Carletti, R.; (1996) Characteristics of NMDA receptor ligands in rodent brain in vivo & in vitro under normal conditions and after chronic ischaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In the present study permanent MCA-O in mouse was used to investigate the temporal progression of the focal infarction and to evaluate the extent of protection offered by antagonists acting at different sites of the NMDA receptor complex. The neuroprotective effect of various doses of dizocilpine was compared to the effect produced by CGP 37849, a competitive antagonist at the NMDA receptor complex and compound Z, a novel antagonist at the glycine site of the NMDA receptor complex. An 8-arm radial maze was also used to compare the effect of systemic administration of ligands for the glycine site with the effect produced by dizocilpine on spatial orientation. Systemic administration of the glycine antagonist compound Z either before or after MCA-O resulted in a significant neuroprotective effect comparable to that obtained with dizocilpine. Also, compound Z and the partial agonist, HA-966, did not produce any impairment in radial maze performance, indicating a better side effect profile over dizocilpine. If the NMDA receptor complex is to be a target for neuroprotective agents administered post-ischaemia, it is important to determine not only the time course of the functional integrity of the receptor but also the post-ischaemia period during which drugs can gain access to the receptors in the region of the infarct. Thus, we have studied the ex vivo distribution of 3H-dizocilpine binding sites in mouse brain after MCA-O and have compared this with the in vitro distribution of 3H-dizocilpine binding sites at different times after MCA-O, using receptor autoradiography. Although the population of NMDA receptors is maintained in the infarct region for a relatively long time, access to them in vivo appears to be sufficiently impaired within 2 or 4 hours of ischaemic insult. Another important purpose of the present study was to verify whether it is possible to modulate the NMDA receptor complex under physiological conditions. Thus, the influence of modulators of NMDA receptor function on the ex vivo binding of 3H- dizocilpine in normal mouse brain has been examined using receptor autoradiography to detect subtle changes in the regional levels of binding. Although significant changes in the levels of specific ex vivo 3H-dizocilpine binding were produced by D-serine and D-cycloserine, it is suggested that ex vivo 3H-dizocilpine binding does not represent a sensitive marker for modulation of the NMDA receptor complex in vivo.

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