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Biomedical subjects

G P Reynolds

Publications and source records attributed to G P Reynolds.

At least 19 recordsLinked to original sources
PubMed1999

Agonist-stimulated GTPgamma[35S] binding to 5-HT(1A) receptors in human post-mortem brain.

In this study, we have demonstrated that the technique of agonist-stimulated guanosine-5'-O-(3-[35S]thio)-triphosphate (GTPgamma[35S]) binding can be successfully used to study the functional activity of the human 5-HT(1A) receptor in post-mortem tissue. Full agonist and antagonist actions of ligands specific for this site have been shown. Utilising 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-fluorobenzamido]- ethyl-piperazine ([3H]MPPF), the affinity of several antipsychotics for the 5-HT(1A) receptor was determined; clozapine and quetiapine were found to have K(i) values at this receptor that, relative to their dopamine D(2) receptor affinities, indicated at least partial receptor occupancy at clinical doses. The agonist/antagonist activity of these two antipsychotics was studied using GTPgamma[35S] binding. Both compounds show partial agonism, and in addition, clozapine exhibited a larger degree of antagonism against 5-HT-stimulated binding than did quetiapine.

Aged↗
PubMed1999

Deficits of NMDA receptors and glutamate uptake sites in the frontal cortex in AIDS.

HIV infection frequently leads to neurological deficits and is associated with neuronal loss and damage. We have investigated two neurochemical indicators of the integrity of glutamatergic systems in brain tissue taken postmortem from the frontal cortex of AIDS patients and age-matched controls. NMDA receptor density was determined by saturation analysis of [3H]L-689,560 occupation of the glycine binding site, while saturable [3H]D-aspartate binding provided a marker of the glutamate uptake site. NMDA receptor density was significantly reduced by 33% in the AIDS group, an effect which was more profound in the demented patients, and ligand binding to the glutamate uptake site was significantly reduced by >50% in demented AIDS patients compared with the control group. These reported glutamatergic deficits are consistent with an NMDA-receptor mediated excitotoxic mechanism being responsible for the neuronal loss occurring in AIDS.

AIDS Dementia Complex↗
PubMed1999

Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens.

The present study investigated the effects of excitotoxic lesions of the prefrontal cortex (PFC) on dopamine (DA) and excitatory amino acid (EAA) function in the nucleus accumbens core using in vivo microdialysis in freely moving rats. As a postsynaptic marker of neuronal function, the nuclear levels of the transcriptional factor CREB and its active phosphorylated form, CREB-P, were measured in the ventral tegmental area (VTA), and in the core and shell subregions of the nucleus accumbens of sham and lesioned animals. PFC-lesioned animals exhibited a greater locomotor response to novelty and amphetamine administration (125-500 microg/kg i.v.). No change was observed in extracellular levels of glutamate or saturable d-aspartate binding (a marker for the high-affinity EAA transporter) in the nucleus accumbens of PFC-lesioned animals. Extracellular levels of DA were comparable in sham and lesioned animals under tonic conditions, however, following amphetamine administration, DA efflux was significantly attenuated in lesioned animals. No correlation was observed between microdialysate levels of amino acids and the attenuated dopaminergic response to amphetamine in lesioned animals. Further, no effect of the lesion was found on nuclear CREB protein in saline- and amphetamine-treated rats. The density of CREB-P immunoreactive nuclei, while remaining unchanged in the VTA, increased in the nucleus accumbens shell following amphetamine treatment in lesioned animals. The results show that an important modulatory role of the PFC on the behavioural response to novelty and amphetamine is associated with the level of immediate-early gene regulation rather than levels of extracellular DA and amino acids in the ventral striatum.

Amphetamine↗
PubMed1999

Brain neurotransmitter deficits in mice transgenic for the Huntington's disease mutation.

Huntington's disease (HD) is associated with an expansion in the CAG repeat sequence of a gene on chromosome 4, resulting in a neurodegenerative process particularly affecting the striatum and with profound but selective changes in content of various neurotransmitters. Recently, transgenic mice expressing a fragment of the human HD gene containing a large CAG expansion have been generated; these mice exhibit a progressive neurological phenotype that includes motor disturbances, as well as neuronal deficits. To investigate their underlying neurotransmitter pathology, we have determined concentrations of GABA, glutamate, and the monoamine neurotransmitters in several brain regions in these mice and control animals at times before and after the emergence of the behavioural phenotype. In contrast to the findings in HD, striatal GABA was unaffected, although a deficit was observed in the cerebellum, consistent with a dysfunction of Purkinje cells. Losses of the monoamine transmitters were observed, some of which are not seen in HD. Thus, 5-hydroxytryptamine and, to a greater extent, 5-hydroxyindoleacetic acid levels were diminished in all brain regions studied, and noradrenaline was particularly affected in the hippocampus. Dopamine was decreased in the striatum in older animals, parallelling evidence for diminished dopaminergic activity in HD.

