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Title: Receptor regulation of cortical pyramidal neurone activity : implications for the treatment of Alzheimer's disease
Author: Dijk, Sas Nikolaas
ISNI:       0000 0001 3424 3842
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1996
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Pyramidal cells, the major neuron type in the cerebral cortex, are considered to play a pivotal role in Alzheimer's disease. Loss of pyramidal cells has been shown to not only to occur in the disease process and to correlate with a variety of measures of severity of dementia, but also to be the major locus of neurofibrillary tangle formation. Pyramidal cells use excitatory amino acids as neurotransmitters. In order to investigate whether specific drugs, including a class in clinical use for Alzheimer's disease, can activate cortical neurones, an in vivo model was established using the intact corticostriatal pathway. This approach combines microdialysis with high performance liquid chromatography. In this model drugs are topically applied to the frontal cortex of the anaesthetised rat, and a microdialysis probe, positioned in the striatum, is used to measure increases in the extracellular concentration of excitatory amino acids glutamate and aspartate. Using this model it was established that NMDA, topically applied to the frontal cortex increased concentrations in the striatum of both glutamate and aspartate. This effect was both tetrodotoxin sensitive and calcium dependent The selective 5-HT1A antagonist WAY100135 modulated the NMDA-induced response. This effect was also tetrodotoxin sensitive and calcium dependent. The cholinesterase inhibitor physostigmine and the partial agonist at the M1 receptor, PD 142505-0028, also increased extracellular concentrations in the striatum of glutamate but not aspartate. Additionally it was shown that the effect of PD 142505-0028 can be potentiated by WAY 100135. All these effects were tetrodotoxin sensitive and calcium dependent. Preliminary data using the push-pull technique suggest that increasing extracellular concentrations of potassium, possibly mimicking depolarisation, increases amyloid precursor protein like-immunoreactivity in striatal push-pull perfusate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine