphin A fragments can be used for autoradiographic studies of kappa opioid receptors in brain.
Animals↗
Regional changes in [3H]D-aspartate and [3H]TCP binding sites in Alzheimer's disease brains.
The specific binding of [3H]D-aspartate, a marker for the presynaptic glutamate uptake site, and [3H]N-(1-[2-Thienyl]cyclohexyl)-piperidine [( 3H]TCP), a high affinity ligand for the N-methyl-D-aspartate (NMDA)-associated phencyclidine binding site, was measured in homogenates of brain from normal subjects and from subjects with neuropathologically confirmed Alzheimer's disease. Alzheimer's disease was associated with a reduction in [3H]D-aspartate binding density in temporal cortex and caudate nucleus. By contrast, a reduction in the receptor density for [3H]TCP binding was only recorded in the frontal cortex. Thus, glutamate-containing nerve terminals are severely reduced in Alzheimer's disease, whilst the postsynaptic NMDA-phencyclidine receptor complex is much less affected. These findings have implications for theories of glutamate neurotoxicity in Alzheimer's disease.
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