Animals↗
PubMed1998

Increased density of glutamate/N-methyl-D-aspartate receptors in putamen from schizophrenic patients.

Saturable radioligand binding of [3H]L-689,560 to the glycine site of the N-methyl-D-aspartate (NMDA) glutamate receptor complex was employed to determine the density of this receptor in putamen, caudate and nucleus accumbens taken post mortem from schizophrenic patients and matched controls. Receptor density was found to be significantly increased in putamen of schizophrenics (P=0.012), although no significant change was found in the other two areas studied. Further experiments following 21 days administration of haloperidol to rats provided no evidence that the increase was related to prior drug treatment.

Animals↗
PubMed1998

Increased peripheral benzodiazepine binding sites in the brain of patients with Huntington's disease.

Huntington's disease (HD) is a hereditary disorder associated with the development of dyskinesias and dementia, characterised by profound atrophy of the striatum and, to a lesser extent, other brain areas. A relative gliosis has been described. One marker for such inflammatory gliosis is an elevation of peripheral type benzodiazepine binding sites (PTBBS); these have also been shown to be increased following acute experimental and chronic degenerative neuronal damage. The present study investigates [3H]PK11195 binding to PTBBS in three brain areas of HD patients. We found a highly significant increase in PTBBS density in the putamen, a moderate but significant increase in the frontal cortex of HD patients and no significant change in the temporal cortex. Comparing these results to findings in other neurodegenerative diseases, e.g. Alzheimer's disease, where inflammation is discussed as a possible primary as well as a secondary pathological mechanism, our observations point to a possible involvement of inflammation in the neurodegenerative process in HD.

Adult↗
PubMed1998

Antipsychotic drug affinities at alpha2-adrenoceptor subtypes in post-mortem human brain.

Although there is substantial interest in the possible role of alpha2-adrenoceptors in the antipsychotic efficacy of clozapine, there has so far been no systematic investigation of antipsychotic drug affinities for alpha2-adrenoceptor subtypes in the human brain. We have assessed the ability of three classical and four 'atypical' antipsychotic drugs to displace binding of [3H]RX821002 to alpha2-adrenoceptors in human post-mortem brain tissue. All seven drugs displaced radioligand from an apparent single site in the frontal cortex, consistent with the sole presence of the alpha2A-subtype in this region. In the caudate nucleus, all drugs except risperidone differentiated two sites, of which one was equivalent to the cortical alpha2A-subtype and the second, accounting for approximately two-thirds of specific radioligand binding, showed higher affinity for the antipsychotics. This second site, on the basis of prazosin's relatively high affinity, is consistent with an alpha2B-adrenoceptor identity. The new antipsychotic quetiapine showed the greatest selectivity for this receptor site; both quetiapine and clozapine had affinities for the alpha2B site which were greater than their affinities for human D2 dopamine receptors. The possible role of this site in the mechanisms underlying aspects of antipsychotic drug atypicality is discussed.

Antipsychotic Agents↗
PubMed1997

Deficits of [3H]D-aspartate binding to glutamate uptake sites in striatal and accumbens tissue in patients with schizophrenia.

The hypothesis involving glutamate in the neuropathology of schizophrenia has attracted great interest. Several studies report dysfunctions in glutamatergic systems, including alterations in kainate and N-methyl-D-aspartate (NMDA) receptors in various areas, as well as changes in the number of glutamate uptake sites. We have studied this further using [3H]D-aspartate binding to glutamate uptake sites as a measure of the integrity of presynaptic glutamate systems in several areas (caudate nucleus, putamen, nucleus accumbens, frontal cortex and temporal cortex) of brain tissue taken at autopsy from schizophrenic patients and controls. A significant decrease in the number of glutamate uptake sites was apparent in caudate nucleus, putamen and nucleus accumbens in the schizophrenia group, indicating an impaired glutamatergic innervation of these subcortical regions. However, no significant changes were found in the two cortical regions studied.

