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Title: A biochemical investigation of the N-methyl-D-aspartate receptor in the rat central nervous system
Author: Davidson, Avril
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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Activation of the N-methyl-D-aspartate(NMDA) receptor is important in both physiological and pathological phenomena, including synaptogenesis, long-term potentiation, neuroexcitotoxicity and epilepsy. Although implicated in postnatal formation of synaptic connections, over-activation of the NMDA receptor in the neonate, as a result of say a hypoxic-ischaemic insult, can lead to neuronal damage. Antagonists for specific sites on the NMDA receptor complex may therefore prove to be novel therapeutic agents for preventing excitotoxic neuronal damage. I have therefore investigated the ontogeny of the NMDA receptor complex as well as modulation of the receptor in both adult and neonatal rat brain tissue. Radioligand binding studies were performed using high-affinity NMDA receptor antagonists. [3H]3-((±)-2-carboxypiperazin-4-yl)propyl-1-phosphonoate ([^3H]CPP) and [^3H]D-2-amino-5-phosphonopentanoate([^3H]D-AP5), both competitive antagonists which bind to the NMDA neurotransmitter recognition site, and [^3H]dizocilpine a non-competitive antagonist which binds to a site within the lumen of the NMDA-associated ion channel, were used. Optimal experimental conditions were established for the binding of each ligand to membranes prepared from rat brain tissue. This allowed reliable and reproducible measurements to be made under different modulatory conditions. Using mature tissue the binding of [^3H]CPP was compared with that of [^3H]AP5 in the presence of compounds active at the glycine modulatory site including glycine, 7-chlorokynurenate and 3-amino-1-hydroxypyrrolid-2-one(HA-966). Differential effects were seen on the binding of each ligand. The findings provide further evidence for the hypothesis that the NMDA receptor exists in more than one conformational state, these being regulated by glycine. [^3H]CPP and [^3H]dizocilpine were used to investigate the ontogeny of their respective binding sites. Each ligand bound to membranes prepared at various postnatal ages between birth and adulthood. The binding of both ligands was detectable at the earliest ages examined, increasing with postnatal age.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available