Aged↗
PubMed1997

Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics.

Recent studies have provided evidence for a functional impairment of gamma-aminobutyric acid (GABA)-containing interneurons in the prefrontal cortex of schizophrenics. This evidence includes reported deficits of basket and chandelier cells, which are known to contain the calcium-binding protein parvalbumin. Using a monoclonal antibody against parvalbumin we investigated possible changes in this subpopulation of neurons in the prefrontal cortex of schizophrenic cases and controls. Significantly reduced numbers of parvalbumin-immunoreactive neurons were observed in laminae III and IV, while no difference was detected in cortical width. Our findings are consistent with damage following a toxic insult, occurring during a developmental 'window of vulnerability' and specifically affecting this subpopulation of GABAergic neurons.

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PubMed1997

What is an atypical antipsychotic?

This is an exciting time for research into the drug treatment of schizophrenia. Modern techniques in imaging and molecular biology have contributed to our understanding of the receptor mechanisms of antipsychotic drug action. Several new antipsychotics are, or will shortly be, available and each of these new drugs promise improvements over classical antipsychotics. This review will discuss the concept of atypicality in antipsychotic drugs, and will describe some of the models for identification of improved antipsychotic action. The various receptor mechanisms proposed to underlie atypical antipsychotic action, several of which have featured in recent debates in this journal, will be considered in the light of the pharmacology of some of the newly-emerging antipsychotic drugs.

Antipsychotic Agents↗
PubMed1996

An improved model for examining delayed excitotoxic neurodegeneration in isolated chick retina.

Extensive use of the embryonic chick retina model has been made for examining mechanisms of acute excitotoxicity. The standard retina model does not, however, address the concept of delayed excitotoxicity. In previous retina based studies extending the time course to 24 h has proven problematic owing to damage arising in control tissue. Recently a model for examining delayed excitotoxicity in isolated retina was proposed. This method relied on a significant reduction in incubating temperature to avoid the variable damage occurring in control tissue. The data in the present study suggest that a reduction in temperature results in N-methyl-D-aspartate (NMDA) receptor dysfunction, preventing accurate assessment of NMDA receptor mediated excitotoxicity. An improved model is proposed which permits incubation at 37 degrees C without damage occurring in control tissue.

Animals↗
PubMed1996

Imidazoline binding sites in Huntington's and Parkinson's disease putamen.

Binding of [3H]2-(2-benzofuranyl)-2-imidazoline ([3H]BFI) to the imidazoline I2 receptor was determined in putamen taken post mortem from patients with two extrapyramidal motor disorders, Parkinson's and Huntington's diseases, and age-matched control subjects. No deficit of binding was apparent in Parkinson's disease, indicating that the receptors are not present on nigrostriatal terminals. A significant loss (by 56%) in imidazoline I2 receptor binding was observed in Huntington's disease, consistent with the receptors being sited on degenerating neurons.

Adrenergic alpha-Antagonists↗
PubMed1996

Dopamine deficits in the brain: the neurochemical basis of parkinsonian symptoms in AIDS.

We sought to determine whether the motor dysfunctions and neuroleptic sensitivity that can occur in patients with AIDS relates to a deficit of striatal dopamine innervation similar to that of Parkinson's disease. For this purpose we measured concentrations of dopamine and its major metabolite homovanillic acid (HVA) in caudate nucleus tissue taken post-mortem from patients with AIDS and from appropriate age-matched control subjects. Dopamine and HVA concentrations were both significantly reduced in the AIDS group, with 20 of 34 patients exhibiting dopamine concentrations below the control range. This finding is consistent with a loss of nigrostriatal dopaminergic neurones, and may underlie the motor dysfunction and neuroleptic sensitivity that can occur in AIDS patients, indicating the potential value of antiparkinsonian therapy in such patients.

AIDS Dementia Complex↗
PubMed1996

Characterization of [3H]GR 113808 binding to 5-HT4 receptors in brain tissues from patients with neurodegenerative disorders.

[3H]GR 113808 binding studies in guinea-pig brain tissue revealed a temperature dependency and pharmacological specificity consistent with labelling of a 5-HT4 receptor. Detailed comparison of competition data between brain regions from human and guinea-pig suggest minor differences in the rank order of affinity. Studies in brain tissue from patients with Alzheimer's Huntington's and Parkinson's disease have revealed specific deficits in 5-HT4 receptor densities.

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